110 results on '"Qi, Q"'
Search Results
2. Abstract P3-06-15: Young breast cancer patients demonstrate worse survival associated with aggressive oncogene expression but not with mutation load, tumor heterogeneity or pro-tumor immune cell infiltrations
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Young, JS, primary, Asaoka, M, additional, Katsuta, E, additional, Kawaguchi, T, additional, Qi, Q, additional, Liu, S, additional, Yan, L, additional, and Takabe, K, additional
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- 2019
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3. Abstract P2-01-19: Sphingosine-1-phosphate affects tumor-associated macrophages in breast cancer patients
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Tsuchida, J, primary, Nagahashi, M, additional, Moro, K, additional, Ikarashi, M, additional, Koyama, Y, additional, Sakata, J, additional, Kobayashi, T, additional, Kameyama, H, additional, Qi, Q, additional, Yan, L, additional, Takabe, K, additional, and Wakai, T, additional
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- 2019
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4. Abstract P5-07-08: Survival relevance of tamoxifen sensitivity-related microRNAs, miR-342 and miR-221/222, in breast cancer patients
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Young, JS, primary, Kawaguchi, T, additional, Yan, L, additional, Qi, Q, additional, Liu, S, additional, and Takabe, K, additional
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- 2018
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5. Abstract P2-05-14: Young breast cancer patients (<40 yo) have unfavorable subtypes, higher stage and worse survival
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Young, JS, primary, Kawaguchi, T, additional, Yan, L, additional, Qi, Q, additional, Liu, S, additional, and Takabe, K, additional
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- 2018
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6. Abstract P5-07-07: Prognostic relevance of microRNA-155 and microRNA-21 in breast cancer patients
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Kim, SY, primary, Kawaguchi, T, additional, Yan, L, additional, Young, J, additional, Qi, Q, additional, and Takabe, K, additional
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- 2018
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7. Abstract P6-06-06: Immunogenomics approach elucidating clinical significance of DNA repair genes and tumor infiltrating immune cells in breast cancer
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Takabe, K, primary, Kawaguchi, T, additional, Yan, L, additional, Peng, X, additional, Qi, Q, additional, Okano, M, additional, Young, J, additional, and Liu, S, additional
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- 2018
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8. Abstract P1-07-31: Integrated transcriptomics analyses identify novel three microRNAs signature to predict poor prognosis and metastasis in breast cancer
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Takabe, K, primary, Kawaguchi, T, additional, Yan, L, additional, Qi, Q, additional, Peng, X, additional, Young, J, additional, and Liu, S, additional
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- 2018
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9. Hypoxia Stimulates PYGB Enzymatic Activity to Promote Glycogen Metabolism and Cholangiocarcinoma Progression.
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Pan Y, Zhou Y, Shen Y, Xu L, Liu H, Zhang N, Huang T, Meng K, Liu Y, Wang L, Bai G, Chen Q, Zhu Y, Zou X, Wang S, Wang Z, and Wang L
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- Humans, Animals, Mice, Cell Line, Tumor, Prognosis, Mice, Nude, Male, Female, Xenograft Model Antitumor Assays, Phosphoglycerate Kinase metabolism, Phosphoglycerate Kinase genetics, Mice, Inbred BALB C, Cholangiocarcinoma pathology, Cholangiocarcinoma metabolism, Cholangiocarcinoma drug therapy, Bile Duct Neoplasms pathology, Bile Duct Neoplasms metabolism, Bile Duct Neoplasms drug therapy, Glycogen metabolism, Disease Progression, Glycolysis, Cell Proliferation, Glycogen Phosphorylase, Brain Form metabolism, Glycogen Phosphorylase, Brain Form genetics
- Abstract
Cholangiocarcinoma (CCA) displays enhanced glycolysis, pivotal for fulfilling the heightened energy demands intrinsic to its malignant progression. Recent research has indicated that endogenous glycogen rather than exogenous glucose acts as the major carbon source for glycolysis, highlighting the need to better understand the regulation of glycogen homeostasis in CCA. Here, through comprehensive integrative analysis, we identified that glycogen phosphorylase brain form (PYGB), the main enzyme involved in glycogen homeostasis, was markedly upregulated in CCA tissues, serving as an independent prognostic indicator for human patients with CCA. Moreover, elevated PYGB expression potentiated cholangiocarcinogenesis and augmented CCA cell proliferation in both organoid and xenograft models. Hypoxia stimulated PYGB activity in a phosphoglycerate kinase 1-dependent manner, leading to glycogenolysis and the subsequent release of glucose-6-phosphate (G6P) and thereby facilitating aerobic glycolysis. Notably, a virtual screening pinpointed the β-blocker carvedilol as a potent pharmacologic inhibitor of PYGB that could attenuate CCA progression. Collectively, these findings position PYGB as a promising prognostic biomarker and therapeutic target for CCA. Significance: Cholangiocarcinoma cells exhibit high glycogen phosphorylase activity under hypoxic conditions that mediates metabolic reprograming to promote glycolysis and support tumor development., (©2024 American Association for Cancer Research.)
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- 2024
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10. Spatial and Single Cell Analyses Reveal Heterogeneity of DNAM-1 Receptor-Ligand Interactions that Instructs Intratumoral γδT-Cell Activity.
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Wang X, Wang H, Lu Z, Liu X, Chai W, Wang W, Feng J, Yang S, Yang W, Cheng H, Chen C, Zhang S, Sun N, Liu Q, Li Q, Song W, Jin F, Zeng Q, Wang S, Su Y, Wang H, Ni X, and Gui J
- Abstract
The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial metabolome analysis, from neuroblastoma (NB) revealed that the expression levels and localization of CD112 and CD155 varied across and within tumors, correlating with differentiation status, metabolic pathways, and ultimately disease prognosis and patient survival. Both in vivo tumor xenograft experiments and in vitro co-culture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT-cell-mediated cytotoxicity, while a low-ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1-mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via TRIM21-mediated ubiquitin proteasomal degradation. By interacting with tumor cells differentially expressing CD112 and CD155, intratumoral γδT cells exhibited varying degrees of activation and DNAM-1 expression, representing three major functional subsets. This study underscores the complexity of tumor-immune crosstalk, offering insights into how tumor heterogeneity shapes the immune landscape.
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- 2024
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11. The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.
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Sudalagunta PR, Canevarolo RR, Meads MB, Silva M, Zhao X, Cubitt CL, Sansil SS, DeAvila G, Alugubelli RR, Bishop RT, Tungesvik A, Zhang Q, Hampton O, Teer JK, Welsh EA, Yoder SJ, Shah BD, Hazlehurst L, Gatenby RA, Van Domelen DR, Chai Y, Wang F, DeCastro A, Bloomer AM, Siegel EM, Lynch CC, Sullivan DM, Alsina M, Nishihori T, Brayer J, Cleveland JL, Dalton W, Walker CJ, Landesman Y, Baz R, Silva AS, and Shain KH
- Abstract
Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes. This analysis revealed a MM transcriptomic topology that generates "footprints" in association with ex vivo drug sensitivity that have both predictive and mechanistic applications. Validation of the transcriptomic footprints for the anti-CD38 monoclonal antibody daratumumab and the nuclear export inhibitor selinexor demonstrated that these footprints can accurately classify clinical responses. The analysis further revealed that daratumumab and selinexor have anti-correlated mechanisms of resistance, and treatment with a selinexor-based regimen immediately after a daratumumab-containing regimen was associated with improved survival in three independent clinical trials, supporting an evolutionary-based strategy involving sequential therapy. These findings suggest that this unique repository and computational framework can be leveraged to inform underlying biology and to identify therapeutic strategies to improve treatment of MM.
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- 2024
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12. β-Catenin Activation Reprograms Ammonia Metabolism to Promote Senescence Resistance in Hepatocellular Carcinoma.
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Wang Y, Cheng C, Lu Y, Lian Z, Liu Q, Xu Y, Li Y, Li H, Zhang L, Jiang X, Li B, and Yu D
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- Animals, Humans, Male, Mice, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glutamate Dehydrogenase metabolism, Glutamate Dehydrogenase genetics, Mice, Nude, Prognosis, Ammonia metabolism, beta Catenin metabolism, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular genetics, Cellular Senescence, Liver Neoplasms metabolism, Liver Neoplasms pathology, Liver Neoplasms genetics
- Abstract
Hepatocellular carcinoma (HCC) is a typical tumor that undergoes metabolic reprogramming, differing from normal liver tissue in glucose, lipid, nucleic acid, and amino acid metabolism. Although ammonia is a toxic metabolic by-product, it has also been recently recognized as a signaling molecule to activate lipid metabolism, and it can be a nitrogen source for biosynthesis to support tumorigenesis. In this study, we revealed that β-catenin activation increases ammonia production in HCC mainly by stimulating glutaminolysis. β-Catenin/LEF1 activated the transcription of the glutamate dehydrogenase GLUD1, which then promoted ammonia utilization to enhance the production of glutamate, aspartate, and proline as evidenced by 15NH4Cl metabolic flux. β-Catenin/TCF4 induced the transcription of SLC4A11, an ammonia transporter, to excrete excess ammonia. SLC4A11 was upregulated in HCC tumor tissues, and high SLC4A11 expression was associated with poor prognosis and advanced disease stages. Loss of SLC4A11 induced HCC cell senescence in vitro by blocking ammonia excretion and reduced β-catenin-driven tumor growth in vivo. Furthermore, elevated levels of plasma ammonia promoted the progression of β-catenin mutant HCC, which was impeded by SLC4A11 deficiency. Downregulation of SLC4A11 led to ammonia accumulation in tumor interstitial fluid and decreased plasma ammonia levels in HCC with activated β-catenin. Altogether, this study indicates that β-catenin activation reprograms ammonia metabolism and that blocking ammonia excretion by targeting SLC4A11 could be a promising approach to induce senescence in β-catenin mutant HCC., Significance: Ammonia metabolism reprogramming mediated by aberrant activation of β-catenin induces resistance to senescence in HCC and can be targeted by inhibiting SLC4A11 as a potential therapy for β-catenin mutant liver cancer., (©2024 American Association for Cancer Research.)
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- 2024
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13. Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer.
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Shi Q, Xu G, Jiang Y, Yang J, Han X, Wang Q, Li Y, Zhang Z, Wang K, Peng H, Chen F, Ma Y, Zhao L, Chen Y, Liu Z, Yang L, Jia X, Wen T, Tong Z, Cui X, and Li F
- Subjects
- Humans, Phosphorylation, Protein Kinase C-alpha metabolism, Cell Line, Tumor, Phosphoinositide Phospholipase C genetics, Phosphoinositide Phospholipase C metabolism, Gene Expression Regulation, Neoplastic, Cell Proliferation, Minichromosome Maintenance Complex Component 7 genetics, Minichromosome Maintenance Complex Component 7 metabolism, Esophageal Neoplasms pathology, Esophageal Squamous Cell Carcinoma metabolism, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Phospholipase C epsilon 1 (PLCE1) is a well-established susceptibility gene for esophageal squamous cell carcinoma (ESCC). Identification of the underlying mechanism(s) regulated by PLCE1 could lead to a better understanding of ESCC tumorigenesis. In this study, we found that PLCE1 enhances tumor progression by regulating the replicative helicase MCM7 via two pathways. PLCE1 activated PKCα-mediated phosphorylation of E2F1, which led to the transcriptional activation of MCM7 and miR-106b-5p. The increased expression of miR-106b-5p, located in intron 13 of MCM7, suppressed autophagy and apoptosis by targeting Beclin-1 and RBL2, respectively. Moreover, MCM7 cooperated with the miR-106b-25 cluster to promote PLCE1-dependent cell-cycle progression both in vivo and in vitro. In addition, PLCE1 potentiated the phosphorylation of MCM7 at six threonine residues by the atypical kinase RIOK2, which promoted MCM complex assembly, chromatin loading, and cell-cycle progression. Inhibition of PLCE1 or RIOK2 hampered MCM7-mediated DNA replication, resulting in G1-S arrest. Furthermore, MCM7 overexpression in ESCC correlated with poor patient survival. Overall, these findings provide insights into the role of PLCE1 as an oncogenic regulator, a promising prognostic biomarker, and a potential therapeutic target in ESCC., Significance: PLCE1 promotes tumor progression in ESCC by activating PKCα-mediated phosphorylation of E2F1 to upregulate MCM7 and miR-106b-5p expression and by potentiating MCM7 phosphorylation by RIOK2., (©2023 American Association for Cancer Research.)
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- 2024
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14. A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy.
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Yang J, Liu Q, and Shyr Y
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- Humans, Feedback, Reproducibility of Results, Immunotherapy, Macrophages, Biomarkers, Tumor genetics, Mutation, T-Lymphocytes, Neoplasms genetics, Neoplasms therapy
- Abstract
Although considerable efforts have been dedicated to identifying predictive signatures for immune checkpoint inhibitor (ICI) treatment response, current biomarkers suffer from poor generalizability and reproducibility across different studies and cancer types. The integration of large-scale multiomics studies holds great promise for discovering robust biomarkers and shedding light on the mechanisms of immune resistance. In this study, we conducted the most extensive meta-analysis involving 3,037 ICI-treated patients with genetic and/or transcriptomics profiles across 14 types of solid tumor. The comprehensive analysis uncovered both known and novel reliable signatures associated with ICI treatment outcomes. The signatures included tumor mutational burden (TMB), IFNG and PDCD1 expression, and notably, interactions between macrophages and T cells driving their activation and recruitment. Independent data from single-cell RNA sequencing and dynamic transcriptomic profiles during the ICI treatment provided further evidence that enhanced cross-talk between macrophages and T cells contributes to ICI response. A multivariable model based on eight nonredundant signatures significantly outperformed existing models in five independent validation datasets representing various cancer types. Collectively, this study discovered biomarkers predicting ICI response that highlight the contribution of immune cell networks to immunotherapy efficacy and could help guide patient treatment., Significance: Identification of robust immunogenomic connections, particularly macrophage T-cell interactions, in a large-scale pan-cancer meta-analysis and development of a predictive model for immunotherapy response that outperformed existing models could facilitate clinical decision-making., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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15. Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib.
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Zeng X, Zhao F, Jia J, Ma X, Jiang Q, Zhang R, Li C, Wang T, Liu W, Hao Y, Tao K, Lou Z, and Zhang P
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- Humans, Imatinib Mesylate pharmacology, Tumor Suppressor Protein p53 genetics, Pyrimidines pharmacology, Pyrimidines therapeutic use, Apoptosis, Cell Line, Tumor, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-kit metabolism, Proto-Oncogene Proteins c-bcl-6 genetics, Proto-Oncogene Proteins c-bcl-6 metabolism, Gastrointestinal Stromal Tumors drug therapy, Gastrointestinal Stromal Tumors genetics, Gastrointestinal Stromal Tumors metabolism, Gastrointestinal Neoplasms drug therapy, Gastrointestinal Neoplasms genetics, Gastrointestinal Neoplasms metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use
- Abstract
Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4 to 6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST., Significance: BCL6 drives resistance to imatinib by inhibiting p53-mediated apoptosis and can be targeted in combination with imatinib to synergistically suppress tumor growth, providing a therapeutic strategy for treating gastrointestinal stromal tumor., (©2023 American Association for Cancer Research.)
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- 2023
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16. DNA Methylation-Based Testing in Peripheral Blood Mononuclear Cells Enables Accurate and Early Detection of Colorectal Cancer.
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Xie Y, Li P, Sun D, Qi Q, Ma S, Zhao Y, Zhang S, Wang T, Wang J, Li S, Gong T, Xu H, Xiong M, Li G, You C, Luo Z, Li J, Wang C, and Du L
- Subjects
- Humans, Leukocytes, Mononuclear metabolism, DNA genetics, Early Detection of Cancer, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, DNA Methylation, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics
- Abstract
An effective blood-based method for the diagnosis of colorectal cancer has not yet been developed. Molecular alterations of immune cells occur early in tumorigenesis, providing the theoretical underpinning for early cancer diagnosis based on immune cell profiling. Therefore, we aimed to develop an effective detection method based on peripheral blood mononuclear cells (PBMC) to improve the diagnosis of colorectal cancer. Analysis of the genome-wide methylation landscape of PBMCs from patients with colorectal cancer and healthy controls by microarray, pyrosequencing, and targeted bisulfite sequencing revealed five DNA methylation markers for colorectal cancer diagnosis, especially early-stage colorectal cancer. A single-tube multiple methylation-specific quantitative PCR assay (multi-msqPCR) for simultaneous detection of five methylation markers was established, which allowed quantitative analysis of samples with as little as 0.1% PBMC DNA and had better discriminative performance than single-molecule detection. Then, a colorectal cancer diagnostic model (CDM) based on methylation markers and the multi-msqPCR method was constructed that achieved high accuracy for early-stage colorectal cancer (AUC = 0.91; sensitivity = 81.18%; specificity = 89.39%), which was improved compared with CEA (AUC = 0.79). The CDM also enabled a high degree of discrimination for advanced adenoma cases (AUC = 0.85; sensitivity = 63.04%). Follow-up data also demonstrated that the CDM could identify colorectal cancer potential up to 2 years before currently used diagnostic methods. In conclusion, the approach constructed in this study based on PBMC-derived DNA methylation markers and a multi-msqPCR method is a promising and easily implementable diagnostic method for early-stage colorectal cancer., Significance: Development of a diagnostic model for early colorectal cancer based on epigenetic analysis of PBMCs supports the utility of altered DNA methylation in immune cells for cancer diagnosis., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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17. GTP Cyclohydrolase Drives Breast Cancer Development and Promotes EMT in an Enzyme-Independent Manner.
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Wang Z, Zhang N, Zhang M, Jiang Y, Ng AS, Bridges E, Zhang W, Zeng X, Luo Q, Liang J, Győrffy B, Hublitz P, Liang Z, Fischer R, Kerr D, Harris AL, and Cai S
- Subjects
- Animals, Female, Humans, Mice, Biopterins analogs & derivatives, Biopterins metabolism, Cell Line, Tumor, Cell Proliferation, HSP90 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins genetics, Mice, Nude, Receptor, ErbB-2 metabolism, Receptor, ErbB-2 genetics, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms genetics, Vimentin metabolism, Breast Neoplasms pathology, Breast Neoplasms metabolism, Breast Neoplasms genetics, Epithelial-Mesenchymal Transition, GTP Cyclohydrolase metabolism, GTP Cyclohydrolase genetics
- Abstract
GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. The catalysis of BH4 biosynthesis is tightly regulated for physiological neurotransmission, inflammation, and vascular tone. Paradoxically, BH4 has emerged as an oncometabolite regulating tumor growth, but the effects on tumor development remain controversial. Here, we found that GCH1 potentiated the growth of triple-negative breast cancer (TNBC) and HER2+ breast cancer and transformed nontumor breast epithelial cells. Independent of BH4 production, GCH1 protein induced epithelial-to-mesenchymal transition by binding to vimentin (Vim), which was mediated by HSP90. Conversely, GCH1 ablation impaired tumor growth, suppressed Vim in TNBC, and inhibited EGFR/ERK signaling while activating the p53 pathway in estrogen receptor-positive tumor cells. GCH1 deficiency increases tumor cell sensitivity to HSP90 inhibition and endocrine treatments. In addition, high GCH1 correlated with poor breast cancer survival. Together, this study reveals an enzyme-independent oncogenic role of GCH1, presenting it as a potential target for therapeutic development., Significance: GTP cyclohydrolase functions as an oncogene in breast cancer and binds vimentin to induce epithelial-to-mesenchymal transition independently of its enzyme activity, which confers targetable vulnerabilities for developing breast cancer treatment strategies., (©2023 American Association for Cancer Research.)
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- 2023
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18. PTTG1 Reprograms Asparagine Metabolism to Promote Hepatocellular Carcinoma Progression.
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Zhou Q, Li L, Sha F, Lei Y, Tian X, Chen L, Chen Y, Liu H, and Guo Y
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- Animals, Mice, Asparagine genetics, Asparagine metabolism, Gene Expression Regulation, Neoplastic, Hepatitis B virus metabolism, Prognosis, TOR Serine-Threonine Kinases metabolism, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology
- Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, suggesting it could play an important role in hepatocellular carcinogenesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)-induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN- and HBx-induced hepatocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, asparaginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC., Significance: PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression., (©2023 American Association for Cancer Research.)
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- 2023
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19. FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner.
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He F, Tay AHM, Calandigary A, Malki E, Suzuki S, Liu T, Wang Q, Fernández-Moro C, Kaisso M, Olofsson-Sahl P, Melssen M, Sze SK, Björnstedt M, Löhr MJ, Karlsson MCI, Heuchel R, and Sarhan D
- Subjects
- Mice, Male, Female, Animals, Proteomics, T-Cell Exhaustion, Myeloid Cells, Mice, Knockout, Tumor Microenvironment, Pancreatic Neoplasms genetics
- Abstract
Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy., Significance: FPR2 is a sex-dependent mediator of macrophage function in pancreatic cancer and can be targeted to reprogram macrophages and stimulate antitumor immunity in females., (©2023 American Association for Cancer Research.)
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- 2023
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20. USP48 Stabilizes Gasdermin E to Promote Pyroptosis in Cancer.
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Ren Y, Feng M, Hao X, Liu X, Li J, Li P, Gao J, Qi Q, Du L, Wang C, Wang Q, and Wang Y
- Subjects
- Animals, Mice, Apoptosis, Caspases metabolism, Gasdermins, Tumor Microenvironment, Ubiquitin-Specific Proteases metabolism, Neoplasms genetics, Pyroptosis physiology
- Abstract
Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress tumor development and induce antitumor immunity, and activating pyroptosis is a potential treatment strategy for cancer. To uncover approaches to harness the anticancer effects of pyroptosis, we aimed to identify regulators of pyroptosis in cancer. A CRISPR-Cas9 screen identified that loss of USP48, a deubiquitinating enzyme, significantly inhibited cell pyroptosis. USP48 promoted pyroptosis by stabilizing gasdermin E (GSDME). USP48 bound GSDME and removed K48-linked ubiquitination at positions K120 and K189. Clinical tissue testing confirmed that the expression of USP48 positively correlated with GSDME and pyroptosis-related factors. Single-cell sequencing showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment were inhibited after USP48 knockout. Finally, overexpression of USP48 enhanced the therapeutic efficacy of programmed cell death protein 1 inhibitors in tumors in mouse models. Together, these findings define a pyroptosis regulation pathway and indicate that pharmacologic activation of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis and improve response to immunotherapy., Significance: USP48 promotes pyroptosis by deubiquitinating GSDME and enhances antitumor immunity, indicating that increasing USP48 activity may be a future therapeutic strategy for treating cancer., (©2023 American Association for Cancer Research.)
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- 2023
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21. Sustained Aurora Kinase B Expression Confers Resistance to PI3K Inhibition in Head and Neck Squamous Cell Carcinoma.
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Shah PA, Sambandam V, Fernandez AM, Zhao H, Mazumdar T, Shen L, Wang Q, Ahmed KM, Ghosh S, Frederick MJ, Wang J, and Johnson FM
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- Humans, Squamous Cell Carcinoma of Head and Neck genetics, Aurora Kinase B genetics, Proto-Oncogene Proteins c-akt metabolism, Cell Line, Tumor, Receptor, Notch1 metabolism, Cell Proliferation, Phosphatidylinositol 3-Kinases metabolism, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics
- Abstract
Tumor suppressor mutations in head and neck squamous cell carcinoma (HNSCC) dominate the genomic landscape, hindering the development of effective targeted therapies. Truncating and missense mutations in NOTCH1 are frequent in HNSCC, and inhibition of PI3K can selectively target NOTCH1 mutant (NOTCH1MUT) HNSCC cells. In this study, we identify several proteins that are differentially regulated in HNSCC cells after PI3K inhibition based on NOTCH1MUT status. Expression of Aurora kinase B (Aurora B), AKT, and PDK1 following PI3K inhibition was significantly lower in NOTCH1MUT cell lines than in wild-type NOTCH1 (NOTCH1WT) cells or NOTCH1MUT cells with acquired resistance to PI3K inhibition. Combined inhibition of PI3K and Aurora B was synergistic, enhancing apoptosis in vitro and leading to durable tumor regression in vivo. Overexpression of Aurora B in NOTCH1MUT HNSCC cells led to resistance to PI3K inhibition, while Aurora B knockdown increased sensitivity of NOTCH1WT cells. In addition, overexpression of Aurora B in NOTCH1MUT HNSCC cells increased total protein levels of AKT and PDK1. AKT depletion in NOTCH1WT cells and overexpression in NOTCH1MUT cells similarly altered sensitivity to PI3K inhibition, and manipulation of AKT levels affected PDK1 but not Aurora B levels. These data define a novel pathway in which Aurora B upregulates AKT that subsequently increases PDK1 selectively in NOTCH1MUT cells to mediate HNSCC survival in response to PI3K inhibition. These findings may lead to an effective therapeutic approach for HNSCC with NOTCH1MUT while sparing normal cells., Significance: Aurora B signaling facilitates resistance to PI3K inhibition in head and neck squamous cell carcinoma, suggesting that combined inhibition of PI3K and Aurora kinase is a rational therapeutic strategy to overcome resistance., (©2022 American Association for Cancer Research.)
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- 2022
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22. Quantitative Micro-Elastography Enables In Vivo Detection of Residual Cancer in the Surgical Cavity during Breast-Conserving Surgery.
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Gong P, Chin SL, Allen WM, Ballal H, Anstie JD, Chin L, Ismail HM, Zilkens R, Lakhiani DD, McCarthy M, Fang Q, Firth D, Newman K, Thomas C, Li J, Sanderson RW, Foo KY, Yeomans C, Dessauvagie BF, Latham B, Saunders CM, and Kennedy BF
- Subjects
- Female, Humans, Breast Neoplasms pathology, Breast Neoplasms surgery, Margins of Excision, Elasticity Imaging Techniques methods, Mastectomy, Segmental methods, Neoplasm, Residual diagnostic imaging
- Abstract
Breast-conserving surgery (BCS) is commonly used for the treatment of early-stage breast cancer. Following BCS, approximately 20% to 30% of patients require reexcision because postoperative histopathology identifies cancer in the surgical margins of the excised specimen. Quantitative micro-elastography (QME) is an imaging technique that maps microscale tissue stiffness and has demonstrated a high diagnostic accuracy (96%) in detecting cancer in specimens excised during surgery. However, current QME methods, in common with most proposed intraoperative solutions, cannot image cancer directly in the patient, making their translation to clinical use challenging. In this proof-of-concept study, we aimed to determine whether a handheld QME probe, designed to interrogate the surgical cavity, can detect residual cancer directly in the breast cavity in vivo during BCS. In a first-in-human study, 21 BCS patients were scanned in vivo with the QME probe by five surgeons. For validation, protocols were developed to coregister in vivo QME with postoperative histopathology of the resected tissue to assess the capability of QME to identify residual cancer. In four cavity aspects presenting cancer and 21 cavity aspects presenting benign tissue, QME detected elevated stiffness in all four cancer cases, in contrast to low stiffness observed in 19 of the 21 benign cases. The results indicate that in vivo QME can identify residual cancer by directly imaging the surgical cavity, potentially providing a reliable intraoperative solution that can enable more complete cancer excision during BCS., Significance: Optical imaging of microscale tissue stiffness enables the detection of residual breast cancer directly in the surgical cavity during breast-conserving surgery, which could potentially contribute to more complete cancer excision., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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23. Targeting Plk1 Sensitizes Pancreatic Cancer to Immune Checkpoint Therapy.
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Zhang Z, Cheng L, Li J, Qiao Q, Karki A, Allison DB, Shaker N, Li K, Utturkar SM, Atallah Lanman NM, Rao X, Rychahou P, He D, Konieczny SF, Wang C, Shao Q, Evers BM, and Liu X
- Subjects
- Acute Disease, Animals, B7-H1 Antigen, Cell Cycle Proteins, Ceruletide therapeutic use, Humans, Immune Checkpoint Inhibitors, Mice, NF-kappa B metabolism, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Polo-Like Kinase 1, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Pancreatitis
- Abstract
Polo-like kinase 1 (Plk1) plays an important role in cell-cycle regulation. Recent work has suggested that Plk1 could be a biomarker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in patients with PDAC. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NF-κB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NF-κB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an antitumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NF-κB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC., Significance: Inhibition of Plk1 induces upregulation of PD-L1 expression in pancreatic ductal adenocarcinoma, stimulating antitumor immunity and sensitizing tumors to immunotherapy., (©2022 American Association for Cancer Research.)
- Published
- 2022
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24. GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors.
- Author
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Li Y, Li B, Xu Y, Qian L, Xu T, Meng G, Li H, Wang Y, Zhang L, Jiang X, Liu Q, Xie Y, Cheng C, Sun B, and Yu D
- Subjects
- Animals, Humans, Mice, Antioxidants, Aspartate Aminotransferases genetics, Aspartate Aminotransferases metabolism, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glutaminase genetics, Glutaminase metabolism, Glutamine metabolism, Glutathione metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, TOR Serine-Threonine Kinases metabolism, Aspartate Aminotransferase, Mitochondrial metabolism, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Liver Neoplasms metabolism, Liver Neoplasms pathology
- Abstract
Hepatocellular carcinoma (HCC) is one of the primary liver malignancies with a poor prognosis. Glutamic-oxaloacetic transaminase 2 (GOT2) is a highly tissue-specific gene in the liver, but the roles GOT2 plays in the progression of HCC remain unclear. Here, we report that GOT2 is downregulated in HCC tumor tissues and that low expression of GOT2 is associated with advanced progression and poor prognosis. In HCC cells, knockdown of GOT2 promoted proliferation, migration, and invasion. In mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, silencing of GOT2 enhanced glutaminolysis, nucleotide synthesis, and glutathione synthesis by reprogramming glutamine metabolism to support the cellular antioxidant system, which activated the PI3K/AKT/mTOR pathway to contribute to HCC progression. Furthermore, HCC with low expression of GOT2 was highly dependent on glutamine metabolism and sensitive to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, GOT2 is involved in glutamine metabolic reprogramming to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC., Significance: Altered glutamine metabolism induced by GOT2 loss supports HCC growth and metastasis but confers a targetable vulnerability to glutaminase inhibitors., (©2022 American Association for Cancer Research.)
- Published
- 2022
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25. Addressing Common Misuses and Pitfalls of P values in Biomedical Research.
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Wang M and Long Q
- Subjects
- Bias, Electronic Health Records, Humans, Reproducibility of Results, Research Design, Biomedical Research methods
- Abstract
In recent years, there has been a growing recognition that P values, albeit useful in reporting data analysis results, have often been misused or misinterpreted in biomedical research. The emergence of big health data such as genomics data and electronic health records, sometimes combined with inadequate experimental design, has exacerbated this problem, which has become a major cause of the ongoing crisis in reproducibility in biomedical research. We aim to shed light and raise awareness of common misuses and pitfalls of P values and discuss potential mitigation strategies that leverage state-of-the-art statistical methods. The best practices always start with a sound study design including a robust data collection strategy to minimize data bias and a carefully thought-out analysis plan that can address potential misuses and pitfalls of P values. We highly encourage biomedical researchers to engage and involve statisticians from the very beginning of their studies., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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26. Computational Identification of Preneoplastic Cells Displaying High Stemness and Risk of Cancer Progression.
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Liu T, Zhao X, Lin Y, Luo Q, Zhang S, Xi Y, Chen Y, Lin L, Fan W, Yang J, Ma Y, Maity AK, Huang Y, Wang J, Chang J, Lin D, Teschendorff AE, and Wu C
- Subjects
- Animals, Biomarkers, Tumor genetics, DNA Methylation, Gene Expression Regulation, Neoplastic, Humans, Mice, Esophageal Neoplasms pathology, Esophageal Squamous Cell Carcinoma genetics
- Abstract
Evidence points toward the differentiation state of cells as a marker of cancer risk and progression. Measuring the differentiation state of single cells in a preneoplastic population could thus enable novel strategies for early detection and risk prediction. Recent maps of somatic mutagenesis in normal tissues from young healthy individuals have revealed cancer driver mutations, indicating that these do not correlate well with differentiation state and that other molecular events also contribute to cancer development. We hypothesized that the differentiation state of single cells can be measured by estimating the regulatory activity of the transcription factors (TF) that control differentiation within that cell lineage. To this end, we present a novel computational method called CancerStemID that estimates a stemness index of cells from single-cell RNA sequencing data. CancerStemID is validated in two human esophageal squamous cell carcinoma (ESCC) cohorts, demonstrating how it can identify undifferentiated preneoplastic cells whose transcriptomic state is overrepresented in invasive cancer. Spatial transcriptomics and whole-genome bisulfite sequencing demonstrated that differentiation activity of tissue-specific TFs was decreased in cancer cells compared with the basal cell-of-origin layer and established that differentiation state correlated with differential DNA methylation at the promoters of these TFs, independently of underlying NOTCH1 and TP53 mutations. The findings were replicated in a mouse model of ESCC development, and the broad applicability of CancerStemID to other cancer-types was demonstrated. In summary, these data support an epigenetic stem-cell model of oncogenesis and highlight a novel computational strategy to identify stem-like preneoplastic cells that undergo positive selection., Significance: This study develops a computational strategy to dissect the heterogeneity of differentiation states within a preneoplastic cell population, allowing identification of stem-like cells that may drive cancer progression., (©2022 American Association for Cancer Research.)
- Published
- 2022
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27. Identification of Active Bronchioalveolar Stem Cells as the Cell of Origin in Lung Adenocarcinoma.
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Yin H, Jing B, Xu D, Guo W, Sun B, Zhang J, Liao Y, Song H, Wang T, Liu S, Kuang Y, Hu M, Li K, Zhang S, Zhang H, Xu J, Li X, Du J, Wu Y, Wu Y, Wang Q, Yao F, Chin YE, Zhou BP, and Deng J
- Subjects
- Animals, Carcinogenesis, Cell Transformation, Neoplastic, ErbB Receptors genetics, ErbB Receptors metabolism, Humans, Lung metabolism, Mice, Mice, Knockout, NF-kappa B metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung metabolism, Lung Neoplasms genetics, Lung Neoplasms metabolism, Stem Cells
- Abstract
While initiation is established as a critical step in tumorigenesis, the identity of the cell of origin for lung adenocarcinoma and the mechanism controlling susceptibility to initiation remain elusive. Here we show that lung tumor suppressor Gprc5a-knockout (KO) mice are susceptible to initiation of lung tumorigenesis. Bronchioalveolar stem cells (BASC) and alveolar type 2 (AT2) cells were aberrantly expanded in Gprc5a-KO mouse lungs compared with those in wild-type (WT) mice, suggesting that Gprc5a-KO might confer susceptibility to initiation by increasing the cell of origin in mouse lungs. BASCs from Gprc5a-KO mice (KO-BASC) exhibited significantly increased stemness and self-renewal potential and reduced differentiation capacity compared with BASCs from WT mice (WT-BASC). AT2 cells did not possess self-renewal potential regardless of Gprc5a status. KO-BASCs expressed a stem-like gene profile with upregulated Abcg2, EGFR, and NF-κB signaling compared with WT-BASCs. Blockade of EGFR and NF-κB signaling inhibited both expansion of BASC and AT2 cells and lung tumorigenesis. Abcg2 was expressed in active KO-BASCs as well as in lung tumor cells but not in quiescent WT-BASCs or AT2 cells, supporting that lung adenocarcinoma cells are derived from Abcg2-positive KO-BASCs (active). Taken together, Gprc5a deletion leads to expansion of active BASCs via dysregulated EGFR and NF-κB signaling that confers susceptibility to initiation of lung tumorigenesis, marking Abcg2-positive BASCs as candidate cell of origin for lung adenocarcinoma., Significance: Identification of active bronchioalveolar stem cells as lung adenocarcinoma cells of origin provides insights into mechanisms of lung tumorigenesis and could facilitate development of effective strategies for cancer prevention and therapy. See related commentary by Osborne and Minna, p. 972., (©2022 American Association for Cancer Research.)
- Published
- 2022
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28. The Protein Kinase Activity of NME7 Activates Wnt/β-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma.
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Ren X, Rong Z, Liu X, Gao J, Xu X, Zi Y, Mu Y, Guan Y, Cao Z, Zhang Y, Zeng Z, Fan Q, Wang X, Pei Q, Wang X, Xin H, Li Z, Nie Y, Qiu Z, Li N, Sun L, and Deng Y
- Subjects
- Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Cell Proliferation, Humans, Liver Neoplasms pathology, Carbon metabolism, Carcinoma, Hepatocellular genetics, Liver Neoplasms genetics, Nucleoside-Diphosphate Kinase metabolism, Protein Kinases metabolism, Wnt Signaling Pathway genetics, beta Catenin metabolism
- Abstract
Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/β-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/β-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo , whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3β to promote β-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of β-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, β-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/β-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC. SIGNIFICANCE: The identification of NME7 as an activator of Wnt/β-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease., (©2021 American Association for Cancer Research.)
- Published
- 2022
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29. A pan-cancer immunogenomic atlas for immune checkpoint blockade immunotherapy.
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Yang J, Zhao S, Wang J, Sheng Q, Liu Q, and Shyr Y
- Abstract
The ability to identify robust genomic signatures that predict response to immune checkpoint blockade is restricted by limited sample sizes and ungeneralizable performance across cohorts. To address these challenges, we established Cancer-Immu (http://bioinfo.vanderbilt.edu/database/Cancer-Immu/) a comprehensive platform that integrates large-scale multidimensional omics data, including genetic, bulk, and single-cell transcriptomic, proteomic, and dynamic genomic profiles, with clinical phenotypes to explore consistent and rare immunogenomic connections. Currently Cancer-Immu has incorporated data for 3,652 samples for 16 cancer types. It provides easy access to immunogenomic data and empowers researchers to translate omics datasets into biological insights and clinical applications.
- Published
- 2021
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30. MYC-Activated LncRNA MNX1-AS1 Promotes the Progression of Colorectal Cancer by Stabilizing YB1.
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Wu QN, Luo XJ, Liu J, Lu YX, Wang Y, Qi J, Liu ZX, Huang QT, Liu ZK, Lu JB, Jin Y, Pu HY, Hu PS, Zheng JB, Zeng ZL, Ju HQ, Xie D, Zhao Q, and Xu R
- Subjects
- Animals, Apoptosis, Cell Proliferation, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Disease Progression, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Prognosis, Proto-Oncogene Proteins c-myc genetics, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Y-Box-Binding Protein 1 genetics, Y-Box-Binding Protein 1 metabolism, Colorectal Neoplasms pathology, Gene Expression Regulation, Neoplastic, Homeodomain Proteins genetics, Proto-Oncogene Proteins c-myc metabolism, RNA, Antisense genetics, RNA, Long Noncoding genetics, Transcription Factors genetics, Y-Box-Binding Protein 1 chemistry
- Abstract
Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer-related lncRNA, MNX1-AS1 . MNX1 - AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1 - AS1 promotes the proliferation of colorectal cancer cells. MNX1 - AS1 bound to and activated Y-box-binding protein 1 (YB1), a multifunctional RNA/DNA-binding protein, and prevented its ubiquitination and degradation. A marked overlap between genes that are differentially expressed in MNX1 - AS1 knockdown cells and transcriptional targets of YB1 was observed. YB1 knockdown mimicked the loss of viability phenotype observed upon depletion of MNX1 - AS1 . In addition, MYC bound the promoter of the MNX1 - AS1 locus and activated its transcription. In vivo experiments showed that ASO inhibited MNX1 - AS1 , which suppressed the proliferation of colorectal cancer cells in both cell-based and patient-derived xenograft models. Collectively, these findings suggest that the MYC- MNX1-AS1 -YB1 axis might serve as a potential biomarker and therapeutic target in colorectal cancer. SIGNIFICANCE: This study highlights the discovery of a novel colorectal cancer biomarker and therapeutic target, MNX1 - AS1 , a long noncoding RNA that drives proliferation via a MYC/ MNX1-AS1 /YB1 signaling pathway. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2636/F1.large.jpg., (©2021 American Association for Cancer Research.)
- Published
- 2021
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31. Estrogen Receptor β-Mediated Inhibition of Actin-Based Cell Migration Suppresses Metastasis of Inflammatory Breast Cancer.
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Thomas C, Karagounis IV, Srivastava RK, Vrettos N, Nikolos F, Francois N, Huang M, Gong S, Long Q, Kumar S, Koumenis C, Krishnamurthy S, Ueno NT, Chakrabarti R, and Maity A
- Subjects
- Actin Cytoskeleton metabolism, Animals, Cohort Studies, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Estrogen Receptor beta genetics, Female, Gene Knockout Techniques, HEK293 Cells, Humans, Inflammatory Breast Neoplasms genetics, Inflammatory Breast Neoplasms pathology, MCF-7 Cells, Mice, Neoplasm Metastasis genetics, Transfection, Tumor Burden genetics, Xenograft Model Antitumor Assays, Actins metabolism, Cell Movement genetics, Estrogen Receptor beta metabolism, Inflammatory Breast Neoplasms metabolism, Signal Transduction genetics
- Abstract
Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ERα) negativity. Here we explored the role of the second ER subtype, ERβ, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERβ in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein-coupled receptors and downstream effectors that activate Rho GTPases. Analysis of preclinical mouse models of IBC revealed decreased metastasis of IBC tumors when ERβ was expressed or activated by chemical agonists. Our findings support a tumor-suppressive role of ERβ by demonstrating the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis. On the basis of these findings, we propose ERβ as a potentially novel biomarker and therapeutic target that can inhibit IBC metastasis and reduce its associated mortality. SIGNIFICANCE: These findings demonstrate the capacity of ERβ to elicit antimetastatic effects in highly aggressive inflammatory breast cancer and propose ERβ and the identified associated genes as potential therapeutic targets in this disease., (©2021 American Association for Cancer Research.)
- Published
- 2021
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32. Dysregulated Glutamate Transporter SLC1A1 Propels Cystine Uptake via Xc - for Glutathione Synthesis in Lung Cancer.
- Author
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Guo W, Li K, Sun B, Xu D, Tong L, Yin H, Liao Y, Song H, Wang T, Jing B, Hu M, Liu S, Kuang Y, Ling J, Li Q, Wu Y, Wang Q, Yao F, Zhou BP, Lin SH, and Deng J
- Subjects
- Animals, Antiporters metabolism, Cell Death, Cell Line, Tumor, Glutamine deficiency, Lung Neoplasms etiology, Lung Neoplasms pathology, Mice, Mice, Nude, Oxidative Stress, Receptors, G-Protein-Coupled, Stress, Physiological, Up-Regulation, Cystine metabolism, Excitatory Amino Acid Transporter 3 metabolism, Glutamic Acid metabolism, Glutathione biosynthesis, Lung Neoplasms metabolism
- Abstract
Cancer cells need to generate large amounts of glutathione (GSH) to buffer oxidative stress during tumor development. A rate-limiting step for GSH biosynthesis is cystine uptake via a cystine/glutamate antiporter Xc
- . Xc- is a sodium-independent antiporter passively driven by concentration gradients from extracellular cystine and intracellular glutamate across the cell membrane. Increased uptake of cystine via Xc- in cancer cells increases the level of extracellular glutamate, which would subsequently restrain cystine uptake via Xc- . Cancer cells must therefore evolve a mechanism to overcome this negative feedback regulation. In this study, we report that glutamate transporters, in particular SLC1A1, are tightly intertwined with cystine uptake and GSH biosynthesis in lung cancer cells. Dysregulated SLC1A1, a sodium-dependent glutamate carrier, actively recycled extracellular glutamate into cells, which enhanced the efficiency of cystine uptake via Xc- and GSH biosynthesis as measured by stable isotope-assisted metabolomics. Conversely, depletion of glutamate transporter SLC1A1 increased extracellular glutamate, which inhibited cystine uptake, blocked GSH synthesis, and induced oxidative stress-mediated cell death or growth inhibition. Moreover, glutamate transporters were frequently upregulated in tissue samples of patients with non-small cell lung cancer. Taken together, active uptake of glutamate via SLC1A1 propels cystine uptake via Xc- for GSH biosynthesis in lung tumorigenesis. SIGNIFICANCE: Cellular GSH in cancer cells is not only determined by upregulated Xc- but also by dysregulated glutamate transporters, which provide additional targets for therapeutic intervention., (©2020 American Association for Cancer Research.)- Published
- 2021
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33. Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.
- Author
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Sun Y, Meyers BA, Czako B, Leonard P, Mseeh F, Harris AL, Wu Q, Johnson S, Parker CA, Cross JB, Di Francesco ME, Bivona BJ, Bristow CA, Burke JP, Carrillo CC, Carroll CL, Chang Q, Feng N, Gao G, Gera S, Giuliani V, Huang JK, Jiang Y, Kang Z, Kovacs JJ, Liu CY, Lopez AM, Ma X, Mandal PK, McAfoos T, Miller MA, Mullinax RA, Peoples M, Ramamoorthy V, Seth S, Spencer ND, Suzuki E, Williams CC, Yu SS, Zuniga AM, Draetta GF, Marszalek JR, Heffernan TP, Kohl NE, and Jones P
- Subjects
- Acrylamides pharmacology, Aniline Compounds pharmacology, Animals, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation drug effects, ErbB Receptors genetics, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, Mutation, Neoplasms, Experimental genetics, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Neoplasms, Experimental pathology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 antagonists & inhibitors
- Abstract
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo . Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib., (©2020 American Association for Cancer Research.)
- Published
- 2020
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34. KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis.
- Author
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Li G, Kanagasabai T, Lu W, Zou MR, Zhang SM, Celada SI, Izban MG, Liu Q, Lu T, Ballard BR, Zhou X, Adunyah SE, Matusik RJ, Yan Q, and Chen Z
- Subjects
- Animals, Carcinogenesis pathology, Cell Line, Tumor, DNA-Binding Proteins metabolism, Humans, Male, Mice, Mice, Knockout, Prostatic Neoplasms metabolism, Signal Transduction physiology, Carcinogenesis metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Nuclear Proteins metabolism, Phosphatidylinositol 3-Kinases metabolism, Prostatic Neoplasms pathology, Proto-Oncogene Proteins c-akt metabolism, Repressor Proteins metabolism
- Abstract
KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b . Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten -null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo . KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. SIGNIFICANCE: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer., (©2020 American Association for Cancer Research.)
- Published
- 2020
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35. The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity.
- Author
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Carles A, Trigo-Gonzalez G, Cao Q, Cheng SG, Moksa M, Bilenky M, Huntsman DG, Morin GB, and Hirst M
- Subjects
- Cell Line, Tumor, Female, Granulosa Cell Tumor metabolism, Humans, Mutation, Missense, Point Mutation, Protein Binding, DNA metabolism, Forkhead Box Protein L2 genetics, Forkhead Box Protein L2 metabolism, Gene Expression Regulation, Neoplastic genetics, Granulosa Cell Tumor genetics
- Abstract
The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2
WT - and V5-FOXL2C134W -inducible isogenic cell lines and performed chromatin immunoprecipitation sequencing and transcriptome profiling. FOXL2C134W associated with the majority of the FOXL2 wild-type DNA elements as well as a large collection of unique elements genome wide. This model enabled confirmation of altered DNA-binding specificity for FOXL2C134W and identification of unique targets of FOXL2C134W including SLC35F2 , whose expression increased sensitivity to YM155. Our results suggest FOXL2C134W drives AGCT by altering the binding affinity of FOXL2-containing complexes to engage an oncogenic transcriptional program. SIGNIFICANCE: A mechanistic understanding of FOXL2C134W -induced regulatory state alterations drives discovery of a rationally designed therapeutic strategy., (©2020 American Association for Cancer Research.)- Published
- 2020
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36. A Novel Locus Predicts Spermatogenic Recovery among Childhood Cancer Survivors Exposed to Alkylating Agents.
- Author
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Sapkota Y, Wilson CL, Zaidi AK, Moon W, Fon Tacer K, Lu L, Liu Q, Baedke J, Dhaduk R, Wang Z, Chemaitilly W, Krasin MJ, Berry FB, Zhang J, Hudson MM, Robison LL, Green DM, and Yasui Y
- Subjects
- Adult, Chromosomes, Human, Pair 7 genetics, Cyclophosphamide adverse effects, Genetic Markers genetics, Humans, Male, Middle Aged, Neoplasms drug therapy, Polymorphism, Single Nucleotide, Young Adult, Antineoplastic Agents, Alkylating adverse effects, Cancer Survivors, Infertility, Male chemically induced, Infertility, Male genetics, Spermatogenesis drug effects
- Abstract
Exposure to high doses of alkylating agents is associated with increased risk of impaired spermatogenesis among nonirradiated male survivors of childhood cancer, but there is substantial variation in this risk. Here we conducted a genetic study for impaired spermatogenesis utilizing whole-genome sequencing data from 167 nonirradiated male childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort treated with cyclophosphamide equivalent dose (CED) ≥4,000 mg/m
2 . Sperm concentration from semen analysis was assessed as the primary outcome. Common variants (MAF > 0.05) were adjusted for age at cancer diagnosis, CED, and top principal components. Rare/low-frequency variants (MAF ≤ 0.05) were evaluated jointly by various functional annotations and 4-kb sliding windows. A novel locus at 7q21.3 containing TAC1 / ASNS was associated with decreased sperm concentration (rs7784118: P = 3.5 × 10-8 ). This association was replicated in two independent samples of SJLIFE survivors of European ancestry, including 34 nonirradiated male survivors treated with 0 < CED < 4,000 mg/m2 ( P = 3.1 × 10-4 ) and 24 male survivors treated with CED ≥4,000 mg/m2 and radiotherapy <40 Gray ( P = 0.012). No association was observed among survivors not exposed to alkylating agents included in the CED ( P > 0.29). rs7784118 conferred 3.48- and 9.73-fold increases in risk for clinically defined oligospermia and azoospermia and improved prediction of normospermic, oligospermic, and azoospermic states by 13.7%, 5.3%, and 21.7%. rs7784118 was associated with decreased testosterone level, increased levels of follicle stimulating and luteinizing hormones, and 8.52-fold increased risk of Leydig cell failure. Additional research is warranted to determine how this SNP influences spermatogenesis and to assess its clinical utility in characterizing high-risk survivors and guiding intervention strategies. SIGNIFICANCE: The identified genetic markers harbor potential clinical utility in characterizing high-risk survivors and guiding intervention strategies including pretreatment patient counseling and use of fertility preservation services., (©2020 American Association for Cancer Research.)- Published
- 2020
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37. Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis.
- Author
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Zhang Y, Cedervall J, Hamidi A, Herre M, Viitaniemi K, D'Amico G, Miao Z, Unnithan RVM, Vaccaro A, van Hooren L, Georganaki M, Thulin Å, Qiao Q, Andrae J, Siegbahn A, Heldin CH, Alitalo K, Betsholtz C, Dimberg A, and Olsson AK
- Subjects
- Animals, Blood Vessels, Colonic Neoplasms blood supply, Epithelial-Mesenchymal Transition, Extracellular Matrix, Gene Knockout Techniques, Hybridization, Genetic, Liver Neoplasms secondary, Lung Neoplasms secondary, Melanoma blood supply, Melanoma secondary, Mice, Neoplastic Cells, Circulating, Pancreatic Neoplasms, Pericytes metabolism, Platelet Activation physiology, Proto-Oncogene Proteins c-sis deficiency, Proto-Oncogene Proteins c-sis genetics, Receptor, Platelet-Derived Growth Factor beta genetics, Receptor, Platelet-Derived Growth Factor beta metabolism, Thrombocytopenia, Tumor Hypoxia, Tumor Microenvironment, Cell Movement, Endothelium, Vascular metabolism, Pericytes physiology, Proto-Oncogene Proteins c-sis physiology
- Abstract
Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor β-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for platelet-derived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes. SIGNIFICANCE: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis., (©2020 American Association for Cancer Research.)
- Published
- 2020
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38. ZNF143-Mediated H3K9 Trimethylation Upregulates CDC6 by Activating MDIG in Hepatocellular Carcinoma.
- Author
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Zhang L, Huo Q, Ge C, Zhao F, Zhou Q, Chen X, Tian H, Chen T, Xie H, Cui Y, Yao M, Li H, and Li J
- Subjects
- Animals, Carcinoma, Hepatocellular mortality, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular surgery, Cell Line, Tumor, Cohort Studies, DNA Methylation, Datasets as Topic, Dioxygenases metabolism, HEK293 Cells, Hepatectomy, Histone Demethylases metabolism, Histones genetics, Humans, Liver pathology, Liver surgery, Liver Neoplasms mortality, Liver Neoplasms pathology, Liver Neoplasms surgery, Male, Mice, Nuclear Proteins metabolism, Prognosis, Promoter Regions, Genetic genetics, Tissue Array Analysis, Transcriptional Activation, Xenograft Model Antitumor Assays, Carcinoma, Hepatocellular genetics, Cell Cycle Proteins genetics, Dioxygenases genetics, Gene Expression Regulation, Neoplastic, Histone Demethylases genetics, Liver Neoplasms genetics, Nuclear Proteins genetics, Trans-Activators metabolism
- Abstract
Zinc finger protein 143 (ZNF143) belongs to the zinc finger protein family and possesses transcription factor activity by binding sequence-specific DNA. The exact biological role of ZNF143 in hepatocellular carcinoma (HCC) has not been investigated. Here we report that ZNF143 is overexpressed in HCC tissues and its overexpression correlates with poor prognosis. Gain- and loss-of-function experiments showed that ZNF143 promoted HCC cell proliferation, colony formation, and tumor growth in vitro and in vivo . ZNF143 accelerated HCC cell-cycle progression by activating cell division cycle 6 (CDC6). Mechanistically, ZNF143 promoted expression of CDC6 by directly activating transcription of histone demethylase mineral dust-induced gene (MDIG), which in turn reduced H3K9me3 enrichment in the CDC6 promoter region. Consistently, ZNF143 expression correlated significantly with MDIG and CDC6 expression in HCC. Collectively, we propose a model for a ZNF143-MDIG-CDC6 oncoprotein axis that provides novel insight into ZNF143, which may serve as a therapeutic target in HCC. SIGNIFICANCE: These findings describe the mechanism by which ZNF143 promotes HCC proliferation and provide important clues for exploring new targets and strategies for clinical treatment of human liver cancer., (©2020 American Association for Cancer Research.)
- Published
- 2020
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39. Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53.
- Author
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Chen Y, Xin H, Peng H, Shi Q, Li M, Yu J, Tian Y, Han X, Chen X, Zheng Y, Li J, Yang Z, Yang L, Hu J, Huang X, Liu Z, Huang X, Zhou H, Cui X, and Li F
- Subjects
- Animals, Autophagy physiology, Carcinogenesis, Cell Line, Tumor, DNA Methylation, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Esophageal Squamous Cell Carcinoma genetics, Esophageal Squamous Cell Carcinoma pathology, Gene Knockdown Techniques, Heterografts, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Phosphoinositide Phospholipase C genetics, Promoter Regions, Genetic, Protein Stability, Ubiquitination, Up-Regulation, Esophageal Neoplasms metabolism, Esophageal Squamous Cell Carcinoma metabolism, Phosphoinositide Phospholipase C metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignant diseases. Multiple studies with large clinic-based cohorts have revealed that variations of phospholipase C epsilon 1 (PLCE1) correlate with esophageal cancer susceptibility. However, the causative role of PLCE1 in ESCC has remained elusive. Here, we observed that hypomethylation-mediated upregulation of PLCE1 expression was implicated in esophageal carcinogenesis and poor prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and promoted p53 ubiquitination, whereas it increased the half-life of mouse double minute 2 homolog (MDM2) and inhibited its ubiquitination, leading to MDM2 stabilization. Mechanistically, the function of PLCE1 correlated with its direct binding to both p53 and MDM2, which promoted MDM2-dependent ubiquitination of p53 and subsequent degradation in vitro . Consequently, knockdown of PLCE1 combined with transfection of a recombinant adenoviral vector encoding wild-type p53 resulted in significantly increased levels of autophagy and apoptosis of esophageal cancer in vivo . Clinically, the upregulation of PLCE1 and mutant p53 protein predicted poor overall survival of patients with ESCC, and PLCE1 was positively correlated with p53 in ESCC cohorts. Collectively, this work identified an essential role for PLCE1- and MDM2-mediated ubiquitination and degradation of p53 in inhibiting ESCC autophagy and indicates that targeting the PLCE1-MDM2-p53 axis may provide a novel therapeutic approach for ESCC. SIGNIFICANCE: These findings identify hypomethylation-mediated activation of PLCE1 as a potential oncogene that blocks cellular autophagy of esophageal carcinoma by facilitating the MDM2-dependent ubiquitination of p53 and subsequent degradation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2175/F1.large.jpg., (©2020 American Association for Cancer Research.)
- Published
- 2020
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40. Blockade of DC-SIGN + Tumor-Associated Macrophages Reactivates Antitumor Immunity and Improves Immunotherapy in Muscle-Invasive Bladder Cancer.
- Author
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Hu B, Wang Z, Zeng H, Qi Y, Chen Y, Wang T, Wang J, Chang Y, Bai Q, Xia Y, Wang Y, Liu L, Zhu Y, Dai B, Guo J, Xu L, Zhang W, and Xu J
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Neutralizing, Antineoplastic Agents, Immunological therapeutic use, CD8-Positive T-Lymphocytes immunology, Cell Adhesion Molecules metabolism, Cytokines metabolism, Disease Progression, Female, Humans, Lectins, C-Type metabolism, Macrophage Inflammatory Proteins metabolism, Macrophages metabolism, Male, Middle Aged, Neoplasm Proteins metabolism, Prognosis, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Receptors, Cell Surface metabolism, Sequence Analysis, RNA, Tumor Microenvironment immunology, Urinary Bladder Neoplasms immunology, Urinary Bladder Neoplasms pathology, Young Adult, Cell Adhesion Molecules antagonists & inhibitors, Immunotherapy methods, Lectins, C-Type antagonists & inhibitors, Macrophages immunology, Receptors, Cell Surface antagonists & inhibitors, Tumor Escape immunology, Urinary Bladder Neoplasms therapy
- Abstract
Tumor-associated macrophages (TAM) play an indispensable role in the modulation of the cancer immune microenvironment. Despite the fact that TAMs may exert both antitumor and protumor activities, the molecular mechanisms involved remain poorly understood. Here, we characterized a subpopulation of TAMs expressing dendritic cell-specific C-type lectin (DC-SIGN) and investigated its relevance to the prognosis and immune microenvironment of muscle-invasive bladder cancer (MIBC). DC-SIGN
+ TAMs were abundant in a significant proportion of human MIBC specimens. High levels of DC-SIGN+ TAMs were associated with dismal prognosis and unresponsiveness to adjuvant chemotherapy in MIBC. Notably, multiple anti-inflammatory cytokines were enriched in DC-SIGN+ TAMs. RNA-seq analysis revealed that multiple M2-like signaling pathways were significantly upregulated in DC-SIGN+ TAMs. High infiltration of DC-SIGN+ TAMs was associated with CD8+ T-cell tolerance in MIBC. Moreover, abrogating DC-SIGN function using a neutralizing antibody led to impaired expression of anti-inflammatory cytokines and augmented PD-1 inhibitor pembrolizumab-mediated cytotoxic effects of CD8+ T cells toward MIBC cells. In summary, these results suggest that DC-SIGN+ TAM infiltration is closely linked to a protumor immune microenvironment and may serve as a promising therapeutic target in the immunotherapy of MIBC. SIGNIFICANCE: DC-SIGN+ TAMs have an immunosuppressive and tumor-promoting function and may serve as a prognostic indicator and therapeutic target in MIBC., (©2020 American Association for Cancer Research.)- Published
- 2020
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41. Diagnostic Accuracy of Quantitative Micro-Elastography for Margin Assessment in Breast-Conserving Surgery.
- Author
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Kennedy KM, Zilkens R, Allen WM, Foo KY, Fang Q, Chin L, Sanderson RW, Anstie J, Wijesinghe P, Curatolo A, Tan HEI, Morin N, Kunjuraman B, Yeomans C, Chin SL, DeJong H, Giles K, Dessauvagie BF, Latham B, Saunders CM, and Kennedy BF
- Subjects
- Adenocarcinoma, Mucinous pathology, Adenocarcinoma, Mucinous surgery, Adult, Aged, Breast Neoplasms pathology, Breast Neoplasms surgery, Carcinoma, Ductal, Breast pathology, Carcinoma, Ductal, Breast surgery, Elasticity Imaging Techniques standards, Female, Humans, Mastectomy, Segmental standards, Middle Aged, Reoperation, Tomography, Optical Coherence, Adenocarcinoma, Mucinous diagnostic imaging, Breast Neoplasms diagnostic imaging, Carcinoma, Ductal, Breast diagnostic imaging, Elasticity Imaging Techniques methods, Margins of Excision, Mastectomy, Segmental methods
- Abstract
Inadequate margins in breast-conserving surgery (BCS) are associated with an increased likelihood of local recurrence of breast cancer. Currently, approximately 20% of BCS patients require repeat surgery due to inadequate margins at the initial operation. Implementation of an accurate, intraoperative margin assessment tool may reduce this re-excision rate. This study determined, for the first time, the diagnostic accuracy of quantitative micro-elastography (QME), an optical coherence tomography (OCT)-based elastography technique that produces images of tissue microscale elasticity, for detecting tumor within 1 mm of the margins of BCS specimens. Simultaneous OCT and QME were performed on the margins of intact, freshly excised specimens from 83 patients undergoing BCS and on dissected specimens from 7 patients undergoing mastectomy. The resulting three-dimensional images (45 × 45 × 1 mm) were coregistered with postoperative histology to determine tissue types present in each scan. Data from 12 BCS patients and the 7 mastectomy patients served to build a set of images for reader training. One hundred and fifty-four subimages (10 × 10 × 1 mm) from the remaining 71 BCS patients were included in a blinded reader study, which resulted in 69.0% sensitivity and 79.0% specificity using OCT images, versus 92.9% sensitivity and 96.4% specificity using elasticity images. The quantitative nature of QME also facilitated development of an automated reader, which resulted in 100.0% sensitivity and 97.7% specificity. These results demonstrate high accuracy of QME for detecting tumor within 1 mm of the margin and the potential for this technique to improve outcomes in BCS. SIGNIFICANCE: An optical imaging technology probes breast tissue elasticity to provide accurate assessment of tumor margin involvement in breast-conserving surgery., (©2020 American Association for Cancer Research.)
- Published
- 2020
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42. Clonal Mutations Activate the NF-κB Pathway to Promote Recurrence of Nasopharyngeal Carcinoma.
- Author
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You R, Liu YP, Lin DC, Li Q, Yu T, Zou X, Lin M, Zhang XL, He GP, Yang Q, Zhang YN, Xie YL, Jiang R, Wu CY, Zhang C, Cui C, Wang JQ, Wang Y, Zhuang AH, Guo GF, Hua YJ, Sun R, Yun JP, Zuo ZX, Liu ZX, Zhu XF, Kang TB, Qian CN, Mai HQ, Sun Y, Zeng MS, Feng L, Zeng YX, and Chen MY
- Subjects
- Humans, Mutation, NF-kappa B genetics, Neoplasm Recurrence, Local, Carcinoma, Nasopharyngeal Carcinoma, Nasopharyngeal Neoplasms
- Abstract
The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components ( TRAF3, CYLD , and NFKBIA ) were significantly mutated in both pNPC and rNPC. Notably, mutations in TRAF3, CYLD , and NFKBIA were all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity in vitro and in vivo . In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival. SIGNIFICANCE: This study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications. See related commentary by Sehgal and Barbie, p. 5915 ., (©2019 American Association for Cancer Research.)
- Published
- 2019
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43. N 6 -Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma.
- Author
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Li F, Yi Y, Miao Y, Long W, Long T, Chen S, Cheng W, Zou C, Zheng Y, Wu X, Ding J, Zhu K, Chen D, Xu Q, Wang J, Liu Q, Zhi F, Ren J, Cao Q, and Zhao W
- Subjects
- Adenosine metabolism, Alternative Splicing physiology, Animals, Carcinogenesis metabolism, Cell Line, Tumor, Cell Proliferation physiology, Female, Gene Expression Regulation, Neoplastic physiology, Glioma metabolism, Humans, Methyltransferases metabolism, Mice, Mice, Inbred BALB C, Mice, Nude, Neural Stem Cells metabolism, Transcriptome physiology, Adenosine analogs & derivatives, Glioblastoma metabolism, Nonsense Mediated mRNA Decay physiology, RNA, Messenger metabolism
- Abstract
The N
6 -methyladenosine (m6 A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6 A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m6 A modification peaks were enriched at metabolic pathway-related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6 A modification levels of serine- and arginine-rich splicing factors ( SRSF ), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6 A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression. SIGNIFICANCE: These findings establish the oncogenic role of m6 A writer METTL3 in glioblastoma stem cells., (©2019 American Association for Cancer Research.)- Published
- 2019
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44. IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma.
- Author
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Chong PSY, Zhou J, Lim JSL, Hee YT, Chooi JY, Chung TH, Tan ZT, Zeng Q, Waller DD, Sebag M, and Chng WJ
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis, Bortezomib pharmacology, Cell Proliferation, Female, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Neoplasm Proteins genetics, Phosphorylation, Prognosis, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Protein Tyrosine Phosphatases genetics, STAT3 Transcription Factor genetics, Signal Transduction, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Neoplastic drug effects, Interleukin-6 pharmacology, Multiple Myeloma pathology, Neoplasm Proteins metabolism, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Protein Tyrosine Phosphatases metabolism, STAT3 Transcription Factor metabolism
- Abstract
Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed "deactivation" of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify high-risk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma. SIGNIFICANCE: IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn re-phosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma., (©2019 American Association for Cancer Research.)
- Published
- 2019
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45. Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling.
- Author
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D'Agostino L, Nie Y, Goswami S, Tong K, Yu S, Bandyopadhyay S, Flores J, Zhang X, Balasubramanian I, Joseph I, Sakamori R, Farrell V, Li Q, Yang CS, Gao B, Ferraris RP, Yehia G, Bonder EM, Goldenring JR, Verzi MP, Zhang L, Ip YT, and Gao N
- Subjects
- Adenomatous Polyposis Coli Protein genetics, Animals, Animals, Genetically Modified, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Epithelial Cells metabolism, Hippo Signaling Pathway, Humans, Mice, Knockout, Protein Serine-Threonine Kinases metabolism, Stem Cells metabolism, Stem Cells pathology, rab GTP-Binding Proteins genetics, Colorectal Neoplasms metabolism, Endosomes metabolism, Epithelial Cells pathology, rab GTP-Binding Proteins metabolism
- Abstract
The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo . A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations. Loss of Rab11 protein led to epithelial dysplasia in early animal development and synergized with oncogenic pathways to accelerate tumor progression initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the intestinal stem cell pool along with cell-autonomous Yki/Yap activation following disruption of Rab11a-mediated recycling endosomes. Intestinal tumors lacking Rab11a traffic exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, and amphiregulin-MAPK signaling, whereas suppression of Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and hyperplasia. Examination of Rab11a function in enteroids or cultured cell lines suggested that this endosome unit is required for suppression of the Yap pathway by Hippo kinases. Thus, recycling endosomes in mature epithelia constitute key tumor suppressors, loss of which accelerates carcinogenesis. SIGNIFICANCE: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism., (©2019 American Association for Cancer Research.)
- Published
- 2019
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46. Correction: ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis.
- Author
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Lu YX, Ju HQ, Liu ZX, Chen DL, Wang Y, Zhao Q, Wu QN, Zeng ZL, Qiu HB, Hu PS, Wang ZQ, Zhang DS, Wang F, and Xu RH
- Published
- 2019
- Full Text
- View/download PDF
47. Stabilized Peptide HDAC Inhibitors Derived from HDAC1 Substrate H3K56 for the Treatment of Cancer Stem-Like Cells In Vivo .
- Author
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Wang D, Li W, Zhao R, Chen L, Liu N, Tian Y, Zhao H, Xie M, Lu F, Fang Q, Liang W, Yin F, and Li Z
- Subjects
- Animals, Apoptosis, Cell Cycle, Cell Movement, Cell Proliferation, Female, Histone Deacetylase Inhibitors chemistry, Histones chemistry, Humans, Lysine chemistry, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasms enzymology, Neoplasms pathology, Neoplastic Stem Cells enzymology, Neoplastic Stem Cells pathology, Peptide Fragments chemistry, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Histone Deacetylase 1 antagonists & inhibitors, Histone Deacetylase Inhibitors pharmacology, Histones metabolism, Lysine metabolism, Neoplasms drug therapy, Neoplastic Stem Cells drug effects, Peptide Fragments pharmacology
- Abstract
FDA-approved HDAC inhibitors exhibit dose-limiting adverse effects; thus, we sought to improve the therapeutic windows for this class of drugs. In this report, we describe a new class of peptide-based HDAC inhibitors derived from the HDAC1-specific substrate H3K56 with improved nonspecific toxicity compared with traditional small-molecular inhibitors. We showed that our designed peptides exerted superior antiproliferation effects on cancer stem-like cells with minimal toxicity to normal cells compared with the small-molecular inhibitor SAHA, which showed nonspecific toxicity to normal and cancer cells. These peptide inhibitors also inactivated cellular HDAC1 and HDAC6 and disrupted the formation of the HDAC1, LSD1, and CoREST complex. In ovarian teratocarcinoma (PA-1) and testicular embryonic carcinoma (NTERA-2) cell xenograft animal models (5 mice/group, 50 mg/kg, every other day, intraperitoneal injection), these peptides inhibited tumor growth by 80% to 90% with negligible organ (heart, liver, spleen, lung, kidney, brain) lesions. These results represent the first attempt to design chemically stabilized peptide inhibitors to investigate HDAC inhibition in cancer stem-like cells. These novel peptide inhibitors have significantly enhanced therapeutic window and offer promising opportunities for cancer therapy. SIGNIFICANCE: Selective antiproliferative effects of stabilized peptide HDAC inhibitors toward cancer stem-like cells provide a therapeutic alternative that avoids high nonspecific toxicity of current drugs. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1769/F1.large.jpg., (©2019 American Association for Cancer Research.)
- Published
- 2019
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48. A RIPK3-PGE 2 Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis.
- Author
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Yan G, Zhao H, Zhang Q, Zhou Y, Wu L, Lei J, Wang X, Zhang J, Zhang X, Zheng L, Du G, Xiao W, Tang B, Miao H, and Li Y
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms mortality, Cyclooxygenase 2 metabolism, Gene Expression Regulation, Neoplastic, Humans, Immunosuppression Therapy, Immunosuppressive Agents, Immunotherapy, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, NF-kappa B metabolism, Prognosis, Signal Transduction, Treatment Outcome, Carcinogenesis metabolism, Colorectal Neoplasms metabolism, Dinoprostone metabolism, Myeloid-Derived Suppressor Cells metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Receptors, Prostaglandin E, EP2 Subtype metabolism
- Abstract
Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E
2 (PGE2 ). PGE2 exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE2 receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer. Significance: A novel signaling circuit involving RIPK3 and PGE2 enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg Cancer Res; 78(19); 5586-99. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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49. ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer.
- Author
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Li Y, Yang Q, Guan H, Shi B, Ji M, and Hou P
- Subjects
- Animals, Apoptosis, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor Proteins metabolism, DNA Methylation, Dual-Specificity Phosphatases metabolism, Female, HEK293 Cells, HSP27 Heat-Shock Proteins metabolism, Heat-Shock Proteins, Humans, Mice, Mice, Nude, Molecular Chaperones, Neoplasm Transplantation, Phosphorylation, Promoter Regions, Genetic, RNA, Small Interfering metabolism, Treatment Outcome, Zinc Fingers, DNA-Binding Proteins physiology, Proto-Oncogene Proteins c-akt metabolism, Thyroid Neoplasms drug therapy, Thyroid Neoplasms pathology
- Abstract
The zinc finger protein 677 (ZNF677) belongs to the zinc finger protein family, which possesses transcription factor activity by binding sequence-specific DNA. Previous studies have reported its downregulated by promoter methylation in non-small cell lung cancer. However, its biological role and exact mechanism in human cancers, including thyroid cancer, remain unknown. In this study, we demonstrate that ZNF677 is frequently downregulated by promoter methylation in primary papillary thyroid cancers (PTC) and show that decreased expression of ZNF677 is significantly associated with poor patient survival. Ectopic expression of ZNF677 in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice and induced cell-cycle arrest and apoptosis. Conversely, knockdown of ZNF677 promoted thyroid cancer cell proliferation and colony formation. ZNF677 exerted its tumor suppressor functions in thyroid cancer cells through transcriptional repression of two targets CDKN3 and HSPB1 (or HSP27), thereby inhibiting phosphorylation and activation of Akt via distinct mechanisms. Taken together, our data show that ZNF677 functions as a tumor suppressor and is frequently silenced via promoter methylation in thyroid cancer. Significance: These findings report a tumor suppressive role of the zinc-finger protein ZNF677 in primary papillary thyroid cancer through inhibition of Akt phosphorylation. Cancer Res; 78(18); 5216-28. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
- Full Text
- View/download PDF
50. Identification of Metastatic Lymph Nodes in MR Imaging with Faster Region-Based Convolutional Neural Networks.
- Author
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Lu Y, Yu Q, Gao Y, Zhou Y, Liu G, Dong Q, Ma J, Ding L, Yao H, Zhang Z, Xiao G, An Q, Wang G, Xi J, Yuan W, Lian Y, Zhang D, Zhao C, Yao Q, Liu W, Zhou X, Liu S, Wu Q, Xu W, Zhang J, Wang D, Sun Z, Gao Y, Zhang X, Hu J, Zhang M, Wang G, Zheng X, Wang L, Zhao J, and Yang S
- Subjects
- Female, Humans, Lymph Nodes pathology, Lymphatic Metastasis diagnosis, Lymphatic Metastasis pathology, Magnetic Resonance Imaging, Male, Neural Networks, Computer, Image Processing, Computer-Assisted, Lymph Nodes diagnostic imaging, Lymphatic Metastasis diagnostic imaging
- Abstract
MRI is the gold standard for confirming a pelvic lymph node metastasis diagnosis. Traditionally, medical radiologists have analyzed MRI image features of regional lymph nodes to make diagnostic decisions based on their subjective experience; this diagnosis lacks objectivity and accuracy. This study trained a faster region-based convolutional neural network (Faster R-CNN) with 28,080 MRI images of lymph node metastasis, allowing the Faster R-CNN to read those images and to make diagnoses. For clinical verification, 414 cases of rectal cancer at various medical centers were collected, and Faster R-CNN-based diagnoses were compared with radiologist diagnoses using receiver operating characteristic curves (ROC). The area under the Faster R-CNN ROC was 0.912, indicating a more effective and objective diagnosis. The Faster R-CNN diagnosis time was 20 s/case, which was much shorter than the average time (600 s/case) of the radiologist diagnoses. Significance: Faster R-CNN enables accurate and efficient diagnosis of lymph node metastases. Cancer Res; 78(17); 5135-43. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
- Full Text
- View/download PDF
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