62 results on '"Chunyan Gu"'
Search Results
2. Research progress on non-protein-targeted drugs for cancer therapy
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Yiwen Zhang, Lu Lu, Feifeng Song, Xiaozhou Zou, Yujia Liu, Xiaowei Zheng, Jinjun Qian, Chunyan Gu, Ping Huang, and Ye Yang
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Cancer Research ,Oncology - Abstract
Non-protein target drugs, especially RNA-based gene therapies for treating hereditary diseases, have been recognized worldwide. As cancer is an insurmountable challenge, no miracle drug is currently available. With the advancements in the field of biopharmaceuticals, research on cancer therapy has gradually focused on non-protein target-targeted drugs, especially RNA therapeutics, including oligonucleotide drugs and mRNA vaccines. This review mainly summarizes the clinical research progress in RNA therapeutics and highlights that appropriate target selection and optimized delivery vehicles are key factors in increasing the effectiveness of cancer treatment in vivo.
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- 2023
3. AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma
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Chunyan Gu, Yajun Wang, Lulin Zhang, Li Qiao, Shanliang Sun, Miaomiao Shao, Xiaozhu Tang, Pinggang Ding, Chao Tang, Yuhao Cao, Yanyan Zhou, Mengjie Guo, Rongfang Wei, Nianguang Li, Yibei Xiao, Jinao Duan, and Ye Yang
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Cancer Research ,KU-177 ,Gene Expression Profiling ,Research ,Bufalin ,Proliferation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Antineoplastic Agents ,Transfection ,Bufanolides ,Disease Models, Animal ,Mice ,Oncology ,Mice, Inbred NOD ,Multiple myeloma ,Drug resistance ,AHSA1 ,Animals ,Humans ,HSP90 ,Proteasome Inhibitors ,Proteasomal inhibitor ,RC254-282 ,Cell Proliferation ,Molecular Chaperones - Abstract
Background Currently, multiple myeloma (MM) is still an incurable plasma cell malignancy in urgent need of novel therapeutic targets and drugs. Methods Bufalin was known as a highly toxic but effective anti-cancer compound. We used Bufalin as a probe to screen its potential targets by proteome microarray, in which AHSA1 was the unique target of Bufalin. The effects of AHSA1 on cellular proliferation and drug resistance were determined by MTT, western blot, flow cytometry, immunohistochemistry staining and xenograft model in vivo. The potential mechanisms of Bufalin and KU-177 in AHSA1/HSP90 were verified by co-immunoprecipitation, mass spectrometry, site mutation and microscale thermophoresis assay. Results AHSA1 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. Furthermore, AHSA1 promoted MM cell proliferation and proteasome inhibitor (PI) resistance in vitro and in vivo. Mechanism exploration indicated that AHSA1 acted as a co-chaperone of HSP90A to activate CDK6 and PSMD2, which were key regulators of MM proliferation and PI resistance respectively. Additionally, we identified AHSA1-K137 as the specific binding site of Bufalin on AHSA1, mutation of which decreased the interaction of AHSA1 with HSP90A and suppressed the function of AHSA1 on mediating CDK6 and PSMD2. Intriguingly, we discovered KU-177, an AHSA1 selective inhibitor, and found KU-177 targeting the same site as Bufalin. Bufalin and KU-177 treatments hampered the proliferation of flow MRD-positive cells in both primary MM and recurrent MM patient samples. Moreover, KU-177 abrogated the cellular proliferation and PI resistance induced by elevated AHSA1, and decreased the expression of CDK6 and PSMD2. Conclusions We demonstrate that AHSA1 may serve as a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.
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- 2022
4. G6PD promotes cell proliferation and dexamethasone resistance in multiple myeloma via increasing anti-oxidant production and activating Wnt/β-catenin pathway
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Rui, Li, Mengying, Ke, Mingming, Qi, Zhenru, Han, Yuhao, Cao, Zhendong, Deng, Jinjun, Qian, Ye, Yang, and Chunyan, Gu
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Cancer Research ,Oncology ,Hematology - Abstract
Background Glucose-6-phosphate dehydrogenase (G6PD) as the rate-limiting enzyme in the pentose phosphate pathway (PPP) is well-established as an aberrantly expressed protein in numerous clinical diseases; however, its role in cancer, specifically in multiple myeloma (MM) remains elusive. Methods In this study, serum metabolites in 70 normal people and 70 newly diagnosed MM patients were analyzed using untargeted metabolomics and the results were verified using ELISA. The survival analysis of multiple clinical datasets was performed to identify a potential target gene in MM. The oncogenic role of G6PD was investigated using lentivirus-based overexpression or knockdown of G6PD using RNAi or an inhibitor in vitro, and in a xenograft mouse model in vivo. The mechanisms of induced Dexamethasone (Dexa)-resistance of G6PD were further explored using the above established MM cell lines in vitro. Results Based on the screening of potential genes, PPP was shown to be involved in the occurrence of MM, which was evidenced by the differential expression of serum metabolites of G6P and Dehydroepiandrosterone sulfate (DHEAS, the more stable sulfate ester form of an endogenously uncompetitive G6PD inhibitor known as DHEA). Elevated G6PD promoted MM cell proliferation. Mechanistically, high G6PD expression enhanced enzymatic generation of the antioxidant NADPH via the PPP and decreased the production of reactive oxygen species (ROS), thus inducing the proliferation and Dexa resistance in MM cells. Furthermore, canonical Wnt/β-catenin signaling also participated in regulating G6PD-induced drug resistance and cellular redox levels of ROS. Intriguingly, DHEA treatment could enhance the sensitivity of MM cells to Dexa primarily through augmenting cellular oxidative stress. Conclusions Our data demonstrate that G6PD enhances the generation of the enzymatic anti-oxidant NADPH and decreases ROS generation, thereby promoting resistance to Dexa-induced apoptosis via the enzymatic PPP and non-enzymatic Wnt/β-catenin signaling pathway in MM. Targeting G6PD to harness cellular redox may serve as a promising novel strategy for the management of MM.
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- 2022
5. Elevated SFXN2 limits mitochondrial autophagy and increases iron-mediated energy production to promote multiple myeloma cell proliferation
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Ying Chen, Jinjun Qian, Pinggang Ding, Wang Wang, Xinying Li, Xiaozhu Tang, Chao Tang, Ye Yang, and Chunyan Gu
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Cancer Research ,Iron ,Immunology ,Membrane Proteins ,Cell Biology ,Antioxidants ,Mitochondria ,Cellular and Molecular Neuroscience ,Autophagy ,Humans ,Multiple Myeloma ,Cation Transport Proteins ,Heme Oxygenase-1 ,Cell Proliferation - Abstract
Human sideroflexin 2 (SFXN2) belongs to the SFXN protein family, which is a mitochondrial outer membrane protein involved in mitochondrial iron metabolism. Mitochondria are indispensable for cellular energy production and iron metabolism. However, it remains elusive how SFXN2 modulates mitochondrial homeostasis and cellular iron metabolism in multiple myeloma (MM). In this study, we first found that SFXN2 was significantly elevated and correlated to poor outcomes in MM patients from clinical datasets. SFXN2 overexpression promoted MM cell proliferation and suppressed starvation-induced autophagy/mitophagy, while SFXN2 knockdown aggravated mitochondria damage and autophagic processes in ARP1 and H929 MM cell lines. Furthermore, inhibition of SFXN2 exerted effectively anti-myeloma activity in vivo by using myeloma xenograft model. Mechanism studies indicated that heme oxygenase 1 (HO1) with anti-oxidant function contributed to the process of autophagy suppression and cellular proliferation mediated by SFXN2. Our study revealed the critical role of SFXN2 in regulating mitochondrial bioenergetics, mitophagy, cellular iron metabolism, and redox homeostasis in interconnected and intricate way. Collectively, these findings not only provide insights into the metabolic reprogramming of tumor cells, but also highlight the therapeutic potential of SFXN2 in combination with iron metabolism as target for prognosis and treatment in MM patients.
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- 2022
6. NAT10 acetylates BCL-XL mRNA to promote the proliferation of multiple myeloma cells through PI3K-AKT pathway
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Yuanjiao, Zhang, Zhendong, Deng, Shanliang, Sun, Siyuan, Xie, Mingmei, Jiang, Bing, Chen, Chunyan, Gu, and Ye, Yang
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Cancer Research ,Oncology - Abstract
Multiple myeloma (MM) is a clinically distinctive plasma cell malignancy in the bone marrow (BM), in which epigenetic abnormalities are featured prominently. Epigenetic modifications including acetylation have been deemed to contribute to tumorigenesis. N-acetyltransferase 10 (NAT10) is an important regulator of mRNA acetylation in many cancers, however its function in MM is poorly studied. We first analyzed MM clinical databases and found that elevated NAT10 expression conferred a poor prognosis in MM patients. Furthermore, overexpression of NAT10 promoted MM cell proliferation. The correlation analysis of acRIP-seq screened BCL-XL (BCL2L1) as a significant downstream target of NAT10. Further RNA decay assay showed that increased NAT10 improved the stability of BCL-XL mRNA and promoted protein translation to suppress cell apoptosis. NAT10 activated PI3K-AKT pathway and upregulated CDK4/CDK6 to accelerate cellular proliferation. Importantly, inhibition of NAT10 by Remodelin suppressed MM cell growth and induced cell apoptosis. Our findings show the important role of NAT10/BCL-XL axis in promoting MM cell proliferation. Further explorations are needed to fully define the potential of targeting NAT10 therapy in MM treatment.
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- 2022
7. The IFN-γ-related long non-coding RNA signature predicts prognosis and indicates immune microenvironment infiltration in uterine corpus endometrial carcinoma
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Chunyan Gu, Chen Lin, Zheng Zhu, Li Hu, Fengxu Wang, Xuehai Wang, Junpu Ruan, Xinyuan Zhao, and Sen Huang
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Cancer Research ,Oncology - Abstract
BackgroundOne of the most common diseases that have a negative impact on women’s health is endometrial carcinoma (EC). Advanced endometrial cancer has a dismal prognosis and lacks solid prognostic indicators. IFN-γ is a key cytokine in the inflammatory response, and it has also been suggested that it has a role in the tumor microenvironment. The significance of IFN-γ-related genes and long non-coding RNAs in endometrial cancer, however, is unknown.MethodsThe Cancer Genome Atlas (TCGA) database was used to download RNA-seq data from endometrial cancer tissues and normal controls. Genes associated with IFN-γ were retrieved from the gene set enrichment analysis (GSEA) website. Co-expression analysis was performed to find lncRNAs linked to IFN-γ gene. The researchers employed weighted co-expression network analysis (WGCNA) to find lncRNAs that were strongly linked to survival. The prognostic signature was created using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. The training cohort, validation cohort, and entire cohort of endometrial cancer patients were then split into high-risk and low-risk categories. To investigate variations across different risk groups, we used survival analysis, enrichment analysis, and immune microenvironment analysis. The platform for analysis is R software (version X64 3.6.1).ResultsBased on the transcript expression of IFN-γ-related lncRNAs, two distinct subgroups of EC from TCGA cohort were formed, each with different outcomes. Ten IFN-γ-related lncRNAs were used to build a predictive signature using Cox regression analysis and the LASSO regression, including CFAP58, LINC02014, UNQ6494, AC006369.1, NRAV, BMPR1B-DT, AC068134.2, AP002840.2, GS1-594A7.3, and OLMALINC. The high-risk group had a considerably worse outcome (p < 0.05). In the immunological microenvironment, there were also substantial disparities across different risk categories.ConclusionOur findings give a reference for endometrial cancer prognostic type and immunological status assessment, as well as prospective molecular markers for the disease.
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- 2022
8. AIMP1 promotes multiple myeloma malignancy through interacting with ANP32A to mediate histone H3 acetylation
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Rongfang Wei, Yan Zhu, Yuanjiao Zhang, Wene Zhao, Xichao Yu, Ling Wang, Chunyan Gu, Xiaosong Gu, and Ye Yang
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Cancer Research ,Nuclear Proteins ,RNA-Binding Proteins ,Acetylation ,Mice, SCID ,Amino Acyl-tRNA Synthetases ,Histones ,Mice ,Oncology ,Mice, Inbred NOD ,Animals ,Humans ,Cytokines ,Multiple Myeloma - Abstract
Multiple myeloma (MM) is the second most common hematological malignancy. An overwhelming majority of patients with MM progress to serious osteolytic bone disease. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) participates in several steps during cancer development and osteoclast differentiation. This study aimed to explore its role in MM.The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis. Enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotting were used to detect AIMP1 expression. Protein chip analysis, RNA-sequencing, and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1. The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in vitro and a xenograft model in vivo. Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro. A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes. Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A) to regulate histone H3 acetylation. In addition, AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2 (GAREM2) to increase the phosphorylation of extracellular-regulated kinase 1/2 (p-ERK1/2). Furthermore, AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1 (NFATc1) in vitro. In contrast, exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM, which accelerates MM malignancy via activation of the MAPK signaling pathway.
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- 2022
9. Targeting<scp>CTLA</scp>‐4 in cancer: Is it the ideal companion for<scp>PD</scp>‐1 blockade immunotherapy combinations?
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Cinzia Solinas, Marco Aiello, Karen Willard-Gallo, Chunyan Gu-Trantien, Edoardo Migliori, and Pushpamali De Silva
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,chemical and pharmacologic phenomena ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Immune system ,Neoplasms ,Internal medicine ,medicine ,Animals ,Humans ,Cytotoxic T cell ,CTLA-4 Antigen ,Molecular Targeted Therapy ,Adverse effect ,biology ,business.industry ,Immunity ,Immunotherapy ,Immune checkpoint ,Blockade ,CTLA-4 ,030220 oncology & carcinogenesis ,biology.protein ,Antibody ,business - Abstract
Immunotherapy approaches boosting spontaneous and durable antitumor immune responses through immune checkpoint blockade are revolutionizing treatment and patient outcomes in solid tumors and hematological malignancies. Among the various inhibitory molecules employed by the immune system to regulate the adaptive immune responses, cytotoxic T lymphocyte antigen-4 (CTLA-4) is the first successfully targeted immune checkpoint molecule in the clinic, giving rise to significant but selective benefit either when targeted alone or in combination with anti-programmed cell death protein-1 (PD-1) antibodies (Abs). However, the use of anti-CTLA-4 Abs was associated with the incidence of autoimmune-like adverse events (AEs), which were particularly frequent and severe with the use of combinational strategies. Nevertheless, the higher incidence of AEs is associated with an improved clinical benefit indicating treatment response. A prompt recognition of AEs followed by early and adequate treatment with immunosuppressive agents allows the management of these potentially serious AEs. This narrative review aims to summarize CTLA-4 biology, the rationale for the use as a companion for anti-PD-1 Abs in humans with results from the most relevant Phase III clinical trials including anti-CTLA-4 Abs in combination with anti-PD-1 Abs in solid tumors.
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- 2020
10. Exosome-mediated siRNA delivery to suppress postoperative breast cancer metastasis
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Hongyan Zhu, Liuwan Zhao, Lanlan Shao, Ye Gan, Chunyan Gu, and Hongwei Chen
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Pharmaceutical Science ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,02 engineering and technology ,Exosomes ,Exosome ,Metastasis ,03 medical and health sciences ,Drug Delivery Systems ,Breast cancer ,In vivo ,Cell Line, Tumor ,medicine ,Humans ,RNA, Small Interfering ,Bovine serum albumin ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Serum Albumin, Bovine ,021001 nanoscience & nanotechnology ,medicine.disease ,Primary tumor ,Microvesicles ,Drug delivery ,Cancer research ,biology.protein ,Nanoparticles ,Female ,0210 nano-technology ,business - Abstract
High recurrence and metastasis of triple-negative breast cancer (TNBC) after operation is a leading cause of breast cancer related death. The pre-metastatic niche (PMN) is an environment in a secondary organ conducive to the metastasis of a primary tumor. Herein, we identify exosomes from autologous breast cancer cells that show effective lung targeting ability. Based on this, we developed the biomimetic nanoparticles (cationic bovine serum albumin (CBSA) conjugated siS100A4 and exosome membrane coated nanoparticles, CBSA/siS100A4@Exosome) to improve drug delivery to the lung PMN. CBSA/siS100A4@Exosome self-assembled nanoparticles formed homogeneous sizes of ~200 nm, protected siRNA from degradation, and showed excellent biocompatibility. Further in vivo studies showed that CBSA/siS100A4@Exosome had a higher affinity toward lung in comparison to the CBSA/siS100A4@Liposome, and exhibited outstanding gene-silencing effects that significantly inhibited the growth of malignant breast cancer cells. Taken together, these results indicate that CBSA/siS100A4@Exosome self-assembled nanoparticles are a promising strategy to suppress postoperative breast cancer metastasis.
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- 2020
11. Activation of BDNF-AS/ADAR/p53 Positive Feedback Loop Inhibits Glioblastoma Cell Proliferation
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Xinwen Lv, Chunyan Gu, and Shiwen Guo
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0301 basic medicine ,Transcription, Genetic ,Adenosine Deaminase ,RNA Stability ,Down-Regulation ,Biology ,Biochemistry ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Downregulation and upregulation ,Transcription (biology) ,Cell Line, Tumor ,Humans ,RNA, Messenger ,Transcription factor ,Cell Proliferation ,Messenger RNA ,Cell growth ,RNA-Binding Proteins ,General Medicine ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cell culture ,Apoptosis ,ADAR ,Cancer research ,RNA, Long Noncoding ,Tumor Suppressor Protein p53 ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
Despite progress in conventional treatment for glioblastoma (GBM), the prognosis remains poor due to high tumor recurrence. Therefore, identification of new molecular mechanisms is a pressing need for betterment of GBM patient outcomes. qRT-PCR was used to determine BDNF-AS expression in GBM cells. CCK-8, EdU incorporation, and caspase-3 activity assays were employed to analyze biological functions of BDNF-AS. RIP and RNA pull-down were conducted to detect the interactions among BDNF-AS, ADAR, and p53. Actinomycin D was utilized to examine the stability of p53 mRNA. ChIP and luciferase reporter assays were performed to detect transcriptional activation of BDNF-AS by p53. We found that BDNF-AS was significantly downregulated in GBM cell lines, and its overexpression inhibited GBM cell growth, and promoted apoptosis. Importantly, we illustrated that BDNF-AS coupled with ADAR protein to potentiate stability of p53 mRNA and thus upregulate p53. Interestingly, we further identified p53 as a transcription factor of BDNF-AS, activating transcription of BNDF-AS. This study firstly demonstrated that BDNF-AS acted as a tumor suppressor in GBM and the positive feedback circuit of BDNF-AS/ADAR/p53 served an important mechanism to control GBM proliferation. Targeting this auto-regulatory loop may provide a potential therapeutic strategy for GBM patients.
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- 2020
12. Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine
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Mengying Ke, Jinjun Qian, Feng Hao, Xinying Li, Hongjie Wu, Xian Luo, Bin Xu, Chunyan Gu, and Ye Yang
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Cancer Research ,Arginine ,business.industry ,Bortezomib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Ornithine ,Pharmacology ,medicine.disease ,Group A ,metabolomics ,Ornithine decarboxylase ,multiple myeloma ,chemistry.chemical_compound ,chemistry ,Oncology ,In vivo ,ornithine ,medicine ,Acupuncture ,ODC1 ,business ,Multiple myeloma ,acupuncture ,RC254-282 ,medicine.drug - Abstract
Multiple myeloma (MM) is a hematological malignancy worldwide in urgent need for novel therapeutic strategies. Since Velcade (bortezomib) was approved for the treatment of relapsed/refractory MM in 2003, we have seen considerable improvement in extending MM patient survival. However, most patients are fraught with high recurrence rate and incurability. Acupuncture is known for alleviating patient symptoms and improving the quality of life, but it is not well investigated in MM, especially in combination with bortezomib. In this study, we employed LC-MS and UHPLC-MS together with bioinformatics methods to test serum samples from 5TMM3VT MM murine model mice with four different treatments [control (C) group, bortezomib (V) treatment group, acupuncture (A) group, and combined (VA) group]. MM mice in group VA had longer survival time than mice in group A or group V. Joint pathway analysis indicated the underlying arginine and proline metabolism pathway among the 32 significantly decreased metabolites in group VA. CCK-8 assay and in vivo experiments validated that ornithine, the metabolite of arginine, promoted MM cell proliferation. In addition, gene expression omnibus (GEO) database analysis suggested that MM patients with higher ornithine decarboxylase 1 (ODC1) expression were evidently associated with poor overall survival. In summary, this study demonstrates the synergistic effects of acupuncture and bortezomib on extending the survival of MM model mice and provides potential therapeutic targets in the treatment of MM.
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- 2021
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13. BUB1B and circBUB1B_544aa aggravate multiple myeloma malignancy through evoking chromosomal instability
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Pinggang Ding, Mengjie Guo, Ye Yang, Xiaosong Gu, Mengying Ke, Zhendong Deng, Xiaozhu Tang, Muxi Li, Zigen Lin, Chunyan Gu, Yuxia Yuan, and Yanyan Zhou
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Male ,Cancer Research ,QH301-705.5 ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Plasma cell ,BUB1B ,Malignancy ,Disease-Free Survival ,Article ,Non-coding RNAs ,Mice ,In vivo ,Cell Line, Tumor ,Chromosomal Instability ,Chromosome instability ,Genetics ,medicine ,Animals ,Humans ,Biology (General) ,RNA, Small Interfering ,Multiple myeloma ,Cell Proliferation ,Haematological cancer ,Chemistry ,Kinase ,RNA, Circular ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Cancer research ,Medicine ,Heterografts ,Female ,Bone marrow ,Neoplasm Recurrence, Local ,Multiple Myeloma - Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability (CIN), which contributes to the acquisition of heterogeneity, along with MM progression, drug resistance, and relapse. In this study, we elucidated that the expression of BUB1B increased strikingly in MM patients and was closely correlated with poor outcomes. Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in vivo, while genetic targeting BUB1B abrogated this effect. Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN resulting in MM poor outcomes mainly through phosphorylating CEP170. Interestingly, we discovered the existence of circBUB1B_544aa containing the kinase catalytic center of BUB1B, which was translated by a circular RNA of BUB1B. The circBUB1B_544aa elevated in MM peripheral blood samples was closely associated with MM poor outcomes and played a synergistic effect with BUB1B on evoking CIN. In addition, MM cells could secrete circBUB1B_544aa and interfere the MM microenvironmental cells in the same manner as BUB1B full-length protein. Intriguingly, BUB1B siRNA, targeting the kinase catalytic center of both BUB1B and circBUB1B_544aa, significantly inhibited MM malignancy in vitro and in vivo. Collectively, BUB1B and circBUB1B_544aa are promising prognostic and therapeutic targets of MM.
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- 2021
14. Novel insights into the impact of the SUMOylation pathway in hematological malignancies (Review)
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Ling Wang, Ye Yang, Jinjun Qian, and Chunyan Gu
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Cancer Research ,Cell ,SUMO protein ,SUMO enzymes ,Biology ,medicine.disease_cause ,Chromosome instability ,medicine ,Humans ,hematological malignancies ,Cancer ,Sumoylation ,Articles ,Cell cycle ,medicine.disease ,Sumoylation Pathway ,multiple myeloma ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Hematologic Neoplasms ,Cancer research ,Small Ubiquitin-Related Modifier Proteins ,Carcinogenesis ,Signal Transduction - Abstract
The small ubiquitin‑like modifier (SUMO) system serves an important role in the regulation of protein stability and function. SUMOylation sustains the homeostatic equilibrium of protein function in normal tissues and numerous types of tumor. Accumulating evidence has revealed that SUMO enzymes participate in carcinogenesis via a series of complex cellular or extracellular processes. The present review outlines the physiological characteristics of the SUMOylation pathway and provides examples of SUMOylation participation in different cancer types, including in hematological malignancies (leukemia, lymphoma and myeloma). It has been indicated that the SUMO pathway may influence chromosomal instability, cell cycle progression, apoptosis and chemical drug resistance. The present review also discussed the possible relationship between SUMOylation and carcinogenic mechanisms, and evaluated their potential as biomarkers and therapeutic targets in the diagnosis and treatment of hematological malignancies. Developing and investigating inhibitors of SUMO conjugation in the future may offer promising potential as novel therapeutic strategies.
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- 2021
15. Corrigendum: Dihydroartemisinin Induces Growth Arrest and Overcomes Dexamethasone Resistance in Multiple Myeloma
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Ying Chen, Rui Li, Yuqi Zhu, Sixia Zhong, Jinjun Qian, Dongqing Yang, Artur Jurczyszyn, Meral Beksac, Chunyan Gu, and Ye Yang
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Cancer Research ,drug resistance ,business.industry ,medicine.medical_treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Dihydroartemisinin ,dexamethasone ,Drug resistance ,medicine.disease ,multiple myeloma ,dihydroartemisinin ,artemisinin ,Oncology ,Growth arrest ,medicine ,Cancer research ,Artemisinin ,business ,RC254-282 ,Multiple myeloma ,Dexamethasone ,medicine.drug - Published
- 2021
16. YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis
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Zhen Hua, Rongfang Wei, Mengjie Guo, Zigen Lin, Xichao Yu, Xinying Li, Chunyan Gu, and Ye Yang
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Cancer Research ,Adenosine ,RNA Stability ,Tumor Suppressor Proteins ,MAP Kinase Kinase 2 ,Genetics ,STAT5 Transcription Factor ,Humans ,RNA-Binding Proteins ,Multiple Myeloma ,Molecular Biology ,Cell Proliferation - Abstract
Multiple myeloma (MM) is still incurable partially due to lacking effective therapeutic targets. Aberrant N6-methyladenosine (m6A) RNA modification plays a vital role in many cancers, however few researches are executed in MM. We first screened the m6A-related genes in MM patient cohorts and correlated these genes with patient outcomes. We found that YTHDF2, a well-recognized m6A reader, was increased in MM patients and associated with poor outcomes. Decreased YTHDF2 expression hampered MM cell proliferation in vitro and in vivo, while enforced YTHDF2 expression reversed those effects. The analyses of m6A-RIP-seq and RIP-PCR indicated that STAT5A was the downstream target of YTHDF2, which was binding to the m6A modification site of STAT5A to promote its mRNA degradation. ChIP-seq and PCR assays revealed that STAT5A suppressed MM cell proliferation by occupying the transcription site of MAP2K2 to decrease ERK phosphorylation. In addition, we confirmed that YTHDF2 mediated the unphosphorylated form of STAT5A to inhibit the expression of MAP2K2/p-ERK. In conclusion, our study highlights that YTHDF2/STAT5A/MAP2K2/p-ERK axis plays a key role in MM proliferation and targeting YTHDF2 may be a promising therapeutic strategy.
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- 2021
17. RFWD2 induces cellular proliferation and selective proteasome inhibitor resistance by mediating P27 ubiquitination in multiple myeloma
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Ting Lu, Li Qiao, Ye Yang, Ye Hu, Wang Wang, Mengjie Guo, Rui Li, Anja Seckinger, Fenghuang Zhan, Dirk Hose, Rongfang Wei, Miaomiao Shao, Chunyan Gu, Hematology, and Basic (bio-) Medical Sciences
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0301 basic medicine ,Cancer Research ,Ubiquitin-Protein Ligases ,Multiple Myeloma/drug therapy ,Cancer metastasis ,Antineoplastic Agents ,Aggressive disease ,Case-control studies ,Gene mutation ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Tumor Cells, Cultured ,Humans ,Ubiquitin-Protein Ligases/genetics ,Multiple myeloma ,Cyclin-Dependent Kinase Inhibitor p27/genetics ,hematology ,Philosophy ,Ubiquitination ,medicine.disease ,Prognosis ,Proteasome Inhibitors/pharmacology ,Gene Expression Regulation, Neoplastic ,Transplantation ,Survival Rate ,030104 developmental biology ,Bortezomib/pharmacology ,cell proliferation ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Gene Expression Regulation, Neoplastic/drug effects ,Proteasome inhibitor ,Christian ministry ,Multiple Myeloma ,Proteasome Inhibitors ,Humanities ,Resistance (creativity) ,Antineoplastic Agents/pharmacology ,Cyclin-Dependent Kinase Inhibitor p27 ,medicine.drug - Abstract
Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20. CAS Article Google Scholar Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66. CAS Article Google Scholar Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. 2008;112:2489–99. CAS Article Google Scholar Robak P, Drozdz I, Szemraj J, Robak T. Drug resistance in multiple myeloma. Cancer Treat Rev. 2018;70:199–208. CAS Article Google Scholar Balsas P, Galan-Malo P, Marzo I, Naval J. Bortezomib resistance in a myeloma cell line is associated to PSMbeta5 overexpression and polyploidy. Leuk Res. 2012;36:212–8. 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Cell Cycle. 2015;14:2265–73. CAS Article Google Scholar Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108:2020–8. CAS Article Google Scholar Pernet CR, Wilcox RR, Rousselet GA. Robust correlation analyses: false positive and power validation using a new open source matlab toolbox. Front Psychol. 2013;3:606. Article Google Scholar Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood. 2010;116:2543–53. CAS Article Google Scholar Zhan F, Colla S, Wu X, Chen B, Stewart JP, Kuehl WM, et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood. 2007;109:4995–5001. CAS Article Google Scholar Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B, et al. A gene expression signature for high-risk multiple myeloma. Leukemia. 2012;26:2406–13. CAS Article Google Scholar Download references This work was supported by National Key Research and Development Program-precision medicine sub-program 2016YFC0905900 (to YY); National Natural Science Foundation of China 81970196 (to CG), 81670200 (to YY); The Priority Academic Program Development of Jiangsu Higher Education Institutions for Chinese Medicine. These authors contributed equally: Chunyan Gu, Ting Lu The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, China Chunyan Gu, Wang Wang, Rongfang Wei, Mengjie Guo, Rui Li, Li Qiao & Ye Yang School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China Chunyan Gu, Ting Lu, Wang Wang, Miaomiao Shao, Rongfang Wei, Mengjie Guo, Rui Li, Li Qiao, Ye Hu & Ye Yang Key Laboratory for Combination of Acupuncture and Chinese Materia Medica of Chinese Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China Chunyan Gu, Wang Wang, Rongfang Wei, Mengjie Guo, Rui Li, Li Qiao & Ye Yang Internal Medicine, University of Iowa, Iowa City, IA, USA Fenghuang Zhan & Ye Yang Laboratory of Hematology and Immunology & Labor fur Myelomforschung, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090, Jette, Belgium Anja Seckinger & Dirk Hose You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar Correspondence to Ye Yang. No potential conflicts of interest were disclosed. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Reprints and Permissions Gu, C., Lu, T., Wang, W. et al. RFWD2 induces cellular proliferation and selective proteasome inhibitor resistance by mediating P27 ubiquitination in multiple myeloma. Leukemia (2020). https://doi.org/10.1038/s41375-020-01033-z Download citation Received: 03 February 2020 Revised: 12 August 2020 Accepted: 17 August 2020 Published: 08 September 2020 DOI: https://doi.org/10.1038/s41375-020-01033-z
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- 2021
18. Insights into a Crucial Role of TRIP13 in Human Cancer
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Mengjie Guo, Jinjun Qian, Chunyan Gu, Ye Yang, and Lu Sicheng
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TRIP13 ,DNA repair ,lcsh:Biotechnology ,Biophysics ,Review Article ,Biology ,Biochemistry ,Malignant transformation ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,lcsh:TP248.13-248.65 ,Chromosome instability ,Genetics ,medicine ,CIN ,Cancer ,030304 developmental biology ,0303 health sciences ,Thyroid hormone receptor ,Oncogenes ,medicine.disease ,Computer Science Applications ,Spindle checkpoint ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Biotechnology - Abstract
Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) plays a key role in regulating mitotic processes, including spindle assembly checkpoint and DNA repair pathways, which may account for Chromosome instability (CIN). As CIN is a predominant hallmark of cancer, TRIP13 may act as a tumor susceptibility locus. Amplification of TRIP13 has been observed in various human cancers and implicated in several aspects of malignant transformation, including cancer cell proliferation, drug resistance and tumor progression. Here, we discussed the functional significance of TRIP13 in cell progression, highlighted the recent findings on the aberrant expression in human cancers and emphasized its significance for the therapeutic potential., Graphical Abstract Unlabelled Image
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- 2019
19. FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer
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Céline Naveaux, Soizic Garaud, Alexandre de Wind, Pushpamali De Silva, Karen Willard-Gallo, Denis Larsimont, Anaïs Boisson, Chunyan Gu-Trantien, Hugues Duvillier, Martine Piccart-Gebhart, Vinu Jose, Cinzia Solinas, Gert Van den Eyden, Ligia Craciun, and Edoardo Migliori
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0301 basic medicine ,Research paper ,Breast Neoplasms ,FOXP1 ,Biology ,General Biochemistry, Genetics and Molecular Biology ,GZMB ,03 medical and health sciences ,Breast cancer ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Cell Movement ,Tumor Cells, Cultured ,medicine ,Humans ,CXCL10 ,CXCL11 ,CXCL13 ,Tumor-infiltrating lymphocytes ,Généralités ,Forkhead Transcription Factors ,General Medicine ,Prognosis ,medicine.disease ,Survival Analysis ,Primary tumor ,Tumor infiltrating lymphocytes ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,CCL20 ,030104 developmental biology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Cancer research ,Cytokines ,CXCL9 ,Female ,Chemokines - Abstract
Background: FOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC). Methods: FOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and lymphocyte migration in response to primary tumor supernatants (SN) was compared between FOXP1hi and FOXP1lo primary BC. Finding: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1hi tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1lo BC. Silencing FOXP1 in BC cell lines positively impacted cytokine and chemokine expression with the inverse effect associated with overexpression. CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, GZMB and IFNG expression decreased while IL10 and TGFβ increased in FOXP1hi compared to FOXP1lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1hi supernatants. FOXP1lo BC expresses higher levels of chemokines driving TIL migration. The METABRIC gene expression dataset analysis show FOXP1 expression is associated with unfavorable BC outcomes. Interpretation: These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. Fund: Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2019
20. CAR-T therapy alters synthesis of platelet-activating factor in multiple myeloma patients
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Liqing Kang, Ling Wang, Mengying Ke, Hongming Huang, Ye Yang, Yajun Wang, Haiyan Liu, Chunyan Gu, and Shu Yang
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,T cell ,LPCAT1 ,Immunotherapy, Adoptive ,Targeted therapy ,chemistry.chemical_compound ,Refractory ,Cytokine release syndrome ,Multiple myeloma ,Internal medicine ,medicine ,Humans ,Diseases of the blood and blood-forming organs ,Platelet Activating Factor ,Molecular Biology ,Letter to the Editor ,RC254-282 ,Hematology ,Platelet-activating factor ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Lipid Metabolism ,CAR-T therapy ,medicine.anatomical_structure ,chemistry ,Acyltransferase ,Protein Biosynthesis ,Metabolome ,RC633-647.5 ,business - Abstract
The chimera antigen receptor (CAR) T cell therapy is a novel and potential targeted therapy and has achieved satisfactory efficacy in patients with relapsed or refractory multiple myeloma (MM) in recent years. However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics. To explore the potential biomarkers in plasma for evaluating CRS and clinical efficacy, we performed metabolomic and lipidomic profiling of plasma samples from 17 relapsed or refractory MM patients received CAR-T therapy. Our study showed that glycerophosphocholine (GPC), an intermediate of platelet-activating factor (PAF)-like molecule, was significantly decreased when the participants underwent CRS, and the remarkable elevation of lysophosphatidylcholines (lysoPCs), which were catalyzed by lysoPC acyltransferase (LPCAT) was a distinct metabolism signature of relapsed or refractory MM patients with prognostic value post-CAR-T therapy. Both GPC and lysoPC are involved in platelet-activating factor (PAF) remodeling pathway. Besides, these findings were validated by LPCAT1 expression, a key factor in the PAF pathway, associated with poor outcome in three MM GEP datasets of MM. In conclusion, CAR-T therapy alters PAF synthesis in MM patients, and targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01101-6.
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- 2021
21. Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma
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Mengjie Guo, Pinggang Ding, Zhen Zhu, Lu Fan, Yanyan Zhou, Shu Yang, Ye Yang, and Chunyan Gu
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0301 basic medicine ,QH301-705.5 ,proliferation ,P27 ,Drug resistance ,ubiquitination ,03 medical and health sciences ,Cell and Developmental Biology ,0302 clinical medicine ,Ubiquitin ,medicine ,RCHY1 ,Biology (General) ,Original Research ,Gene knockdown ,drug resistance ,biology ,Chemistry ,Cell growth ,Cell Biology ,Cell cycle ,Ubiquitin ligase ,multiple myeloma ,030104 developmental biology ,Proteasome ,030220 oncology & carcinogenesis ,biology.protein ,Proteasome inhibitor ,Cancer research ,RFWD2 ,Developmental Biology ,medicine.drug - Abstract
The potential to overcome resistance to proteasome inhibitors is greatly related with ubiquitin-proteasome system during multiple myeloma (MM) treatment process. The constitutive photomorphogenic 1 (RFWD2), referred to an E3 ubiquitin ligase, has been identified as an oncogene in multiple cancers, yet important questions on the role of RFWD2 in MM biology and treatment remain unclear. Here we demonstrated that MM patients with elevated RFWD2 expression achieved adverse outcome and drug resistance by analyzing gene expression profiling. Moreover, we proved that RFWD2 participated in the process of cell cycle, cell growth and death in MM by mass spectrometry analysis. In vitro study indicated that inducible knockdown of RFWD2 hindered cellular growth and triggered apoptosis in MM cells. Mechanism study revealed that RFWD2 controlled MM cellular proliferation via regulating the degradation of P27 rather than P53. Further exploration unveiled that RFWD2 meditated P27 ubiquitination via interacting with RCHY1, which served as an E3 ubiquitin ligase of P27. Finally, in vivo study illustrated that blocking RFWD2 in BTZ-resistant MM cells overcame the drug resistance in a myeloma xenograft mouse model. Taken together, these findings provide compelling evidence for prompting that targeting RFWD2 may be an effective strategy to inhibit cellular proliferation and overcome drug resistance to proteasome inhibitor in MM.
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- 2021
22. Alternative splicing and cancer: a systematic review
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Chunyan Gu, Yuanjiao Zhang, Ye Yang, and Jinjun Qian
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0301 basic medicine ,Cancer Research ,RNA splicing ,Carcinogenesis ,medicine.medical_treatment ,lcsh:Medicine ,Drug development ,Review Article ,Biology ,medicine.disease_cause ,Non-coding RNAs ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Neoplasms ,Genetics ,medicine ,Humans ,lcsh:QH301-705.5 ,Molecular medicine ,lcsh:R ,Alternative splicing ,Cancer ,RNA ,RNA, Circular ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Alternative Splicing ,030104 developmental biology ,lcsh:Biology (General) ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,RNA Splicing Factors - Abstract
The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.
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- 2021
23. CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma
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Chunyan Gu, Wang Wang, Fenghuang Zhan, Jingxuan Pan, Tingting Xu, Ye Yang, Dirk Hose, Yajun Wang, Xiaozhu Tang, Siegfried Janz, Artur Jurczyszyn, Mengjie Guo, Rongfang Wei, Anja Seckinger, Yanxin Zhang, Meral Beksac, Hematology, and Basic (bio-) Medical Sciences
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0301 basic medicine ,Cancer Research ,Proliferation ,Osteoclasts ,Multiple Myeloma/genetics ,Biology ,Bone and Bones ,Chromosomal Instability/genetics ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Osteoclast ,In vivo ,Chromosomal Instability ,medicine ,Animals ,Humans ,Bone and Bones/pathology ,CHEK1 ,Multiple myeloma ,RC254-282 ,Checkpoint Kinase 1/genetics ,Cell growth ,Kinase ,hematology ,Research ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Transfection ,RNA, Circular ,medicine.disease ,Molecular biology ,In vitro ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,RNA, Circular/genetics ,Drug resistance ,Osteoclasts/metabolism ,Checkpoint Kinase 1 ,Molecular Medicine ,Heterografts ,Bone marrow ,circCHEK1_246aa ,Multiple Myeloma - Abstract
Background Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. Methods Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. Results We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Conclusions Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.
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- 2021
24. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA
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Chen Wang, Chunyan Gu, Siegfried Janz, Ye Yang, Meral Beksac, Jiamin Zhao, Mengying Ke, Fengjie Jiang, Chao Tang, Xiaozhu Tang, Zhen Hua, Fenghuang Zhan, Artur Jurczyszyn, and Shengyao Gao
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0301 basic medicine ,Cancer Research ,RIP-seq ,HNRNPA2B1 ,M6A ,lcsh:RC254-282 ,AKT3 ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,Multiple myeloma ,Heterogeneous-Nuclear Ribonucleoprotein Group A-B ,Humans ,RNA, Messenger ,Nuclear Factor 90 Proteins ,Molecular Biology ,Letter to the Editor ,Messenger RNA ,lcsh:RC633-647.5 ,Cell growth ,Chemistry ,MeRIP-Seq ,RNA ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,RNA stability ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,ILF3 ,In vitro ,Cell biology ,030104 developmental biology ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,Disease Progression ,Proto-Oncogene Proteins c-akt - Abstract
N6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic RNAs while accumulating studies suggest that m6A aberrant expression plays an important role in cancer. HNRNPA2B1 is a m6A reader which binds to nascent RNA and thus affects a perplexing array of RNA metabolism exquisitely. Despite unveiled facets that HNRNPA2B1 is deregulated in several tumors and facilitates tumor growth, a clear role of HNRNPA2B1 in multiple myeloma (MM) remains elusive. Herein, we analyzed the function and the regulatory mechanism of HNRNPA2B1 in MM. We found that HNRNPA2B1 was elevated in MM patients and negatively correlated with favorable prognosis. The depletion of HNRNPA2B1 in MM cells inhibited cell proliferation and induced apoptosis. On the contrary, the overexpression of HNRNPA2B1 promoted cell proliferation in vitro and in vivo. Mechanistic studies revealed that HNRNPA2B1 recognized the m6A sites of ILF3 and enhanced the stability of ILF3 mRNA transcripts, while AKT3 downregulation by siRNA abrogated the cellular proliferation induced by HNRNPA2B1 overexpression. Additionally, the expression of HNRNPA2B1, ILF3 and AKT3 was positively associated with each other in MM tissues tested by immunohistochemistry. In summary, our study highlights that HNRNPA2B1 potentially acts as a therapeutic target of MM through regulating AKT3 expression mediated by ILF3-dependent pattern. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01066-6.
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- 2021
25. Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma
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Meral Beksac, Jinjun Qian, Yanxin Zhang, Chunyan Gu, Siegfried Janz, Mengjie Guo, Ye Yang, Yuxia Yuan, Artur Jurczyszyn, Renjie Dou, Rongfang Wei, Wei Wu, and Shu Yang
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Male ,0301 basic medicine ,Cancer Research ,Immunology ,Antineoplastic Agents ,Apoptosis ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,5-alpha Reductase Inhibitors ,0302 clinical medicine ,3-Oxo-5-alpha-Steroid 4-Dehydrogenase ,Downregulation and upregulation ,Mice, Inbred NOD ,Cell Line, Tumor ,Autophagy ,Animals ,Humans ,lcsh:QH573-671 ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Haematological cancer ,Cell growth ,Chemistry ,lcsh:Cytology ,Adenine ,TOR Serine-Threonine Kinases ,Membrane Proteins ,Cell Biology ,Dutasteride ,Cell cycle ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Enzyme Repression ,Phosphatidylinositol 3-Kinase ,Signal transduction ,Multiple Myeloma ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Steroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.
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- 2021
26. Steroid 5α-Reductase Type I Induces Cell Viability and Migration via Nuclear Factor-κB/Vascular Endothelial Growth Factor Signaling Pathway in Colorectal Cancer
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Rongfang Wei, Sixia Zhong, Li Qiao, Mengjie Guo, Miaomiao Shao, Suyu Wang, Bin Jiang, Ye Yang, and Chunyan Gu
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0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,diagnosis ,colorectal cancer ,Biology ,migration ,lcsh:RC254-282 ,Small hairpin RNA ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,steroid 5-alpha-reductase type I ,medicine ,Viability assay ,cell viability ,Original Research ,dutasteride ,Cell migration ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,digestive system diseases ,Vascular endothelial growth factor ,030104 developmental biology ,chemistry ,Oncology ,030220 oncology & carcinogenesis ,Dihydrotestosterone ,Cancer research ,prognosis ,nuclear factor-κB/vascular endothelial growth factor ,Signal transduction ,medicine.drug - Abstract
Colorectal cancer (CRC) is a common malignant tumor of the digestive system. Steroid 5α-reductase type I (SRD5A1), as an important part of the steroid metabolism, converts testosterone to dihydrotestosterone and regulates sex hormone levels, which accommodates tumor occurrence or development. However, the underlying molecular mechanism of SRD5A1 in CRC remains unclear. We compared SRD5A1 expression in CRC tissues with normal controls by immunohistochemistry and found that elevated SRD5A1 in CRC was relevant for poor patient prognosis. Furthermore, inducible downregulation of SRD5A1 by small hairpin RNA reduced cell viability, promoted cell cycle arrest, and induced cell apoptosis and cellular senescence of CRC cells, as well as attenuated cell migration ability. In the following experiments, we used dutasteride (an inhibitor of SRD5A1/2) to explore its inhibitory effect on the biological processes of CRC cells, as mentioned earlier. Further mechanism study demonstrated that the repression of SRD5A1 abolished the expression of p65 and vascular endothelial growth factor, suggesting that SRD5A1 might regulate cell viability and migration through nuclear factor-κB/vascular endothelial growth factor signaling pathway. Collectively, these findings implicate SRD5A1 acting as a novel biomarker for CRC diagnosis and prognosis and provide compelling evidence for the future evaluation of dutasteride as a promising candidate for CRC treatment.
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- 2020
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27. Exploring the role of glucose‑6‑phosphate dehydrogenase in cancer (Review)
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Wang Wang, Chunyan Gu, Ye Yang, and Rui Li
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congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Erythrocytes ,Carcinogenesis ,Pentose phosphate pathway ,Glucosephosphate Dehydrogenase ,chemistry.chemical_compound ,Mice ,hemic and lymphatic diseases ,Cell Line, Tumor ,Neoplasms ,parasitic diseases ,medicine ,Glucose-6-phosphate dehydrogenase ,Animals ,Humans ,chemistry.chemical_classification ,Reactive oxygen species ,Oncogene ,nutritional and metabolic diseases ,Cancer ,General Medicine ,Glutathione ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Glucose ,Oncology ,chemistry ,Tumor progression ,Mutation ,Cancer research ,Reactive Oxygen Species ,NADP - Abstract
Glucose‑6‑phosphate dehydrogenase (G6PD) is a cytoplasmic enzyme found in human erythrocytes that provides reduced NADPH for cell metabolism. Glutathione produced by the G6PD pathway can reduce the degree of harm caused by reactive oxygen species such as oxygen‑containing free radicals, peroxides and lipid peroxides. Investigation of G6PD has long focused on hemolysis, jaundice and other diseases caused by defects in its function. However, increased mRNA expression levels of G6PD are predictive of adverse clinical outcomes in cancer patients, including increased drug resistance, migration or proliferation of tumor cells. Mutations in the G6PD gene affect protein expression and activity, and alters the balance of redox states, leading to disease. However, the association between G6PD and tumors is incompletely understood. The aim of the present review was to summarize the current body of knowledge on the role of G6PD in tumor progression and the possible regulatory mechanisms involved. It is hypothesized that G6PD will prove to be of value as a target of cancer treatment in the near future.
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- 2020
28. CCN1 promotes hepatic steatosis and inflammation in non-alcoholic steatohepatitis
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Yan Sun, Zhaolian Bian, Linling Ju, Chunyan Gu, Hong Xue, Xiong Ma, Jian-Guo Shao, Lin Chen, Jue Wei, Xi Luo, and Rujian Lu
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Adult ,Male ,Gastrointestinal Diseases ,lcsh:Medicine ,Mice, Obese ,Apoptosis ,Inflammation ,Article ,Mice ,Gastrointestinal cancer ,chemistry.chemical_compound ,Downregulation and upregulation ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,Cell Adhesion ,medicine ,Animals ,Humans ,lcsh:Science ,chemistry.chemical_classification ,Multidisciplinary ,Fatty acid metabolism ,lcsh:R ,Fatty liver ,Fatty acid ,Middle Aged ,Lipid Metabolism ,medicine.disease ,Fatty Liver ,Mice, Inbred C57BL ,Liver ,chemistry ,Hepatocytes ,Cancer research ,Cytokines ,lcsh:Q ,Female ,Steatosis ,Steatohepatitis ,medicine.symptom ,Cysteine-Rich Protein 61 - Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by increased uptake and accumulation of lipids in hepatocytes. Simple steatosis may progress to non-alcoholic steatohepatitis (NASH) with inflammation, hepatocellular injury and fibrosis. CCN1 is an important matrix protein that regulates cell death and promotes immune cell adhesion and may potentially control this process. The role of CCN1 in NASH remains unclear. We investigated the role of CCN1 in the pathogenesis of steatohepatitis. CCN1 upregulation was found to be closely related with steatosis in patients with NASH, obese mice and a FFA-treated hepatocyte model. Controlling the expression of CCN1 in murine NASH models demonstrated that CCN1 increased the severity of steatosis and inflammation. From the sequence results, we found that fatty acid metabolism genes were primarily involved in the MCD mice overexpressing CCN1 compared to the control. Then, the expression of fatty acid metabolism genes was determined using a custom-designed pathway-focused qPCR-based gene expression array. Expression analysis showed that CCN1 overexpression significantly upregulated the expression of fatty acid metabolism-associated genes. In vitro analysis revealed that CCN1 increased the intracellular TG content, the pro-inflammatory cytokines and the expression level of apoptosis-associated proteins in a steatosis model using murine primary hepatocytes. We identified CCN1 as an important positive regulator in NASH.
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- 2020
29. Dihydroartemisinin induces growth arrest and overcomes dexamethasone resistance in multiple myeloma
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Ying Chen, Rui Li, Yuqi Zhu, Sixia Zhong, Jinjun Qian, Dongqing Yang, Artur Jurczyszyn, Meral Beksac, Chunyan Gu, and Ye Yang
- Subjects
Cancer Research ,medicine.medical_treatment ,Dihydroartemisinin ,dexamethasone ,Mitochondrion ,Pharmacology ,lcsh:RC254-282 ,dihydroartemisinin ,In vivo ,medicine ,Dexamethasone ,Original Research ,chemistry.chemical_classification ,Reactive oxygen species ,drug resistance ,biology ,Cytochrome c ,Correction ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,In vitro ,multiple myeloma ,chemistry ,Oncology ,artemisinin ,Apoptosis ,biology.protein ,medicine.drug - Abstract
The discovery of artemisinin (ART) for malaria treatment won the 2015 Nobel Prize in Medicine, which inspired the rediscovery and development of ART for the treatment of other diseases including cancer. In this study, we investigated the potential therapeutic effect of ART and dihydroartemisinin (DHA) on multiple myeloma (MM) cells including primary MM cells and in 5TMM3VT mouse model. Both in vitro and in vivo experiments showed that DHA might be a more promising anti-MM agent with significantly improved efficacy compared to ART. Mechanistic analyses suggested that DHA activated the mitochondrial apoptotic pathway by interacting with ferrous (Fe2+) ions and oxygen to produce reactive oxygen species (ROS). Intriguingly, DHA could reverse the upregulated expression of B-cell lymphoma 2 (Bcl-2) protein, a typical mitochondrial apoptotic marker, induced by dexamethasone (Dexa) in MM. We further demonstrated that DHA treatment could overcome Dexa resistance and enhance Dexa efficacy in MM. Additionally, DHA combined with Dexa resulted in increased ROS production and cytochrome C translocation from the mitochondria to the cytoplasm, resulting in alterations to the mitochondrial membrane potential and caspase-mediated apoptosis. In summary, our study demonstrated that DHA was superior to ART in MM treatment and overcame Dexa resistance both in vitro and in vivo, providing a promising therapeutic strategy for MM therapy.
- Published
- 2020
30. CHEK1 and circCHEK1_246aa Promote Multiple Myeloma Malignancy By Evoking Chromosomal Instability and Bone Lesion
- Author
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Ye Yang, Wang Wang, Xiaozhu Tang, and Chunyan Gu
- Subjects
Gene knockdown ,Chemistry ,Cell growth ,Immunology ,Cell Biology ,Hematology ,Transfection ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Downregulation and upregulation ,Osteoclast ,Cancer research ,medicine ,CHEK1 ,Bone marrow ,Multiple myeloma - Abstract
Key findings CHEK1 and circCHEK1_246aa induce multiple myeloma cell proliferation, drug resistance, and bone lesion formation CHEK1 and circCHEK1_246aa evoke myeloma chromosomal instability, partially through CEP170 activation Abstract Multiple myeloma (MM) is characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. In the present study, we first demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. CHEK1 overexpression increased cellular proliferation in MM cells and evoked drug resistance in vitro, while CHEK1 knockdown abrogated this effect. Moreover, CHEK1 was a high-risk gene for poor outcome in MM patients, and, in paired samples from MM patients taken from newly diagnosed and relapsed MM, CHEK1 expression was upregulated. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced chromosomal instability (CIN), as demonstrated by Giemsa staining, exon sequencing, and immunofluorescence. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by direct phosphorylation and activation of NFATc1, indicating that CHEK1 inhibition could target both MM cell proliferation and macrophage osteoclast differentiation in the BM niche. Intriguingly, we also discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Finally, we demonstrated in vivo in xenograft models that CHEK1 overexpression prompted MM proliferation and drug resistance, while CHEK1 knockdown conversely inhibited MM growth. Together, these findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and the BM niche. Figure Disclosures No relevant conflicts of interest to declare.
- Published
- 2020
31. BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling
- Author
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Chunyan Gu, Hongbao Yang, Lu Sicheng, Gang Yin, Yi Zhang, Ye Yang, Wen Zhang, Hailin Peng, Zhidan Tian, and Yue Lu
- Subjects
0301 basic medicine ,Senescence ,Gerontology ,senescence ,CGI-1746 ,Traditional Chinese medicine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Medicine ,Bruton's tyrosine kinase ,LY294002 ,Protein kinase B ,biology ,business.industry ,AKT ,Cancer ,Cell cycle ,medicine.disease ,multiple myeloma ,030104 developmental biology ,Oncology ,chemistry ,BTK ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Stem cell ,business ,Research Paper - Abstract
// Chunyan Gu 1, 2, 3, * , Hailin Peng 4, * , Yue Lu 5 , Hongbao Yang 6 , Zhidan Tian 7 , Gang Yin 2 , Wen Zhang 8 , Sicheng Lu 2 , Yi Zhang 9 and Ye Yang 1, 2, 10 1 The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China 2 School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing 210023, China 3 Department of Pathology, School of Medicine, University of Iowa, Iowa City, Iowa 52242, USA 4 Department of Laboratory Medicine, Taizhou People’s Hospital, Taizhou 225300, China 5 Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing 210009, China 6 Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China 7 Department of Pathology, Nanjing First Hospital, Nanjing 210006, China 8 Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, China 9 Department of Burns and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China 10 Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, China * These authors have contributed equally to this work Correspondence to: Yi Zhang, email: 198zy@163.com Ye Yang, email: yangye876@sina.com Keywords: multiple myeloma, BTK, senescence, AKT, CGI-1746 Received: February 25, 2017 Accepted: April 04, 2017 Published: May 23, 2017 ABSTRACT We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown BTK expression by shRNA induced MM cellular senescence using β-galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing BTK expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated BTK expression was resistant to MEF senescence after serial cultivation in vitro . Further mechanism study revealed that BTK activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame BTK-overexpression induced cellular senescence resistance. Eventually we demonstrated that BTK inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition in vivo . Summarily, we designate a novel mechanism of BTK in mediating MM growth, and BTK inhibitor is of great potential in vivo and in vitro suggesting BTK is a promising therapeutic target for MM.
- Published
- 2017
32. Opposing impact of AID deficiency on BCL-2 and IL-6 driven B-lymphoma development in BALB/c mice
- Author
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Xuefang Jing, Ye Yang, Siegfried Janz, and Chunyan Gu
- Subjects
biology ,medicine ,Cancer research ,biology.protein ,General Materials Science ,medicine.disease ,biology.organism_classification ,Interleukin 6 ,Lymphoma ,BALB/c - Published
- 2017
33. AURKA is a potential target for multiple myeloma therapy
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Chunyan Gu and Ting Lu
- Subjects
business.industry ,medicine ,Cancer research ,General Materials Science ,medicine.disease ,business ,Multiple myeloma - Published
- 2017
34. Tumor-infiltrating B cells signal functional humoral immune responses in breast cancer
- Author
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Karen Willard-Gallo, Chunyan Gu-Trantien, Denis Larsimont, Laurence Buisseret, Jean-Nicolas Lodewyckx, Anaïs Boisson, Marianne Paesmans, Martine Piccart-Gebhart, Cinzia Solinas, Soizic Garaud, Alexandre de Wind, Isabelle Veys, Céline Naveaux, Lieveke Ameye, Gert Van den Eynden, Hughes Duvillier, and Ligia Craciun
- Subjects
0301 basic medicine ,Receptor, ErbB-2 ,Adaptive Immunity ,Research & Experimental Medicine ,Lymphocyte Activation ,0302 clinical medicine ,PROGNOSTIC-SIGNIFICANCE ,Antigen Presentation ,B-Lymphocytes ,breakpoint cluster region ,hemic and immune systems ,General Medicine ,Middle Aged ,Acquired immune system ,Medicine, Research & Experimental ,PLASMA-CELLS ,030220 oncology & carcinogenesis ,Cytokines ,Female ,Antibody ,Life Sciences & Biomedicine ,Research Article ,MEMORY PHENOTYPE ,Breast Neoplasms ,chemical and pharmacologic phenomena ,CLINICAL IMPACTS ,Biology ,DENDRITIC CELLS ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Immune system ,Breast cancer ,medicine ,Humans ,FAVORABLE PROGNOSIS ,Science & Technology ,CD40 ,Germinal center ,HLA-DR Antigens ,PREDICTIVE-VALUE ,medicine.disease ,Immunity, Humoral ,Tertiary Lymphoid Structures ,030104 developmental biology ,T-CELLS ,Cancer research ,biology.protein ,TERTIARY LYMPHOID STRUCTURES ,DUCTAL CARCINOMA ,CD8 - Abstract
Tumor-infiltrating B-cells (TIL-B) in breast cancer (BC) have previously been associated with improved clinical outcomes; however, their role(s) in tumor immunity is not currently well known. This study confirms and extends the correlation between higher TIL-B densities and positive outcomes through an analysis of HER2-positive and triple-negative BC patients from the BIG 02-98 clinical trial (10yr mean follow-up). Fresh tissue analyses identify an increase in TIL-B density in untreated primary BC compared to normal breast tissues, which is associated with global, CD4+ and CD8+ TIL, higher tumor grades, higher proliferation and hormone receptor negativity. All B-cell differentiation stages are detectable but significant increases in memory TIL-B are consistently present. BC with higher infiltrates are specifically characterized by germinal center TIL-B, which in turn are correlated with TFH TIL and antibody-secreting TIL-B principally located in tertiary lymphoid structures. Some TIL-B also interact directly with tumor cells. Functional analyses reveal TIL-B are responsive to BCR stimulation ex vivo, express activation markers and produce cytokines and immunoglobulins despite reduced expression of the antigen-presenting molecules HLA-DR and CD40. Overall, these data support the concept that ongoing humoral immune responses are generated by TIL-B and help to generate effective anti-tumor immunity at the tumor site. ispartof: JCI INSIGHT vol:4 issue:18 ispartof: location:United States status: published
- Published
- 2019
35. Targeting MK2 Is a Novel Approach to Interfere in Multiple Myeloma
- Author
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Mengjie Guo, Dongdong Sun, Zhimin Fan, Yuxia Yuan, Miaomiao Shao, Jianhao Hou, Yuqi Zhu, Rongfang Wei, Yan Zhu, Jinjun Qian, Fei Li, Ye Yang, and Chunyan Gu
- Subjects
0301 basic medicine ,Cancer Research ,proliferation ,lcsh:RC254-282 ,Flow cytometry ,MK2 ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,medicine ,Doxorubicin ,MTT assay ,Original Research ,combination ,medicine.diagnostic_test ,Chemistry ,Bortezomib ,Cell growth ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,In vitro ,Gene expression profiling ,multiple myeloma ,inhibitor ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,medicine.drug - Abstract
MAPKAPK2 (MK2), the direct substrate of p38 MAPK, has been well-acknowledged as an attractive drug target for cancer therapy. However, few studies have assessed the functions of it in multiple myeloma (MM). In the present study, MK2 expression of MM patients was analyzed by gene expression profiling (GEP) and array-based comparative genomic hybridization (aCGH). Several experiments in vitro including MTT assay, Western blot and flow cytometry analysis were performed to identify the function of MK2 in MM. In addition, we conducted mouse survival experiments to explain the effects of MK2 on MM in vivo. mRNA level of MK2 and chromosomal gain of MK2 locus in MM cells significantly increased compared to normal samples. Furthermore, MM patients with high expression of MK2 were associated with a poor outcome. Follow-up studies showed that MK2 exerted a remarkably positive effect on MM cell proliferation and drug-resistance. Further exploration focusing on MK2 inhibitor IV revealed its inhibitory action on MM growth and drug-resistance, as well as improving survival in mouse models. In addition, a combination of MK2 inhibitor IV and the key MM therapeutic agents including bortezomib, doxorubicin, or dexamethasone facilitated curative effects on inhibiting MM cell proliferation. Taken together, our study reveals the clinical relevance of MK2 inhibition in MM and demonstrates that targeting MK2 may afford a new therapeutic approach to MM.
- Published
- 2019
36. The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy
- Author
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Cinzia Solinas, Karen Willard-Gallo, and Chunyan Gu-Trantien
- Subjects
Cancer Research ,medicine.medical_treatment ,T cell ,Review ,Ligands ,Inducible T-Cell Co-Stimulator Protein ,Immune system ,Cancer immunotherapy ,medicine ,Tumor Microenvironment ,CD278 ,Humans ,Cluster of differentiation ,Chemistry ,Généralités ,T lymphocyte ,immune checkpoint blockade ,Immune checkpoint ,ICOS LIGAND ,medicine.anatomical_structure ,Oncology ,ICOS ,Cancer research ,ICOSL ,Immunotherapy ,tumour microenvironment - Abstract
Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade., SCOPUS: re.j, info:eu-repo/semantics/published
- Published
- 2019
37. Iron metabolism and its contribution to cancer (Review)
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Ye Yang, Chunyan Gu, Zhimin Fan, and Ying Chen
- Subjects
0301 basic medicine ,Cancer Research ,Programmed cell death ,Iron ,Necroptosis ,Apoptosis ,Biology ,Mitochondrion ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Animals ,Homeostasis ,Humans ,Carcinogen ,Macrophages ,Pyroptosis ,Cell cycle ,Mitochondria ,Cell biology ,Cell Transformation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Tumor promotion ,Lipid Peroxidation - Abstract
Iron is an essential element for biological processes. Iron homeostasis is regulated through several mechanisms, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Iron has dual properties, which may facilitate tumor growth or cell death. Cancer cells exhibit an increased dependence on iron compared with normal cells. Macrophages potentially deliver iron to cancer cells, resulting in tumor promotion. Mitochondria utilize cellular iron to synthesize cofactors, including heme and iron sulfur clusters. The latter is composed of essential enzymes involved in DNA synthesis and repair, oxidation‑reduction reactions, and other cellular processes. However, highly increased iron concentrations result in cell death through membrane lipid peroxidation, termed ferroptosis. Ferroptosis, an emerging pathway for cancer treatment, is similar to pyroptosis, apoptosis and necroptosis. In the present review, previous studies on the physiology of iron metabolism and its role in cancer are summarized. Additionally, the significance of iron regulation, and the association between iron homeostasis and carcinogenic mechanisms are discussed.
- Published
- 2019
38. Age-related changes in the BACH2 and PRDM1 genes in lymphocytes from healthy donors and chronic lymphocytic leukemia patients
- Author
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Mohammad Krayem, Vu Luan Dang Chi, Soizic Garaud, Karen Willard-Gallo, Catherine Sibille, Mimoune Berehad, Chunyan Gu-Trantien, Jean Nicolas Lodewyckx, Hugues Duvillier, Pushpamali De Silva, Vincent Thibaud, Dominique Bron, and Basile Stamatopoulos
- Subjects
Male ,0301 basic medicine ,Aging ,Cancer Research ,Chronic lymphocytic leukemia ,Apoptosis ,BACH2 ,0302 clinical medicine ,hemic and lymphatic diseases ,Gene expression ,Positive Regulatory Domain I-Binding Factor 1 -- genetics -- immunology -- metabolism ,Lymphocytes ,Cellular Senescence ,Aged, 80 and over ,biology ,Lymphocyte Subsets -- immunology -- metabolism ,Immunosenescence ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Healthy Volunteers ,Up-Regulation ,Cellular Senescence -- immunology ,Basic-Leucine Zipper Transcription Factors ,Real-time polymerase chain reaction ,Oncology ,030220 oncology & carcinogenesis ,Female ,Untreated Chronic Lymphocytic Leukemia ,Research Article ,Adult ,Down-Regulation -- immunology ,Down-Regulation ,lcsh:RC254-282 ,CD19 ,Young Adult ,03 medical and health sciences ,PRDM1 ,Genetics ,medicine ,Humans ,RNA, Messenger ,Aged ,Leukemia, Lymphocytic, Chronic, B-Cell -- blood -- immunology -- pathology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,RNA, Messenger -- metabolism ,Up-Regulation -- immunology ,Lymphocyte Subsets ,Aging -- immunology ,030104 developmental biology ,Basic-Leucine Zipper Transcription Factors -- genetics -- immunology -- metabolism ,Immunology ,biology.protein ,Positive Regulatory Domain I-Binding Factor 1 ,CD8 ,Hématologie - Abstract
Age-related genetic changes in lymphocyte subsets are not currently well documented. BACH2 is a transcription factor that plays an important role in immune-mediated homeostasis by tightly regulating PRDM1 expression in both B-cells and T-cells. BACH2 gene expression is highly sensitive to DNA damage in aged mice. This concept led us to investigate the variation in BACH2 and also PRDM1 expression in major lymphocyte subsets with age., info:eu-repo/semantics/published
- Published
- 2019
39. Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma
- Author
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Xuefang Jing, Chunyan Gu, Fenghuang Zhan, Siegfried Janz, Guido Tricot, Ramakrishna Sompallae, Ye Yang, and Carol J. Holman
- Subjects
0301 basic medicine ,Cancer Research ,Drug Resistance ,Mice, SCID ,Bortezomib ,Small-drug inhibitor ,Mice, Inbred NOD ,Targeted cancer therapy ,Multiple myeloma ,Mice, Knockout ,biology ,Drug Tolerance ,Plasma cell neoplasm ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Up-Regulation ,3. Good health ,Gene Expression Regulation, Neoplastic ,Oncology ,Multiple Myeloma ,medicine.drug ,Research Article ,Cell Survival ,Plasma-cell neoplasm ,Antineoplastic Agents ,Cellular senescence ,lcsh:RC254-282 ,03 medical and health sciences ,Cyclin-dependent kinase ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Doxorubicin ,Cell Proliferation ,business.industry ,Gene Expression Profiling ,Forkhead Box Protein M1 ,Correction ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Proteasome inhibitor ,biology.protein ,Cancer research ,FOXM1 ,Cyclin-dependent kinase 6 ,business - Abstract
Background Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). Methods FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. Results Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9–5.6 fold) and Dox (1.5–2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively. Conclusions These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels. Electronic supplementary material The online version of this article (10.1186/s12885-018-5015-0) contains supplementary material, which is available to authorized users.
- Published
- 2018
40. Correction to: Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma
- Author
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Ramakrishna Sompallae, Fenghuang Zhan, Xuefang Jing, Chunyan Gu, Guido Tricot, Carol J. Holman, Ye Yang, and Siegfried Janz
- Subjects
0301 basic medicine ,Drug ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Downregulation and upregulation ,Surgical oncology ,030220 oncology & carcinogenesis ,Internal medicine ,Genetics ,medicine ,FOXM1 ,business ,Sensitivity (electronics) ,media_common - Abstract
As a result of an author oversight in the original article [1], the legend of Figure 5A and C is inaccurate and one panel in Figure 5C (FOXM1N H929 cells shown in the top row, left) is wrong.
- Published
- 2019
41. RFWD2 Induces Cellular Proliferation and Proteasome Inhibitor Resistance By Mediating p27 Ubiqutinaiton in Multiple Myeloma
- Author
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Chunyan Gu, Mengjie Guo, and Ye Yang
- Subjects
Bortezomib ,Cell growth ,Chemistry ,Immunology ,Cell Biology ,Hematology ,Drug resistance ,medicine.disease ,Biochemistry ,Proteasome ,Apoptosis ,In vivo ,Cancer research ,medicine ,Proteasome inhibitor ,Multiple myeloma ,medicine.drug - Abstract
Purpose: In recent years, with the emergence of targeted proteasome inhibitors (PIs), the treatment of multiple myeloma (MM) has made great progress and significantly improves the survival rate of patients. However, MM remains an incurable disease, mainly due to the recurrence of drug resistance. The constitutive photomorphogenic 1 (RFWD2, also known as COP1), is closely related to the occurrence and development of tumors, but its role in MM is largely unknown. This study was aimed to explore the mechanism of RFWD2 on cell proliferation and resistance to proteasome inhibitor in MM. Experimental Design: Using gene expression profiling (GEP) samples, we verified the relation of RFWD2 to MM patients' survival and drug-resistance. The effect of RFWD2 on cell proliferation was confirmed by MTT and cell cycle analysis in RFWD2-overexpressed and RFWD2-knockdown MM cells. MTT and apoptosis experiments were performed to evaluate whether RFWD2 influenced the sensitivity of MM cells to several chemotherapy drugs. MM xenografts were established in immunodeficient NOD/SCID mice by injecting wild-type or RFWD2 over-expression MM cells with drug intervention. The mechanism of drug resistance was elucidated by analyzing the association of RFWD2 with E3 ligase of p27. Bortezomib-resistant RPMI 8226 cells were used to construct RFWD2 knockdown cells, which were injected into NOD/SCID mice to assess the effect of RFWD2 on bortezomib resistance in vivo. Results: RFWD2 expression was closely related to poor outcome, relapse and bortezomib resistance in MM patients' GEP cohorts. Elevated RFWD2 induced cell proliferation, while decreased RFWD2 inhibited cell proliferation and induced apoptosis in MM cells. RFWD2-overexpression MM cells resulted in PIs resistance, however, no chemotherapy resistance to adriamycin and dexamethasone was observed in vitro. In addition, overexpressing RFWD2 in MM cells led to bortezomib resistance rather than adriamycin resistance in myeloma xenograft mouse model. RFWD2 regulated the ubiquitination degradation of P27 by interacting with RCHY1 ubiquitin ligase. The knockdown of RFWD2 in bortezomib-resistant RPMI 8226 cells overcame bortezomib resistance in vivo. Conclusions: Our data demonstrate that elevated RFWD2 induces MM cell proliferation and resistance to PIs, but not to adriamycin and dexamethasone both in vitro and in vivo through mediating the ubiquitination of p27. Collectively, RFWD2 is a novel promising therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
42. The Efficacy of a Novel Oral Proteasome Inhibitor NNU546 in Multiple Myeloma
- Author
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Ye Yang, Yongqiang Zhu, and Chunyan Gu
- Subjects
biology ,Chemistry ,Bortezomib ,Endoplasmic reticulum ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Fight-or-flight response ,medicine.anatomical_structure ,Cell culture ,Proteasome inhibitor ,medicine ,Cancer research ,biology.protein ,Bone marrow ,Multiple myeloma ,Caspase ,medicine.drug - Abstract
Proteasome inhibition demonstrates highly effective impact on multiple myeloma (MM) treatment. In this study we aimed to examine a novel well tolerated orally applicable proteasome inhibitor NNU546 and its hydrolyzed pharmacologically active form NNU219. NNU219 showed more selective inhibition to proteasome catalytic subunits and less off-target effect than bortezomib ex vivo. Furthermore, intravenous and oral administration of NNU219 and NNU546, respectively, led to a more sustained pharmacodynamic inhibition of proteasome activities compared with bortezomib. Intriguingly, NNU219 exhibited potential anti-MM activity on both MM cell lines and primary samples in vitro. The anti-MM activity of NNU219 was determined to be associated with induction of G2/M-phase arrest, as well as induction of apoptosis via activation of the caspase cascade and endoplasmic reticulum stress response. At well-tolerated doses, significant growth-inhibitory effects of NNU219 and NNU546 were observed in 3 different human MM xenograft mouse models and significant anti-MM activity was observed even in the presence of a bone marrow microenvironment. Taken together, these findings provided the basis for clinical trials of NNU546 to determine its potential as a candidate for MM treatment. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
43. Quantifying Tertiary Lymphoid Structure-Associated Genes in Formalin-Fixed Paraffin-Embedded Breast Cancer Tissues
- Author
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Jean Nicolas Lodewyckx, Karen Willard-Gallo, Chunyan Gu-Trantien, Cinzia Solinas, Soizic Garaud, and Edoardo Migliori
- Subjects
0301 basic medicine ,Cell type ,Cell ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Breast cancer ,Immune system ,Tumor progression ,030220 oncology & carcinogenesis ,Gene expression ,medicine ,Cancer research ,Immunohistochemistry ,Gene - Abstract
Tertiary lymphoid structures (TLS) have been detected in several types of human solid tumors. These structures are thought to regulate local adaptive immune responses that can promote or antagonize tumor progression. Despite positive prognostic values associated with a TLS presence in several studies, discrepancies still exist. TLS are structurally organized entities composed of varying numbers of multiple cell types making their assessment in tumor tissues, particularly biopsies, challenging. Immunohistochemical staining of TLS-related cell populations is the most frequently used method for identifying and scoring them; however, TLS-related gene expression has also been explored. The protocols described are detailed to allow the user to quantify TLS-related gene expression on formalin-fixed paraffin-embedded human breast tumor tissues.
- Published
- 2018
44. miR-383 inhibits hepatocellular carcinoma cell proliferation via targeting APRIL
- Author
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Guan Haitao, Feng Wang, Chunyan Gu, Jianguo Shao, Lin Chen, and Yali Cao
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Cell cycle checkpoint ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,Down-Regulation ,Apoptosis ,Kaplan-Meier Estimate ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,microRNA ,medicine ,Humans ,RNA, Messenger ,neoplasms ,Cell Proliferation ,Cell growth ,Liver Neoplasms ,Hep G2 Cells ,General Medicine ,Middle Aged ,Cell cycle ,Prognosis ,medicine.disease ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Cell culture ,Tumor progression ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,Female - Abstract
Mounting evidence has shown that microRNAs (miRNAs), a class of small non-coding RNAs, are frequently deregulated in human malignancies and have pivotal roles in diverse biological processes including cancer cell proliferation. Herein, we investigated the expression pattern of miR-383 in 64 hepatocellular carcinoma (HCC) tissues and 4 HCC cell lines and found that miR-383 was downregulated in HCC tissues and cell lines. Moreover, miR-383 expression in HCC was significantly correlated with tumor size and tumor-node-metastasis (TNM) stage. Kaplan-Meier analysis showed that decreased miR-383 expression was associated with poor overall survival of HCC patients. In addition, Cox regression analysis indicated that miR-383 was an independent prognostic factor for HCC patients. Then, functional studies demonstrated that ectopic miR-383 expression could significantly suppress the in vitro proliferation of HCC cells, as well as induce cell cycle arrest and cell apoptosis. Luciferase reporter assay further identified that a proliferation-inducing ligand (APRIL), a member in the tumor necrosis factor (TNF) superfamily, was a novel target gene for miR-383. Subsequent investigation revealed that miR-383 expression was inversely correlated with APRIL messenger RNA (mRNA) expression in HCC tissues. Besides, recombinant human APRIL (rhAPRIL) could rescue HCC cell proliferation inhibited by miR-383. Taken together, our present study provided the first evidence that miR-383 was decreased in HCC and associated with tumor progression and prognosis of HCC patients. Furthermore, our findings confirmed that miR-383 might inhibit HCC cell proliferation partially via downregulating APRIL expression. Thus, this study might provide a promising strategy by targeting with the miR-383-APRIL axis in the treatment of HCC.
- Published
- 2015
45. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer
- Author
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Denis Larsimont, Hugues Duvillier, Vu Luan Dang Chi, Laurence Buisseret, Grégory Noël, Sylvain Brohée, Soizic Garaud, Jean Nicolas Lodewyckx, Edoardo Migliori, Karen Willard-Gallo, Chunyan Gu-Trantien, Stanislas Goriely, Céline Naveaux, and Alexandre de Wind
- Subjects
0301 basic medicine ,T cell ,Cellular differentiation ,Cell ,Germinal center ,General Medicine ,Biology ,Stem cell marker ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,Cancer research ,CXCL13 ,B cell ,030215 immunology ,Research Article - Abstract
T follicular helper cells (TFH cells) are important regulators of antigen-specific B cell responses. The B cell chemoattractant CXCL13 has recently been linked with TFH cell infiltration and improved survival in human cancer. Although human TFH cells can produce CXCL13, their immune functions are currently unknown. This study presents data from human breast cancer, advocating a role for tumor-infiltrating CXCL13-producing (CXCR5-) TFH cells, here named TFHX13 cells, in promoting local memory B cell differentiation. TFHX13 cells potentially trigger tertiary lymphoid structure formation and thereby generate germinal center B cell responses at the tumor site. Follicular DCs are not potent CXCL13 producers in breast tumor tissues. We used the TFH cell markers PD-1 and ICOS to identify distinct effector and regulatory CD4+ T cell subpopulations in breast tumors. TFHX13 cells are an important component of the PD-1hiICOSint effector subpopulation and coexpanded with PD-1intICOShiFOXP3hi Tregs. IL2 deprivation induces CXCL13 expression in vitro with a synergistic effect from TGFβ1, providing insight into TFHX13 cell differentiation in response to Treg accumulation, similar to conventional TFH cell responses. Our data suggest that human TFHX13 cell differentiation may be a key factor in converting Treg-mediated immune suppression to de novo activation of adaptive antitumor humoral responses in the chronic inflammatory breast cancer microenvironment.
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- 2017
46. Abstract 2371: Breast cancer induces tolerogenic state of healthy activated CD4+ lymphocytes, characterized by reduced PI3K, NFκB, JAK-STAT, Notch, and increased TGFβpathway activity
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Anja van de Stolpe, Arie van Doorn, Chunyan Gu-Trantien, Karen Willard-Gallo, Grégory Noël, and Wim Verhaegh
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Cancer Research ,Chemistry ,medicine.medical_treatment ,T cell ,Wnt signaling pathway ,JAK-STAT signaling pathway ,CD28 ,Immunotherapy ,Immune system ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,Checkpoint Blockade Immunotherapy ,PI3K/AKT/mTOR pathway - Abstract
Tumor cells can induce immunotolerance, which is reversed by checkpoint blockade immunotherapy in some patients, although response prediction remains a challenge. CD4+ T cells play an important role in activating adaptive immune responses with their conversion to a suppressed state impairing anti-tumor immune responses. CD4+ T cells function by activating and controlling various signal transduction pathways. Over the past decade we have developed tests that quantitatively measure functional activities of signal transduction pathways (e.g. Hedgehog, Wnt, TGFβ Notch, NFκB, PI3K, JAK-STAT 1/2 and 3, and MAPK). They are based on Bayesian computational model inference of pathway activities from measurements (expression microarray, qPCR) of mRNA levels of target genes of the transcription factor associated with the respective signalling pathways1,2. These tests were extensively biologically validated, including on immune cells, and can be used to characterize their functional activity status. In the present study, this approach was used to investigate cellular mechanisms underlying breast cancer-induced immunosuppression of CD4+ T cells. Method: Generation of Affymetrix gene expression data has been previously described (J Clin Invest 2013;123(7):2873-92) and data is publically available (GEO dataset GSE36766). Briefly, breast cancer tissue sections from fresh surgical specimens were mechanically dissociated in X-VIVO 20. Following activation with anti-CD3/CD28, CD4+ T cells from healthy donor blood were incubated with primary tumor supernatants (SN) and compared to controls. Signaling pathway activities were measured using Affymetrix expression data from the individual CD4+ T cell treatment groups. Results: CD4+ T cell activation resulted in induction of PI3K, NFkB, JAK-STAT1/2, JAK-STAT3, Notch, and parallel decrease in TGFβ pathway activities. Incubation with primary tumor SN did not affect pathway activity in non-activated CD4+ T cells, but reduced activity of PI3K, NFκB, JAK-STAT1/2, JAK-STAT3, Notch, while increasing TGFβ pathway activity in activated CD4+ T cells. Conclusion: A soluble factor(s) from breast tumor tissues increases TGFβ and reduces effector immune pathway activity in activated CD4+ T cells and thereby can induce an immunotolerant state. Investigation into the nature of this soluble factor(s) is in progress. These data demonstrate that signaling pathway assays can be used to quantitatively measure the functional state of immune responses in CD4+ lymphocytes. The ultimate goal is to apply this approach for predicting and monitoring immunotherapy responses and identifying novel drug targets that can reverse tumor-induced immunosuppression. Ref: 1. Verhaegh W, et al. Cancer Res 2014;74(11):2936-45; 2. Ooijen H. van, et al. Am J Pathol 2018;188(9):1956-1972. Citation Format: Anja Van De Stolpe, Wim Verhaegh, Arie van Doorn, Grégory Noël, Chunyan Gu-Trantien, Karen Willard-Gallo. Breast cancer induces tolerogenic state of healthy activated CD4+ lymphocytes, characterized by reduced PI3K, NFκB, JAK-STAT, Notch, and increased TGFβpathway activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2371.
- Published
- 2019
47. Abstract 3132: Immune regulatory gene expression and clinical outcome in the NeoALTTO trial
- Author
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Cinzia Solinas, Pushpamali De Silva, David Venet, Soizic Garaud, Chunyan Gu-Trantien, Florentine Hilbers, Evandro de Azambuja, Olena Werner, Lorena De la Peña, Amylou Dueck, Serena Di Cosimo, Istvan Lang, Jens Huober, Sherko Küemmel, Carsten Denkert, Roberto Salgado, Christos Sotiriou, Martine Piccart-Gebhart, Debora Fumagalli, and Karen Willard-Gallo
- Subjects
Cancer Research ,Oncology - Abstract
Background: The level of immune suppression in an individual breast cancer (BC) patient is relevant for having a major benefit from treatments that act via or are directed to the immune response, such as anti-HER2 agents and immune checkpoint molecules, respectively. The link(s) between the tumor immune microenvironment and treatment responses has been investigated in HER2-positive BC. This study analyzed the association between baseline expression of genes regulating T cell activities (PD1, CTLA4, LAG3, TIM3, PDL1, PDL2, FOXP3, IL10, TGFβ (1-3), FOXP1 and other related genes) and pathologic complete response (pCR) rates in the NeoALTTO trial. Methods: NeoALTTO randomized early-stage HER2-positive BC patients to neoadjuvant trastuzumab (T), lapatinib (L) or T+L for 6 weeks followed by 12 weeks of concurrent paclitaxel. Anthracyclines were given after surgery (FEC). Patients with RNA sequencing data from their baseline tumor samples (N=254 patients out of 455 from the original cohort) were included in the current study. The primary endpoint, pCR, was defined as ypT0/is ypN0. Logistic regression was used for analysis of pCR. Cox regression univariate and multivariate (adjusted for clinicopathological parameters and treatment arms) analyses were performed. Results: In the total cohort analyzed, high PD1 (odds ratio, OR: 1.4, P=0.03), PDL2 (OR: 1.4, P=0.04), CTLA4 (OR: 1.4, P=0.03) and TGFβ3 (OR: 1.4, P=0.02) expression was associated with an increased probability of achieving pCR at the multivariate analysis. ERBB2 (HER2) expression was associated with pCR in the three arms (T: OR: 2.7, P=0.02; L: OR: 2.3, P=0.01; T+L: OR: 5, P Citation Format: Cinzia Solinas, Pushpamali De Silva, David Venet, Soizic Garaud, Chunyan Gu-Trantien, Florentine Hilbers, Evandro de Azambuja, Olena Werner, Lorena De la Peña, Amylou Dueck, Serena Di Cosimo, Istvan Lang, Jens Huober, Sherko Küemmel, Carsten Denkert, Roberto Salgado, Christos Sotiriou, Martine Piccart-Gebhart, Debora Fumagalli, Karen Willard-Gallo. Immune regulatory gene expression and clinical outcome in the NeoALTTO trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3132.
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- 2019
48. Unsupervised analysis of the extent, organization and phenotype of tumor-infiltrating lymphocytes in breast cancer identifies two major clusters
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K Willard-Gallo, P. De Silva, Céline Naveaux, Cinzia Solinas, Soizic Garaud, Francois Richard, Anaïs Boisson, Ligia Craciun, G. Van den Eyden, M. Langouo Fontsa, Hughes Duvillier, Chunyan Gu-Trantien, D. Larsimont, Grégory Noël, and A. De Wind
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Breast cancer ,Oncology ,Tumor-infiltrating lymphocytes ,business.industry ,Cancer research ,Medicine ,Hematology ,business ,medicine.disease ,Phenotype - Published
- 2018
49. Abstract PD1-3: The significance of tumor infiltrating lymphocyte density, subset composition and organization in breast cancer
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Martine Piccart, S Duquenne, Denis Larsimont, Laurence Buisseret, Soizic Garaud, Christos Sotiriou, Karen Willard-Gallo, Alexandre de Wind, and Chunyan Gu-Trantien
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CD20 ,Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,Tumor-infiltrating lymphocytes ,business.industry ,chemical and pharmacologic phenomena ,medicine.disease ,CD19 ,Immune system ,medicine.anatomical_structure ,Breast cancer ,Oncology ,biology.protein ,medicine ,Immunohistochemistry ,business ,B cell ,CD8 - Abstract
The clinical relevance of tumor infiltrating lymphocytes (TIL) in breast cancer (BC) has been clearly established by recent large clinical trials (presented at SABCS 2013). The relationship between protective immunity, observed in some patients, and critical features of lymphoid subset composition and organization remain unknown. Our recent work revealed that tertiary lymphoid structures (TLS), principally composed of T cells, B cells and dendritic cells, are present in the peri-tumoral regions of breast tumors and associated with a CD4+ follicular helper T (Tfh) cell presence. Through retrospective analyses, we determined that TLS were associated with good clinical outcomes in both the neo-adjuvant and adjuvant settings. To gain insight into the immune components linked with a significant TIL and TLS presence, we initiated a prospective flow cytometric study. We systematically immunophenotyped T and B cell TIL in breast tissues from tumors (n=125), non-adjacent non-tumor tissues (NANT, n=115) and normal tissue from mammary reductions (n=26) on the day of surgery. TIL organization and spatial distribution was subsequently analyzed by immunohistochemistry (IHC) and immunofluorescence (IF) on paraffin sections for a subset of patients (n=78). The fresh tissue analyses revealed that TIL density was a continuum across the 125 patients analyzed. A cutoff for TIL-positive and -negative tumors was set at 58 CD45+ TIL per mm3 of tissue based on the number of CD45+ cells present in the remarkably similar normal and NANT tissues. Applying this threshold to BC, 65% were TIL-positive with approximately one-third considered extensively infiltrated. TIL-positive tumors are characterized by an increase in CD4+ T cells and CD19+/CD20+ B cells. The median CD4/CD8 ratio was >1 in TIL-positive compared to 95% of CD45+ cells) IHC and scored by trained pathologists. The best correlation was observed between CD3/CD20 flow cytometry and CD3/CD19 IHC, the latter also associated with lower inter-observer variability. TIL density was positively correlated with proliferation (Ki67 & histological grade) and hormone receptor negativity while TLS were more frequent in younger women. These data suggest that organized immune responses in TLS adjacent to the tumor bed provide an effective location for generating anti-tumor memory T and B cell responses. Citation Format: Karen Willard-Gallo, Laurence Buisseret, Soizic Garaud, Chunyan Gu-Trantien, Alexandre de Wind, Sébastien Duquenne, Denis Larsimont, Christos Sotiriou, Martine Piccart. The significance of tumor infiltrating lymphocyte density, subset composition and organization in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD1-3.
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- 2015
50. Study of Gefitinib and Pemetrexed as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutation
- Author
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Hai Shi, Fengwei Zhu, Hongjun Chu, Xin Yi, Feng Xiao, Hongfei Zhang, Rujian Lu, Jiajun Zhang, Chaolun An, and Chunyan Gu
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Pemetrexed ,Neutropenia ,Placebo ,Disease-Free Survival ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Gefitinib ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lung cancer ,neoplasms ,Survival rate ,Protein Kinase Inhibitors ,Aged ,Chemotherapy ,business.industry ,General Medicine ,medicine.disease ,respiratory tract diseases ,ErbB Receptors ,Survival Rate ,Regimen ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Disease Progression ,Quinazolines ,Female ,business ,medicine.drug - Abstract
To evaluate the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Patients and methods Patients with advanced non-squamous NSCLC harboring asensitive EGFR mutation were included in this study and randomly divided into gefitinib + placebo group and gefitinib + pemetrexed group. Pemetrexed or placebo was administered on day 1 at a dose of 500 mg/m(2), and gefitinib was sequentially administered on days 2 ~ 16. This treatment regimen was repeated every 3 weeks until disease progression. All investigators and participants were masked to treatment allocation. The overall response rate (ORR) and disease control rate (DCR) of gefitinib + pemetrexed group were higher than that of gefitinib + placebo group but only the difference of DCR between two groups was statistically significant (P 0.05). The median progression-free survival (PFS) of gefitinib + placebo group and gefitinib + pemetrexed group were 14.0 months vs. 18 months respectively and the difference was statistically significant (P 0.05). The 2-year PFS rates of gefitinib + pemetrexed group (20.00 %) was higher than that of gefitinib + placebo group (8.89 %) and the difference was statistically significant (P 0.05). The median overall survival (OS) of gefitinib + placebo group and gefitinib + pemetrexed group were 32.0 months vs. 34 months respectively and the difference was not statistically significant (P 0.05). The 3-year OS rates of gefitinib + pemetrexed group (44.44 %) was higher than that of gefitinib + placebo group (35.56 %) but the difference was not statistically significant (P 0.05). Major grade 3 or 4 hematological toxicities included neutropenia, leukopenia and anemia. The main grade 3 or 4 non-hematological toxicities were infection, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, fatigue, diarrhea and pneumonitis. The difference of toxicities between two groups was not statistically significant (P 0.05). The combination regimen of gefitinib + pemetrexed used in this study showed a higher ORR and DCR, longer median PFS and acceptable toxicity.
- Published
- 2015
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