367 results on '"Yu-Sun Chang"'
Search Results
2. Comparison between a novel salivary marker and several clinical prognosticators in oral cavity cancer
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Yi‐Chan Lee, Li‐Yu Lee, Yenlin Huang, Huang‐Kai Kao, Ya‐Ting Chang, Shao‐Yu Hung, Chuieng‐Yi Lu, Yu‐Sun Chang, Jau‐Song Yu, and Kai‐Ping Chang
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matrix metalloproteinase‐1 ,oral squamous cell carcinoma ,saliva ,Otorhinolaryngology ,RF1-547 ,Surgery ,RD1-811 - Abstract
Abstract Objectives This study aimed to investigate the association between salivary matrix metalloproteinase‐1 (MMP‐1) and clinicopathological parameters of oral cavity squamous cell carcinoma (OSCC) and compare the prognostic efficacy of salivary MMP‐1 and other established circulating markers for OSCC. Methods Saliva specimens from 479 OSCC subjects were examined using an enzyme‐linked immunosorbent assay. The area under the curve (AUC) values of salivary MMP‐1 and other markers were calculated, and survival analyses were conducted using Kaplan–Meier and multivariate regression methods. Results Salivary MMP‐1 showed good discrimination in predicting overall survival, with an AUC of 0.638, which was significantly higher than that of albumin (0.530, p = .021) and Charlson comorbidity index (0.568, p = .048) and comparable with neutrophil‐to‐lymphocyte ratio (0.620, p = .987), platelet‐to‐lymphocyte ratio (0.575, p = .125), and squamous cell carcinoma antigen (0.609, p = .605). Elevated levels of salivary MMP‐1 were significantly associated with higher pT classification, pN classification, overall pathological stage, positive extranodal extension, tumor differentiation, positive lymphovascular invasion, positive perineural invasion, and tumor depth (p all
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- 2023
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3. Nasopharyngeal carcinoma patient-derived xenograft mouse models reveal potential drugs targeting cell cycle, mTOR, and autophagy pathways
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Hsin-Pai Li, Chen-Yang Huang, Kar-Wai Lui, Yin-Kai Chao, Chun-Nan Yeh, Li-Yu Lee, Yenlin Huang, Tung-Liang Lin, Yung-Chia Kuo, Mei-Yuan Huang, Hsien-Chi Fan, An-Chi Lin, Chia-Hsun Hsieh, Kai-Ping Chang, Chien-Yu Lin, Hung-Ming Wang, Mei Chao, Jai-Shin Liu, Yu-Sun Chang, and Cheng-Lung Hsu
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NPC ,PDX ,EBV ,mTOR ,Cell cycle ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Nasopharyngeal carcinoma (NPC) is associated with Epstein–Barr virus (EBV) infection. To test preclinical NPC drugs, we established two patient-derived xenograft (PDX) mouse models, EBV-positive PDX-B13 and EBV-negative PDX-Li41, for drug screening. Methods: Based on next generation sequencing (NGS) studies, PDX-B13 had CCND1 copy number (CN) gain but CDKN2A CN loss, whereas PDX-Li41 had CDKN2A and RB1 CN loss, TSC1 (negative regulator of mTOR) frameshift deletion mutation, and increased activation of mTOR, a serine/threonine kinase that governs metabolism, autophagy, and apoptosis. Increased mTOR was also associated with poor NPC prognosis. Results: Everolimus, an mTOR inhibitor, suppressed tumor growth in the two PDX NPC models and had an additive antitumor effect with palbociclib, a CDK4/6 inhibitor. PDX tumors treated with various drugs or untreated were subjected to RNA sequencing, transcriptome profile analysis, and selective Western blotting to understand the interactions between these drugs and gene expression profiles. Palbociclib also suppressed EB viral nuclear antigen (EBNA1) expression in PDX-B13. Everolimus together with autophagy inhibitor, hydroxychloroquine, had additive anti-tumor effect on PDX-B13 tumor. Immunohistochemistry revealed that high mTOR levels were correlated with poor overall survival in patients with metastatic NPC (N = 90). Conclusions: High mTOR levels are a poor prognostic factor in NPC, and cell cycle, mTOR and autophagy pathways may serve as therapeutic targets in NPC. In addition, PDX models can be used for efficiently testing potential NPC drugs.
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- 2023
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4. MicroRNA-based signature for diagnosis and prognosis of colorectal cancer using residuum of fecal immunochemical test
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Chia-Chun Chen, Pi-Yueh Chang, Yu-Sun Chang, Jeng-Fu You, Err-Cheng Chan, Jinn-Shiun Chen, Wen-Sy Tsai, Yen-Lin Huang, Chung-Wei Fan, Hung-Chih Hsu, and Jy-Ming Chiang
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Screening ,Colonoscopy ,Biomarker ,Prioritization ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Background: Colorectal cancer (CRC) is still among the most lethal and prevalent malignancies in the world. Despite continuous efforts, the diagnosis and prognosis of CRC have never been satisfying, especially the non-invasive assays. Methods: Our study comprised three independent cohorts of 835 qualified stool samples. From 46 literature-identified miRNA candidates, four miRNA ratios were selected and developed into a miRNA-based signature after applied to the training and test sets. The clinical performances of this signature were further evaluated in the prospective cohorts. Results: Four miRNA ratios with significant alterations and the highest discriminating power between the CRC and control groups in the training set were successfully validated in the test set. In the training dataset, combining these four miRNA ratios using a logistic regression model improved the area under the curve value to 0.821 and obtained a sensitivity of 73.6% and specificity of 78.9%. This miRNA signature showed consistent performances in the other two sample cohorts, with the highest sensitivity of 85.7% in the prospective cohort. Additionally, the higher miRNA signature was associated with worse disease-free survival (hazard ratio = 2.27) and overall survival (hazard ratio = 1.83) of CRC patients. For fecal immunochemical test (FIT)-positive populations, the positive predictive value for CRC detection in miRNA-positive subjects was 3.43-fold higher in the prospective cohort, compared to FIT alone. Conclusion: This stool miRNA signature is highly associated with poor outcome of CRC and can be added to FIT tests to help identify the most at-risk group to receive prompt colonoscopy examination.
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- 2023
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5. Urinary Metabolomic Analysis of Prostate Cancer by UPLC-FTMS and UPLC-Ion Trap MSn
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Chien-Lun Chen, Yi-Ting Chen, Wen-Yu Liao, Yu-Sun Chang, Jau-Song Yu, and Bao-Rong Juo
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urinary metabolomics ,prostate cancer ,biomarker ,Medicine (General) ,R5-920 - Abstract
Accumulative evidence suggests metabolic disorders correlate with prostate cancer. Metabolic profiling of urine allows the measurement of numerous metabolites simultaneously. This study set up a metabolomic platform consisting of UPLC-FTMS and UPLC-ion trap MSn for urine metabolome analysis. The platform improved retention time, mass accuracy, and signal stability. Additionally, the product ion spectrum obtained from ion trap MSn facilitated structure elucidation of candidate metabolites, especially when authentic standards were not available. Urine samples from six hernia patients and six BPH patients were used for the initial establishment of the analytic platform. This platform was further employed to analyze the urine samples of 27 PCa and 49 BPH patients. Choosing the upper and lower 16% of metabolites, 258 metabolite candidates were selected. Twenty-four of them with AUC values larger than 0.65 were further selected. Eighteen of the twenty-four features can be matched in METLIN and HMDB. Eleven of the eighteen features can be interpreted by MSn experiments. They were used for the combination achieving the best differential power. Finally, four metabolites were combined to reach the AUC value of 0.842 (CI 95, 0.7559 to 0.9279). This study demonstrates the urinary metabolomic analysis of prostate cancer and sheds light on future research.
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- 2023
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6. Genomic and Molecular Signatures of Successful Patient-Derived Xenografts for Oral Cavity Squamous Cell Carcinoma
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Wei-Chen Yen, Ian Yi-Feng Chang, Kai‐Ping Chang, Chun‐Nan Ouyang, Chiao-Rou Liu, Ting-Lin Tsai, Yi-Cheng Zhang, Chun-I Wang, Ya-Hui Wang, Alice L. Yu, Hsuan Liu, Chih-Ching Wu, Yu-Sun Chang, Jau-Song Yu, and Chia-Yu Yang
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patient-derived xenografts ,oral cavity squamous cell carcinoma ,whole-exome sequencing ,transcriptome sequencing ,engraftment ability ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundOral cavity squamous cell carcinoma (OSCC) is an aggressive malignant tumor with high recurrence and poor prognosis in the advanced stage. Patient-derived xenografts (PDXs) serve as powerful preclinical platforms for drug testing and precision medicine for cancer therapy. We assess which molecular signatures affect tumor engraftment ability and tumor growth rate in OSCC PDXs.MethodsTreatment-naïve OSCC primary tumors were collected for PDX models establishment. Comprehensive genomic analysis, including whole-exome sequencing and RNA-seq, was performed on case-matched tumors and PDXs. Regulatory genes/pathways were analyzed to clarify which molecular signatures affect tumor engraftment ability and the tumor growth rate in OSCC PDXs.ResultsPerineural invasion was found as an important pathological feature related to engraftment ability. Tumor microenvironment with enriched hypoxia, PI3K-Akt, and epithelial–mesenchymal transition pathways and decreased inflammatory responses had high engraftment ability and tumor growth rates in OSCC PDXs. High matrix metalloproteinase-1 (MMP1) expression was found that have a great graft advantage in xenografts and is associated with pooled disease-free survival in cancer patients.ConclusionThis study provides a panel with detailed genomic characteristics of OSCC PDXs, enabling preclinical studies on personalized therapy options for oral cancer. MMP1 could serve as a biomarker for predicting successful xenografts in OSCC patients.
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- 2022
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7. Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway
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An‐Ko Chung, Chun‐Nan OuYang, Hsuan Liu, Mei Chao, Ji‐Dung Luo, Cheng‐Yang Lee, Yen‐Jung Lu, I‐Che Chung, Lih‐Chyang Chen, Shao‐Min Wu, Ngan‐Ming Tsang, Kai‐Ping Chang, Cheng‐Lung Hsu, Hsin‐Pai Li, and Yu‐Sun Chang
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copy number variation ,mutation ,nasopharyngeal carcinoma ,next‐generation sequencing ,TGF‐β signaling ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein‐Barr virus (EBV). We envisioned that in‐depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty‐three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep‐sequenced (>1000×) with respect to a panel of 409 cancer‐related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF‐κB, and TGF‐β pathways. In addition, patients harbored CNV among 409 cancer‐related genes and missense mutations in TGF‐β/SMAD signaling were associated with poor overall survival and poor recurrence‐free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD‐dependent TGF‐β signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF‐β‐mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF‐β signaling contributes to exacerbating the NPC pathogenesis.
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- 2019
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8. A circulating miRNA signature for early diagnosis of acute kidney injury following acute myocardial infarction
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Pei-Chun Fan, Chia-Chun Chen, Chen-Ching Peng, Chih-Hsiang Chang, Chia-Hung Yang, Chi Yang, Lichieh Julie Chu, Yung-Chang Chen, Chih-Wei Yang, Yu-Sun Chang, and Pao-Hsien Chu
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MicroRNAs ,Acute kidney injury ,Acute myocardial infarction ,TGF-β ,Medicine - Abstract
Abstract Background Acute kidney injury (AKI) is a common complication of acute myocardial infarction (AMI), and is associated with adverse outcomes. The study aimed to identify a miRNA signature for the early diagnosis of post-AMI AKI. Methods A total of 108 patients admitted to a coronary care unit (CCU) were divided into four subgroups: AMI−AKI−, AMI+AKI−, AMI+AKI+, and AMI−AKI+. Thirty-six miRNA candidates were selected based on an extensive literature review. Real-time quantitative RT-PCR analysis was used to determine the expression levels of these miRNAs in the serum collected on the day of CCU admittance. TargetScan 7.1 and miRDB databases were used for target prediction and Metacore 6.13 was used for pathway analysis. Results Through a stepwise selection based on abundance, hemolytic effect and differential expression between four groups, 9 miRNAs were found to have significantly differential expression levels as potential biomarkers for post-AMI AKI specifically. Noticeably, the expression levels of miR-24, miR-23a and miR-145 were significantly down-regulated in AMI+AKI+ patients compared to those in AMI+AKI− patients. Combination of the three miRNAs as a panel showed the best performance in the early detection of AKI following AMI (AUC = 0.853, sensitivity 95.65%), compared to the analysis of serum neutrophil gelatinase-associated lipocalin (AUC = 0.735, sensitivity 63.16%). Furthermore, bioinformatic analysis indicated that these three miRNAs regulate the transforming growth factor beta signaling pathway and involve in apoptosis and fibrosis in AKI. Conclusions For the first time, this study identify a unique circulating miRNA signature (miR-24-3p, miR-23a-3p, miR-145-5p) that can potentially early detect AKI following AMI and may be involved in renal injury and fibrosis in post-AMI AKI pathogenesis.
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- 2019
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9. Cytoplasmic LIF reprograms invasive mode to enhance NPC dissemination through modulating YAP1-FAK/PXN signaling
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Shu-Chen Liu, Tien Hsu, Yu-Sun Chang, An-Ko Chung, Shih Sheng Jiang, Chun-Nan OuYang, Chiou-Hwa Yuh, Chuen Hsueh, Ya-Ping Liu, and Ngan-Ming Tsang
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Science - Abstract
Molecular pathways regulating nasopharyngeal carcinoma (NPC) metastasis are unclear. Here they report higher levels of cytoplasmic leukemia inhibitory factor (cLIF) and LIF receptor (LIFR) to correlate with higher metastasis in NPC patients, and show cLIF to promote NPC metastasis and vascular dissemination via the YAP1-FAK/PXN axis.
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- 2018
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10. Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma
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Cheng-Lung Hsu, Kar-Wai Lui, Lang-Ming Chi, Yung-Chia Kuo, Yin-Kai Chao, Chun-Nan Yeh, Li-Yu Lee, Yenlin Huang, Tung-Liang Lin, Mei-Yuan Huang, Yi-Ru Lai, Yuan-Ming Yeh, Hsien-Chi Fan, An-Chi Lin, Yen-Jung Lu, Chia-Hsun Hsieh, Kai-Ping Chang, Ngan-Ming Tsang, Hung-Ming Wang, Alex Y. Chang, Yu-Sun Chang, and Hsin-Pai Li
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Nasopharyngeal carcinoma ,Patient derived xenograft ,EBV ,Whole-exome sequencing ,CDK4/6 inhibitor ,RNA sequencing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. Methods We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. Results A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients’ plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. Conclusions Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.
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- 2018
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11. Inactivation of the tight junction gene CLDN11 by aberrant hypermethylation modulates tubulins polymerization and promotes cell migration in nasopharyngeal carcinoma
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Hsin-Pai Li, Chen-Ching Peng, Chih-Ching Wu, Chien-Hsun Chen, Meng-Jhe Shih, Mei-Yuan Huang, Yi-Ru Lai, Yung-Li Chen, Ting-Wen Chen, Petrus Tang, Yu-Sun Chang, Kai-Ping Chang, and Cheng-Lung Hsu
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Nasopharyngeal carcinoma ,Methylation ,Tight junction ,CLDN11 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Aberrant hypermethylation of cellular genes is a common phenomenon to inactivate genes and promote tumorigenesis in nasopharyngeal carcinoma (NPC). Methods Methyl binding domain (MBD)-ChIP sequencing of NPC cells, microarray data of NPC biopsies and gene ontology analysis were conducted to identify a potential tumor suppressor gene CLDN11 that was both hypermethylated and downregulated in NPC. Bisulfite sequencing, qRT-PCR, immunohistochemistry staining of the NPC clinical samples and addition of methylation inhibitor, 5’azacytidine, in NPC cells were performed to verify the correlation between DNA hypermethylation and expression of CLDN11. Promoter reporter and EMSA assays were used to dissect the DNA region responsible for transcription activator binding and to confirm whether DNA methylation could affect activator’s binding, respectively. CLDN11 was transiently overexpressed in NPC cells followed by cell proliferation, migration, invasion assays to characterize its biological roles. Co-immunoprecipitation experiments and proteomic approach were carried out to identify novel interacting protein(s) and the binding domain of CLDN11. Anti-tumor activity of the CLDN11 was elucidated by in vitro functional assay. Results A tight junction gene, CLDN11, was identified as differentially hypermethylated gene in NPC. High methylation percentage of CLDN11 promoter in paired NPC clinical samples was correlated with low mRNA expression level. Immunohistochemistry staining of NPC paired samples tissue array demonstrated that CLDN11 protein expression was relatively low in NPC tumors. Transcription activator GATA1 bound to CLDN11 promoter region − 62 to − 53 and its DNA binding activity was inhibited by DNA methylation. Re-expression of CLDN11 reduced cell migration and invasion abilities in NPC cells. By co-immunoprecipitation and liquid chromatography-tandem mass spectrometry LC-MS/MS, tubulin alpha-1b (TUBA1B) and beta-3 (TUBB3), were identified as the novel CLDN11-interacting proteins. CLDN11 interacted with these two tubulins through its intracellular loop and C-terminus. Furthermore, these domains were required for CLDN11-mediated cell migration inhibition. Treatment with a tubulin polymerization inhibitor, nocodazole, blocked NPC cell migration. Conclusions CLDN11 is a hypermethylated and downregulated gene in NPC. Through interacting with microtubules TUBA1B and TUBB3, CLDN11 blocks the polymerization of tubulins and cell migration activity. Thus, CLDN11 functions as a potential tumor suppressor gene and silencing of CLDN11 by DNA hypermethylation promotes NPC progression.
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- 2018
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12. RNA recombination in Hepatitis delta virus: Identification of a novel naturally occurring recombinant
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Chia-Chi Lin, Chi-Ching Lee, Siao-Han Lin, Po-Jung Huang, Hsin-Pai Li, Yu-Sun Chang, Petrus Tang, and Mei Chao
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Microbiology ,QR1-502 - Abstract
Background/Purpose: Hepatitis delta virus (HDV) is the only animal RNA virus that has an unbranched rod-like genome with ribozyme activity. It replicates in the nucleus by host RNA polymerase via a rolling circle mechanism. Similar to many RNA viruses encoding their own RNA-dependent RNA polymerases, homologous recombination of HDV occurs in mixed-genotype infections and in cultured cells cotransfected with two HDV sequences, as demonstrated by molecular analyses. Methods: Among 237 published complete genomic sequences, 34 sequences were reported from the small and isolated Miyako Island, Japan, and belonged to the Asia-specific genotypes, HDV-2 and HDV-4 (the majority of them belonged to the known Miyako Island-specific subgroup, HDV-4M). We investigated the presence of naturally occurring HDV recombinant in Miyako Island using phylogenetic and recombination analyses. Results: We identified a two-switch HDV-4/4M intersubtype recombinant with an unbranched rod-like RNA genome. Conclusion: Our data suggest that RNA recombination plays an important role in the rapid evolution of HDV, allowing the production of new HDV strains with correct genomic structures. Keywords: hepatitis delta virus, RNA recombination
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- 2017
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13. APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism
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Ting-Wen Chen, Chi-Ching Lee, Hsuan Liu, Chi-Sheng Wu, Curtis R. Pickering, Po-Jung Huang, Jing Wang, Ian Yi-Feng Chang, Yuan-Ming Yeh, Chih-De Chen, Hsin-Pai Li, Ji-Dung Luo, Bertrand Chin-Ming Tan, Timothy En Haw Chan, Chuen Hsueh, Lichieh Julie Chu, Yi-Ting Chen, Bing Zhang, Chia-Yu Yang, Chih-Ching Wu, Chia-Wei Hsu, Lai-Chu See, Petrus Tang, Jau-Song Yu, Wei-Chao Liao, Wei-Fan Chiang, Henry Rodriguez, Jeffrey N. Myers, Kai-Ping Chang, and Yu-Sun Chang
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Science - Abstract
Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.
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- 2017
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14. Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak.
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Irene Gramaglia, Joyce Velez, Yu-Sun Chang, Wilson Caparros-Wanderley, Valery Combes, Georges Grau, Monique F Stins, and Henri C van der Heyde
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Medicine ,Science - Abstract
Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falciparum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- and vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected ip on day 4 PI with quinine-injected ip on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recipients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality.
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- 2019
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15. Spontaneous metastases in immunocompetent mice harboring a primary tumor driven by oncogene latent membrane protein 1 from EpsteinâBarr virus
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Pu-Yuan Chang, Yenlin Huang, Tzu-Yuan Hung, Kowit-Yu Chong, Yu-Sun Chang, Chuck C.-K. Chao, and Kai-Ping N. Chow
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Background: In vitro and clinical studies suggest that the oncogene LMP1 (latent membrane protein 1) encoded by EpsteinâBarr virus (EBV) plays a role in the development of nasopharyngeal carcinoma (NPC) and the formation of metastases in immunocompetent individuals. However, whether LMP1 itself is sufficient to drive these events in immunocompetent hosts remains elusive due to the lack of appropriate experimental models. The aim of this study was to study LMP1-dependent tumorigenesis and metastasis in BALB/c mice inoculated with BALB/c-3T3 cells expressing N-LMP1 (a Taiwanese NPC variant). Methods: Following cancer cell inoculation, metastasis formation was monitored over time using PCR analysis of LMP1 as tumor marker. We also used a luciferase (Luc)-containing N-LMP1 and bioluminescent imaging (BLI) to monitor metastasis formation in a non-invasive manner. Results: N-LMP1 appeared early in draining lymph nodes and in various distant organs before the rapid growth of the primary tumor. Lung metastasis was observed by BLI and further confirmed by histological examination. Furthermore, we detected luciferase signals in the lungs, even before the animals were sacrificed. Conclusions: Our results demonstrate the high metastatic character of N-LMP1 in immunocompetent hosts. Systemic tumor dissemination occurs even before aggressive tumor growth at the primary site, suggesting that early treatment of primary LMP1-associated tumors and distant micro-metastases is critical to achieve positive results. Keywords: Nasopharyngeal carcinoma (NPC), EpsteinâBarr virus (EBV), Oncogene latent membrane protein 1 (N-LMP1), Tumor mouse model, Distant metastasis
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- 2016
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16. circRNAome Profiling in Oral Carcinoma Unveils a Novel circFLNB that Mediates Tumour Growth-Regulating Transcriptional Response
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Yi-Tung Chen, Ian Yi-Feng Chang, Chia-Hua Kan, Yu-Hao Liu, Yu-Ping Kuo, Hsin-Hao Tseng, Hsing-Chun Chen, Hsuan Liu, Yu-Sun Chang, Jau-Song Yu, Kai-Ping Chang, and Bertrand Chin-Ming Tan
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oral cancer ,non-coding RNA ,circular RNA ,miRNA–mRNA network ,biomarkers ,Cytology ,QH573-671 - Abstract
Deep sequencing technologies have revealed the once uncharted non-coding transcriptome of circular RNAs (circRNAs). Despite the lack of protein-coding potential, these unorthodox yet highly stable RNA species are known to act as critical gene regulatory hubs, particularly in malignancies. However, their mechanistic implications in tumor outcome and translational potential have not been fully resolved. Using RNA-seq data, we profiled the circRNAomes of tumor specimens derived from oral squamous cell carcinoma (OSCC), which is a prevalently diagnosed cancer with a persistently low survival rate. We further catalogued dysregulated circRNAs in connection with tumorigenic progression. Using comprehensive bioinformatics analyses focused on co-expression maps and miRNA-interaction networks, we delineated the regulatory networks that are centered on circRNAs. Interestingly, we identified a tumor-associated, pro-tumorigenic circRNA, named circFLNB, that was implicated in maintaining several tumor-associated phenotypes in vitro and in vivo. Correspondingly, transcriptome profiling of circFLNB-knockdown cells showed alterations in tumor-related genes. Integrated in silico analyses further deciphered the circFLNB-targeted gene network. Together, our current study demarcates the OSCC-associated circRNAome, and unveils a novel circRNA circuit with functional implication in OSCC progression. These systems-based findings broaden mechanistic understanding of oral malignancies and raise new prospects for translational medicine.
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- 2020
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17. Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase
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Wei-Cheng Lin, Archan Chakraborty, Shih-Chia Huang, Pei-Yu Wang, Ya-Ju Hsieh, Kun-Yi Chien, Yen-Hsien Lee, Chia-Chun Chang, Hsiang-Yu Tang, Yu-Tsun Lin, Chang-Shung Tung, Ji-Dung Luo, Ting-Wen Chen, Tzu-Yang Lin, Mei-Ling Cheng, Yi-Ting Chen, Chau-Ting Yeh, Ji-Long Liu, Li-Ying Sung, Ming-Shi Shiao, Jau-Song Yu, Yu-Sun Chang, and Li-Mei Pai
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Biology (General) ,QH301-705.5 - Abstract
Summary: CTP synthase (CTPS) forms compartmentalized filaments in response to substrate availability and environmental nutrient status. However, the physiological role of filaments and mechanisms for filament assembly are not well understood. Here, we provide evidence that CTPS forms filaments in response to histidine influx during glutamine starvation. Tetramer conformation-based filament formation restricts CTPS enzymatic activity during nutrient deprivation. CTPS protein levels remain stable in the presence of histidine during nutrient deprivation, followed by rapid cell growth after stress relief. We demonstrate that filament formation is controlled by methylation and that histidine promotes re-methylation of homocysteine by donating one-carbon intermediates to the cytosolic folate cycle. Furthermore, we find that starvation stress and glutamine deficiency activate the GCN2/ATF4/MTHFD2 axis, which coordinates CTPS filament formation. CTPS filament formation induced by histidine-mediated methylation may be a strategy used by cancer cells to maintain homeostasis and ensure a growth advantage in adverse environments. : Metabolic enzymes form membraneless compartments to adapt to environmental changes. Lin et al. demonstrate that histidine catabolism coupled with the folate cycle contributes to methionine synthesis, which promotes protein methylation. This post-translational modification in turn induces CTPS filament formation to preserve CTPS but reduces its enzymatic activity under starvation. Keywords: histidine, CTP synthase, CTPS filament, ATF4, MTHFD2, folate cycle, one carbon, methylation, nutrient deprivation, cancer
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- 2018
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18. The urinary microparticle tumor-associated calcium-signal transducer 2 as a bladder cancer biomarker
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Chien-Lun Chen, Petrus Tang, Chih-Ching Wu, Ting Chung, Jau-Song Yu, Yu-Sun Chang, Phei-Lang Chang, and Yi-Ting Chen
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Diseases of the genitourinary system. Urology ,RC870-923 - Published
- 2016
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19. Tumour inflammasome‐derived IL‐1β recruits neutrophils and improves local recurrence‐free survival in EBV‐induced nasopharyngeal carcinoma
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Lih‐Chyang Chen, Li‐Jie Wang, Nang‐Ming Tsang, David M. Ojcius, Chia‐Chun Chen, Chun‐Nan OuYang, Chuen Hsueh, Ying Liang, Kai‐Ping Chang, Chiu‐Chin Chen, and Yu‐Sun Chang
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cancer ,inflammasome ,neutrophil ,prognosis ,therapy ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Inflammasomes sense infection and cellular damage and are critical for triggering inflammation through IL‐1β production. In carcinogenesis, inflammasomes may have contradictory roles through facilitating antitumour immunity and inducing oncogenic factors. Their function in cancer remains poorly characterized. Here we show that the NLRP3, AIM2 and RIG‐I inflammasomes are overexpressed in Epstein‐Barr virus (EBV)‐associated nasopharyngeal carcinoma (NPC), and expression levels correlate with patient survival. In tumour cells, AIM2 and RIG‐I are required for IL‐1β induction by EBV genomic DNA and EBV‐encoded small RNAs, respectively, while NLRP3 responds to extracellular ATP and reactive oxygen species. Irradiation and chemotherapy can further activate AIM2 and NLRP3, respectively. In mice, tumour‐derived IL‐1β inhibits tumour growth and enhances survival through host responses. Mechanistically, IL‐1β‐mediated anti‐tumour effects depend on infiltrated immunostimulatory neutrophils. We show further that presence of tumour‐associated neutrophils is significantly associated with better survival in NPC patients. Thus, tumour inflammasomes play a key role in tumour control by recruiting neutrophils, and their expression levels are favourable prognostic markers and promising therapeutic targets in patients.
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- 2012
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20. A Genetic Cascade of let-7-ncl-1-fib-1 Modulates Nucleolar Size and rRNA Pool in Caenorhabditis elegans.
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Yung-Hsiang Yi, Tian-Hsiang Ma, Li-Wei Lee, Pey-Tsyr Chiou, Po-Hsiang Chen, Ching-Ming Lee, Yu-De Chu, Hsiang Yu, Kuei-Ching Hsiung, Yi-Tzang Tsai, Chi-Chang Lee, Yu-Sun Chang, Shih-Peng Chan, Bertrand Chin-Ming Tan, and Szecheng J Lo
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Genetics ,QH426-470 - Abstract
Ribosome biogenesis takes place in the nucleolus, the size of which is often coordinated with cell growth and development. However, how metazoans control nucleolar size remains largely unknown. Caenorhabditis elegans provides a good model to address this question owing to distinct tissue distribution of nucleolar sizes and a mutant, ncl-1, which exhibits larger nucleoli than wild-type worms. Here, through a series of loss-of-function analyses, we report that the nucleolar size is regulated by a circuitry composed of microRNA let-7, translation repressor NCL-1, and a major nucleolar pre-rRNA processing protein FIB-1/fibrillarin. In cooperation with RNA binding proteins PUF and NOS, NCL-1 suppressed the translation of FIB-1/fibrillarin, while let-7 targeted the 3'UTR of ncl-1 and inhibited its expression. Consequently, the abundance of FIB-1 is tightly controlled and correlated with the nucleolar size. Together, our findings highlight a novel genetic cascade by which post-transcriptional regulators interplay in developmental control of nucleolar size and function.
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- 2015
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21. The Epstein-Barr virus-encoded microRNA MiR-BART9 promotes tumor metastasis by targeting E-cadherin in nasopharyngeal carcinoma.
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Chung-Yuan Hsu, Yung-Hsiang Yi, Kai-Ping Chang, Yu-Sun Chang, Shu-Jen Chen, and Hua-Chien Chen
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
MicroRNAs (miRNAs) are a family of small RNA molecules that negatively regulate the expression of protein-coding genes and play critical roles in orchestrating diverse cellular processes. This regulatory mechanism is also exploited by viruses to direct their life cycle and evade the host immune system. Epstein-Barr virus (EBV) is an oncogenic virus that is closely associated with multiple human diseases, including nasopharyngeal carcinoma (NPC), which is a highly metastatic type of tumor and is frequently reported in South Asia. Several viral proteins have been found to promote the migration and invasiveness of NPC cells. However, not all tumor tissues express these viral oncoproteins, suggesting that other mechanisms may contribute to the aggressive behavior of NPC tumor cells. A previous sequencing study by our group revealed that the EBV miRNA miR-BART9 was expressed at high levels in all EBV-positive NPC tissues. In the present study, we used gain- and loss-of-function approaches to investigate the effect of miR-BART9 in EBV-negative and EBV-positive NPC cells. We discovered that miR-BART9 promotes the migration and invasiveness of cultured NPC cells. The promigratory activity observed in vitro was manifested as an enhanced metastatic ability in vivo. Computational analysis revealed that miR-BART9 may target E-cadherin, a membrane protein that is pivotal in preserving cell-cell junctions and the epithelial phenotype. Through biochemical assays and functional rescue analysis, we confirmed that miR-BART9 specifically inhibits E-cadherin to induce a mesenchymal-like phenotype and promote the migration of NPC cells. These results indicated that miR-BART9 is a prometastatic viral miRNA and suggested that high levels of miR-BART9 in EBV-positive NPC cells may contribute to the aggressiveness of tumor cells.
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- 2014
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22. Identification of CD24 as a cancer stem cell marker in human nasopharyngeal carcinoma.
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Chun-Hung Yang, Hui-Ling Wang, Yi-Sheng Lin, K P Shravan Kumar, Hung-Chi Lin, Chih-Jung Chang, Chia-Chen Lu, Tsung-Teng Huang, Jan Martel, David M Ojcius, Yu-Sun Chang, John D Young, and Hsin-Chih Lai
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Medicine ,Science - Abstract
Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24+ cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/β-catenin signaling pathway. CD24+ cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24+ cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24+ cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC.
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- 2014
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23. Novel bladder cancer biomarkers discovery by microdissected comparative tissue proteomics
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Chien-Lun Chen, Ting Chung, Chih-Ching Wu, Kwai-Fong Ng, Jau-Song Yu, Cheng-Han Tsai, Yu-Sun Chang, Ying Liang, Ke-Hung Tsui, and Yi-Ting Chen
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Diseases of the genitourinary system. Urology ,RC870-923 - Published
- 2015
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24. How genome-wide SNP-SNP interactions relate to nasopharyngeal carcinoma susceptibility.
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Wen-Hui Su, Yin Yao Shugart, Kai-Ping Chang, Ngan-Ming Tsang, Ka-Po Tse, and Yu-Sun Chang
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Medicine ,Science - Abstract
This study is the first to use genome-wide association study (GWAS) data to evaluate the multidimensional genetic architecture underlying nasopharyngeal cancer. Since analysis of data from GWAS confirms a close and consistent association between elevated risk for nasopharyngeal carcinoma (NPC) and major histocompatibility complex class 1 genes, our goal here was to explore lesser effects of gene-gene interactions. We conducted an exhaustive genome-wide analysis of GWAS data of NPC, revealing two-locus interactions occurring between single nucleotide polymorphisms (SNPs), and identified a number of suggestive interaction loci which were missed by traditional GWAS analyses. Although none of the interaction pairs we identified passed the genome-wide Bonferroni-adjusted threshold for significance, using independent GWAS data from the same population (Stage 2), we selected 66 SNP pairs in 39 clusters with P
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- 2013
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25. Serum CXCL9 levels are associated with tumor progression and treatment outcome in patients with nasopharyngeal carcinoma.
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Li-Jen Hsin, Huang-Kai Kao, I-How Chen, Ngan-Ming Tsang, Cheng-Lung Hsu, Shiau-Chin Liu, Yu-Sun Chang, and Kai-Ping Chang
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Medicine ,Science - Abstract
OBJECTIVES: The aim of this cohort study was to examine the role of the chemokine (C-X-C motif) ligand 9 (CXCL9) on nasopharyngeal carcinoma (NPC). MATERIALS & METHODS: Sera from 205 NPC patients and 231 healthy individuals, and 86 NPC tumor samples were enrolled. CXCL9 expression in tissue samples was analyzed by quantitative real-time PCR and immunohistochemistry. CXCL9 serum concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: CXCL9 expression was significantly higher in tumors than in normal epithelium. CXCL9 serum concentrations were also significantly higher in NPC patients compared to those in healthy individuals (516.8±617.6 vs. 170.7±375.0 pg/mL, P290 pg/mL, median) before treatment had worse prognoses for overall survival and disease-free survival (P = 0.045 and P = 0.008, respectively). Multivariate logistic regression analyses also indicated that higher CXCL9 serum levels were an independent prognostic factor for disease-free survival (P = 0.015). CONCLUSION: Our study demonstrated that CXCL9 is associated with tumor burden and aggressiveness of NPC tumors and the serum level of this ligand may be useful as a prognostic indicator.
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- 2013
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26. Epstein-Barr virus-encoded LMP1 interacts with FGD4 to activate Cdc42 and thereby promote migration of nasopharyngeal carcinoma cells.
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Hao-Ping Liu, Chia-Chun Chen, Chih-Ching Wu, Yi-Chuan Huang, Shu-Chen Liu, Ying Liang, Kai-Ping Chang, and Yu-Sun Chang
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC), a human malignancy notorious for its highly metastatic nature. Among EBV-encoded genes, latent membrane protein 1 (LMP1) is expressed in most NPC tissues and exerts oncogenicity by engaging multiple signaling pathways in a ligand-independent manner. LMP1 expression also results in actin cytoskeleton reorganization, which modulates cell morphology and cell motility- cellular process regulated by RhoGTPases, such as Cdc42. Despite the prominent association of Cdc42 activation with tumorigenesis, the molecular basis of Cdc42 activation by LMP1 in NPC cells remains to be elucidated. Here using GST-CBD (active Cdc42-binding domain) as bait in GST pull-down assays to precipitate active Cdc42 from cell lysates, we demonstrated that LMP1 acts through its transmembrane domains to preferentially induce Cdc42 activation in various types of epithelial cells, including NPC cells. Using RNA interference combined with re-introduction experiments, we identified FGD4 (FYVE, RhoGEF and PH domain containing 4) as the GEF (guanine nucleotide exchange factor) responsible for the activation of Cdc42 by LMP1. Serial deletion experiments and co-immunoprecipitation assays further revealed that ectopically expressed FGD4 modulated LMP1-mediated Cdc42 activation by interacting with LMP1. Moreover, LMP1, through its transmembrane domains, directly bound FGD4 and enhanced FGD4 activity toward Cdc42, leading to actin cytoskeleton rearrangement and increased motility of NPC cells. Depletion of FGD4 or Cdc42 significantly reduced (∼50%) the LMP1-stimulated cell motility, an effect that was partially reversed by expression of a constitutively active mutant of Cdc42. Finally, quantitative RT-PCR and immunohistochemistry analyses showed that FGD4 and LMP1 were expressed in NPC tissues, supporting the potential physiologically relevance of this mechanism in NPC. Collectively, our results not only uncover a novel mechanism underlying LMP1-mediated Cdc42 activation, namely LMP1 interaction with FGD4, but also functionally link FGD4 to NPC tumorigenesis.
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- 2012
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27. Evaluation of human leukocyte antigen-A (HLA-A), other non-HLA markers on chromosome 6p21 and risk of nasopharyngeal carcinoma.
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Wan-Lun Hsu, Ka-Po Tse, Sharon Liang, Yin-Chu Chien, Wen-Hui Su, Kelly J Yu, Yu-Juen Cheng, Ngan-Ming Tsang, Mow-Ming Hsu, Kai-Ping Chang, I-How Chen, Tzu-I Chen, Czau-Siung Yang, Alisa M Goldstein, Chien-Jen Chen, Yu-Sun Chang, and Allan Hildesheim
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Medicine ,Science - Abstract
BACKGROUND:The association between human leukocyte antigen (HLA) genes (located in the Major Histocompatibility Complex [MHC] region of chromosome 6p21) and NPC has been known for some time. Recently, two genome-wide association studies (GWAS) conducted in Taiwan and China confirmed that the strongest evidence for NPC association was mapped to the MHC region. It is still unclear, however, whether these findings reflect direct associations with Human Leukocyte Antigen (HLA) genes and/or to other genes in this gene-rich region. METHODS:To better understand genetic associations for NPC within the MHC region of chromosome 6, we conducted an evaluation that pooled two previously conducted NPC case-control studies in Taiwan (N = 591 cases and N = 521 controls). PCR-based genotyping was performed for 12 significant SNPs identified within 6p21 in the Taiwan NPC GWAS and for the HLA-A gene (exons 2 and 3). FINDINGS:After confirming homogeneity between the two studies, pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. We found that HLA-A (p-trend = 0.0006) and rs29232 (within the GABBR1 gene; p-trend = 0.005) were independent risk factors for NPC after adjustment for age, gender, study and each other. NPC risk was highest among individuals who were homozygous for the HLA-A*0207 risk allele and carriers of the rs29232 risk allele (A). CONCLUSION:Our study suggests that most of the SNPs significantly associated with NPC from GWAS reflect previously identified HLA-A associations. An independent effect of rs29232 (GABBR1), however, remained, suggesting that additional genes within this region might be associated with NPC risk.
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- 2012
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28. A novel role of RASSF9 in maintaining epidermal homeostasis.
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Chiou-Mei Lee, Polung Yang, Lih-Chyang Chen, Chia-Chun Chen, Shinn-Chih Wu, Hsiao-Yun Cheng, and Yu-Sun Chang
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Medicine ,Science - Abstract
The physiological role of RASSF9, a member of the Ras-association domain family (RASSF), is currently unclear. Here, we report a mouse line in which an Epstein-Barr virus Latent Membrane Protein 1 (LMP1) transgene insertion has created a 7.2-kb chromosomal deletion, which abolished RASSF9 gene expression. The RASSF9-null mice exhibited interesting phenotypes that resembled human ageing, including growth retardation, short lifespan, less subcutaneous adipose layer and alopecia. In the wild-type mice, RASSF9 is predominantly expressed in the epidermal keratinocytes of skin, as determined by quantitative reverse-transcription PCR, immunofluorescence and in situ hybridization. In contrast, RASSF9-/- mice presented a dramatic change in epithelial organization of skin with increased proliferation and aberrant differentiation as detected by bromodeoxyuridine incorporation assays and immunofluorescence analyses. Furthermore, characteristic functions of RASSF9-/- versus wild type (WT) mouse primary keratinocytes showed significant proliferation linked to a reduction of p21Cip1 expression under growth or early differentiation conditions. Additionally, in RASSF9-/- keratinocytes there was a drastic down-modulation of terminal differentiation markers, which could be rescued by infection with a recombinant adenovirus, Adv/HA-RASSF9. Our results indicate a novel and significant role of RASSF9 in epidermal homeostasis.
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- 2011
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29. Secretome-based identification of ULBP2 as a novel serum marker for pancreatic cancer detection.
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Ya-Ting Chang, Chih-Ching Wu, Yi-Ming Shyr, Tse-Ching Chen, Tsann-Long Hwang, Ta-Sen Yeh, Kai-Ping Chang, Hao-Ping Liu, Yu-Ling Liu, Ming-Hung Tsai, Yu-Sun Chang, and Jau-Song Yu
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Medicine ,Science - Abstract
BackgroundTo discover novel markers for improving the efficacy of pancreatic cancer (PC) diagnosis, the secretome of two PC cell lines (BxPC-3 and MIA PaCa-2) was profiled. UL16 binding protein 2 (ULBP2), one of the proteins identified in the PC cell secretome, was selected for evaluation as a biomarker for PC detection because its mRNA level was also found to be significantly elevated in PC tissues.MethodsULBP2 expression in PC tissues from 67 patients was studied by immunohistochemistry. ULBP2 serum levels in 154 PC patients and 142 healthy controls were measured by bead-based immunoassay, and the efficacy of serum ULBP2 for PC detection was compared with the widely used serological PC marker carbohydrate antigen 19-9 (CA 19-9).ResultsImmunohistochemical analyses revealed an elevated expression of ULPB2 in PC tissues compared with adjacent non-cancerous tissues. Meanwhile, the serum levels of ULBP2 among all PC patients (n = 154) and in early-stage cancer patients were significantly higher than those in healthy controls (pConclusionsCollectively, our results indicate that ULBP2 may represent a novel and useful serum biomarker for pancreatic cancer primary screening.
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- 2011
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30. Characterization of Epstein-Barr virus miRNAome in nasopharyngeal carcinoma by deep sequencing.
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Shu-Jen Chen, Gian-Hung Chen, Yi-Hsuan Chen, Cheng-Yuan Liu, Kai-Ping Chang, Yu-Sun Chang, and Hua-Chien Chen
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Medicine ,Science - Abstract
Virus-encoded microRNAs (miRNAs) have been shown to regulate a variety of biological processes involved in viral infection and viral-associated pathogenesis. Epstein-Barr virus (EBV) is a herpesvirus implicated in nasopharyngeal carcinoma (NPC) and other human malignancies. EBV-encoded miRNAs were among the first group of viral miRNAs identified. To understand the roles of EBV miRNAs in the pathogenesis of NPC, we utilized deep sequencing technology to characterize the EBV miRNA transcriptome in clinical NPC tissues. We obtained more than 110,000 sequence reads in NPC samples and identified 44 EBV BART miRNAs, including four new mature miRNAs derived from previously identified BART miRNA precursor hairpins. Further analysis revealed extensive sequence variations (isomiRs) of EBV miRNAs, including terminal isomiRs at both the 5' and 3' ends and nucleotide variants. Analysis of EBV genomic sequences indicated that the majority of EBV miRNA nucleotide variants resulted from post-transcriptional modifications. Read counts of individual EBV miRNA in NPC tissue spanned from a few reads to approximately 18,000 reads, confirming the wide expression range of EBV miRNAs. Several EBV miRNAs were expressed at levels similar to highly abundant human miRNAs. Sequence analysis revealed that most of the highly abundant EBV miRNAs share their seed sequences (nucleotides 2-7) with human miRNAs, suggesting that seed sequence content may be an important factor underlying the differential accumulation of BART miRNAs. Interestingly, many of these human miRNAs have been found to be dysregulated in human malignancies, including NPC. These observations not only provide a potential linkage between EBV miRNAs and human malignancy but also suggest a highly coordinated mechanism through which EBV miRNAs may mimic or compete with human miRNAs to affect cellular functions.
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- 2010
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31. Urinary Metabolomic Analysis of Prostate Cancer by UPLC-FTMS and UPLC-Ion Trap MSn
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Juo, Chien-Lun Chen, Yi-Ting Chen, Wen-Yu Liao, Yu-Sun Chang, Jau-Song Yu, and Bao-Rong
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urinary metabolomics ,prostate cancer ,biomarker - Abstract
Accumulative evidence suggests metabolic disorders correlate with prostate cancer. Metabolic profiling of urine allows the measurement of numerous metabolites simultaneously. This study set up a metabolomic platform consisting of UPLC-FTMS and UPLC-ion trap MSn for urine metabolome analysis. The platform improved retention time, mass accuracy, and signal stability. Additionally, the product ion spectrum obtained from ion trap MSn facilitated structure elucidation of candidate metabolites, especially when authentic standards were not available. Urine samples from six hernia patients and six BPH patients were used for the initial establishment of the analytic platform. This platform was further employed to analyze the urine samples of 27 PCa and 49 BPH patients. Choosing the upper and lower 16% of metabolites, 258 metabolite candidates were selected. Twenty-four of them with AUC values larger than 0.65 were further selected. Eighteen of the twenty-four features can be matched in METLIN and HMDB. Eleven of the eighteen features can be interpreted by MSn experiments. They were used for the combination achieving the best differential power. Finally, four metabolites were combined to reach the AUC value of 0.842 (CI 95, 0.7559 to 0.9279). This study demonstrates the urinary metabolomic analysis of prostate cancer and sheds light on future research.
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- 2023
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32. Prognostic value of an APOBEC3 deletion polymorphism for glioma patients in Taiwan
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Chia-Hua Chen, Kuo-Chen Wei, Wei-Chao Liao, You-Yu Lin, Hsiu-Chi Chen, Li-Ying Feng, Chiung-Hui Liu, Chiung-Yin Huang, Ko-Ting Chen, Chi-Sheng Wu, Yu-Sun Chang, Jau-Song Yu, and Ian Yi-Feng Chang
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General Medicine - Abstract
OBJECTIVE The molecular pathogenesis of malignant gliomas, characterized by diverse tumor histology with differential prognosis, remains largely unelucidated. An APOBEC3 deletion polymorphism, with a deletion in APOBEC3B, has been correlated to risk and prognosis in several cancers, but its role in glioma is unclear. The authors aimed to examine the clinical relevance of the APOBEC3 deletion polymorphism to glioma risk and survival in a glioma patient cohort in Taiwan. METHODS The authors detected deletion genotypes in 403 glioma patients and 1365 healthy individuals in Taiwan and correlated the genotypes with glioma risk, clinicopathological factors, patient survival, and patient sex. APOBEC3 gene family expression was measured and correlated to the germline deletion. A nomogram model was constructed to predict patient survival in glioma. RESULTS The proportion of APOBEC3B−/− and APOBEC3B+/− genotypes was higher in glioblastoma (GBM) patients than healthy individuals and correlated with higher GBM risk in males. A higher percentage of cases with APOBEC3B− was observed in male than female glioma patients. The presence of APOBEC3B−/− was correlated with better overall survival (OS) in male astrocytic glioma patients. No significant correlation of the genotypes to glioma risk and survival was observed in the female patient cohort. Lower APOBEC3B expression was observed in astrocytic glioma patients with APOBEC3B−/− and was positively correlated with better OS. A 5-factor nomogram model was constructed based on male patients with astrocytic gliomas in the study cohort and worked efficiently for predicting patient OS. CONCLUSIONS The germline APOBEC3 deletion was associated with increased GBM risk and better OS in astrocytic glioma patients in the Taiwan male population. The APOBEC3B deletion homozygote was a potential independent prognostic factor predicting better survival in male astrocytic glioma patients.
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- 2022
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33. Data from A GWAS Meta-analysis and Replication Study Identifies a Novel Locus within CLPTM1L/TERT Associated with Nasopharyngeal Carcinoma in Individuals of Chinese Ancestry
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Allan Hildesheim, Yi-Xin Zeng, Jian-Jun Liu, Gang-Qiao Zhou, Hongxin Zhang, Yun-Fei Xia, Ka-Po Tse, Soo-Hwang Teo, Kin-Choo Pua, Hao-Yuan Mo, Wen-Sheng Liu, Alan Soo-Beng Khoo, Wei-Hua Jia, Yun-Miao Guo, Qi-Shen Feng, Fu-Tuo Feng, Qian Cui, Ming-Yuan Chen, Li-Zhen Chen, Yu-Sun Chang, Chien-Jen Chen, James D. McKay, Wan-Lun Hsu, Pei-Jen Lou, Yoon-Ming Chin, Kai Yu, Ching-Ching Ng, Wen-Hui Su, and Jin-Xin Bei
- Abstract
Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied.Methods: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case–control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that combined results from the initial GWA and replication studies was performed.Results: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR = 0.81; P value 6.3 × 10−13). Our results also provide support for associations reported from published NPC GWAS—rs6774494 (P = 1.5 × 10−12; located in the MECOM gene region), rs9510787 (P = 5.0 × 10−10; located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P = 2.8 × 10−8, P = 7.0 × 10−7, and P = 8.4 × 10−7, respectively; located in the CDKN2A/B gene region).Conclusions: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity.Impact: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(1); 188–92. ©2015 AACR.
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- 2023
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34. Supplementary Data from Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer
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Ruth M. Pfeiffer, Allan Hildesheim, Hwai-I Yang, Nathaniel Rothman, James D. McKay, Mei-Hsuan Lee, Qing Lan, Ulf Gyllensten, Chien-Jen Chen, Yu-Sun Chang, Meredith Yeager, Kelly J. Yu, Andriy Derkach, and Zhiwei Liu
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Supplementary Materials and Tables
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- 2023
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35. Data from MCP-1 Promoter Polymorphism at −2518 Is Associated with Metastasis of Nasopharyngeal Carcinoma after Treatment
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Yu-Sun Chang, Ling-Ling Hsieh, Sheng-Po Hao, Jau-Song Yu, Kai-Ping Chang, Chuen Hsueh, Ying Liang, Hsin-Pai Li, Kung-Den Chen, Nang-Ming Tsang, and Ka-Po Tse
- Abstract
Purpose: We herein examined whether the single nucleotide polymorphism (SNP) at −2518 of the MCP-1 gene promoter region influences clinical outcomes among nasopharyngeal carcinoma (NPC) patients.Experimental Design: The study population consisted of 411 NPC patients without metastasis at diagnosis. All patients were treated at the Chang Gung Memorial Hospital from March 1994 to November 2004. The MCP-1 SNP−2518 genotype of each patient was determined by TaqMan genotyping kit. Statistical analyses were conducted to compare disease-specific survival (DSS), progression-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) of patients according to genotype. MCP-1 expression in tumor biopsies was examined by immunohistochemistry.Results: Among 411 NPC patients, carriers of AA and AG genotypes were prone to distant metastasis than that of GG genotype (hazard ratio, 2.21; P = 0.017, and hazard ratio, 2.23; P = 0.005, for AA and AG genotype, respectively) after initial radiotherapy. No genotype-specific significant difference was found in DSS, PFS, and LRFS. Furthermore, immunohistochemistry revealed that MCP-1 expression level was higher in NPC tumor cells from GG carriers compared with those from AA and AG carriers.Conclusions:MCP-1 SNP−2518 may be a valuable genetic marker for assessing the risk of developing distant metastasis after the radiotherapy in NPC patients. Carriers of A allele may require more aggressive chemotherapy implicating a potential marker for personalized medicine. We speculate that a regulatory SNP may be associated with the distant metastasis of NPC. Validation studies are warranted.
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- 2023
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36. Supplemental Tables 1S-2S from A GWAS Meta-analysis and Replication Study Identifies a Novel Locus within CLPTM1L/TERT Associated with Nasopharyngeal Carcinoma in Individuals of Chinese Ancestry
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Allan Hildesheim, Yi-Xin Zeng, Jian-Jun Liu, Gang-Qiao Zhou, Hongxin Zhang, Yun-Fei Xia, Ka-Po Tse, Soo-Hwang Teo, Kin-Choo Pua, Hao-Yuan Mo, Wen-Sheng Liu, Alan Soo-Beng Khoo, Wei-Hua Jia, Yun-Miao Guo, Qi-Shen Feng, Fu-Tuo Feng, Qian Cui, Ming-Yuan Chen, Li-Zhen Chen, Yu-Sun Chang, Chien-Jen Chen, James D. McKay, Wan-Lun Hsu, Pei-Jen Lou, Yoon-Ming Chin, Kai Yu, Ching-Ching Ng, Wen-Hui Su, and Jin-Xin Bei
- Abstract
Supplemental Table 1S. Sequenome Primer Design for 43 SNPs included in Our Replications Studies. Supplemental Table 2S. Results from NPC GWAS Meta-Analysis.
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- 2023
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37. Supplemental Figure 1S from A GWAS Meta-analysis and Replication Study Identifies a Novel Locus within CLPTM1L/TERT Associated with Nasopharyngeal Carcinoma in Individuals of Chinese Ancestry
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Allan Hildesheim, Yi-Xin Zeng, Jian-Jun Liu, Gang-Qiao Zhou, Hongxin Zhang, Yun-Fei Xia, Ka-Po Tse, Soo-Hwang Teo, Kin-Choo Pua, Hao-Yuan Mo, Wen-Sheng Liu, Alan Soo-Beng Khoo, Wei-Hua Jia, Yun-Miao Guo, Qi-Shen Feng, Fu-Tuo Feng, Qian Cui, Ming-Yuan Chen, Li-Zhen Chen, Yu-Sun Chang, Chien-Jen Chen, James D. McKay, Wan-Lun Hsu, Pei-Jen Lou, Yoon-Ming Chin, Kai Yu, Ching-Ching Ng, Wen-Hui Su, and Jin-Xin Bei
- Abstract
Supplemental Figure 1S. Individual Study Results from GWAS Meta-Analysis and Replication Studies for Selected SNPs.
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- 2023
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38. Data from Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer
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Ruth M. Pfeiffer, Allan Hildesheim, Hwai-I Yang, Nathaniel Rothman, James D. McKay, Mei-Hsuan Lee, Qing Lan, Ulf Gyllensten, Chien-Jen Chen, Yu-Sun Chang, Meredith Yeager, Kelly J. Yu, Andriy Derkach, and Zhiwei Liu
- Abstract
Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case–control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4+ T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis.Significance:GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.
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- 2023
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39. Supplementary Data from MCP-1 Promoter Polymorphism at −2518 Is Associated with Metastasis of Nasopharyngeal Carcinoma after Treatment
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Yu-Sun Chang, Ling-Ling Hsieh, Sheng-Po Hao, Jau-Song Yu, Kai-Ping Chang, Chuen Hsueh, Ying Liang, Hsin-Pai Li, Kung-Den Chen, Nang-Ming Tsang, and Ka-Po Tse
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Supplementary Figure S1; Supplementary Materials and Methods; Supplementary Tables S1-S2.
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- 2023
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40. Supplementary Data from Macrophage Inflammatory Protein-3α Is a Novel Serum Marker for Nasopharyngeal Carcinoma Detection and Prediction of Treatment Outcomes
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Jau-Song Yu, Yu-Sun Chang, Yin Liang, Pei-Cih Wei, Yu-Lun Liu, Shiau-Chin Liu, Shir-Hwa Ueng, Chen-Lung Hsu, Yun-Shien Lee, Ngan-Ming Tsang, Chih-Ching Wu, Jui-Hung Chang, Sheng-Po Hao, and Kai-Ping Chang
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Supplementary Data from Macrophage Inflammatory Protein-3α Is a Novel Serum Marker for Nasopharyngeal Carcinoma Detection and Prediction of Treatment Outcomes
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- 2023
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41. Data from Macrophage Inflammatory Protein-3α Is a Novel Serum Marker for Nasopharyngeal Carcinoma Detection and Prediction of Treatment Outcomes
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Jau-Song Yu, Yu-Sun Chang, Yin Liang, Pei-Cih Wei, Yu-Lun Liu, Shiau-Chin Liu, Shir-Hwa Ueng, Chen-Lung Hsu, Yun-Shien Lee, Ngan-Ming Tsang, Chih-Ching Wu, Jui-Hung Chang, Sheng-Po Hao, and Kai-Ping Chang
- Abstract
Purpose: We herein examine whether macrophage inflammatory protein-3α (MIP-3α) is a biomarker for nasopharyngeal carcinoma (NPC) and whether it is involved in modulating NPC cell functions.Experimental Design: The study population comprises 275 NPC patients and 250 controls. MIP-3α levels in tissues and sera were examined by immunohistochemistry and ELISA, respectively. EBV DNA load and EBV viral capsid antigen IgA were measured by quantitative real-time PCR and immunofluorescence assay, respectively. Effects of MIP-3α on NPC cell motility were investigated by Transwell migration/invasion assays and RNA interference.Results: MIP-3α was overexpressed in NPC tumor cells. Serum MIP-3α levels were significantly higher in untreated patients, recurrent patients and patients with distant metastases versus non-NPC controls, patients with complete remission, and long-term disease-free patients. In the prospective cohort, serum MIP-3α levels were significantly higher in untreated NPC patients with advanced tumor-node-metastasis stage versus early stage and also correlated with EBV DNA load. Measurement of MIP-3α, EBV DNA, and viral capsid antigen IgA levels in serial serum/plasma samples from treated patients at 6-month intervals revealed a high association between MIP-3α level, EBV DNA load, and disease status. Among 155 consecutive NPC patients, subjects with pretreated MIP-3α serum levels over 65 pg/mL had worse prognoses for overall survival and distant metastasis-free survival in univariate and multivariate analysis. Additionally, cell functional assays showed that MIP-3α contributed to migration and invasion of NPC cells, which could be effectively inhibited by MIP-3α knockdown.Conclusions: MIP-3α may be a novel biomarker and prognosticator for NPC and is involved in migration and invasion of NPC cells.
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- 2023
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42. Supplemental Figures from Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer
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Ruth M. Pfeiffer, Allan Hildesheim, Hwai-I Yang, Nathaniel Rothman, James D. McKay, Mei-Hsuan Lee, Qing Lan, Ulf Gyllensten, Chien-Jen Chen, Yu-Sun Chang, Meredith Yeager, Kelly J. Yu, Andriy Derkach, and Zhiwei Liu
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Supplementary Figures 1-5.
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- 2023
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43. Supplementary Figures 1-10, Tables 1-3 from Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
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Yu-Wei Leu, Shu-Huei Hsiao, Tim H.-M. Huang, Kenneth P. Nephew, Long-Bin Jeng, Kuen-daw Tsai, H. Sunny Sun, Chi-Sheng Wu, Yu-Sun Chang, Shaw-Jenq Tsai, Min-Jen Tseng, Victor X. Jin, Kun-Tu Yeh, Pei-Yi Chu, Kuan-Der Lee, Pei-Chi Hou, and I-Wen Teng
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Supplementary Figures 1-10, Tables 1-3 from Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
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- 2023
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44. Supplementary Figure 4A from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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Yu-Sun Chang, Jau-Song Yu, Ka-Po Tse, Sai Wah Tsao, Chi-Long Chen, Ying Liang, Chuen Hsueh, Yen-Jung Lu, Hsin-Pai Li, and Chia-Lung Tsai
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Supplementary Figure 4B from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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- 2023
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45. Supplementary Figure 2 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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Yu-Sun Chang, Jau-Song Yu, Ka-Po Tse, Sai Wah Tsao, Chi-Long Chen, Ying Liang, Chuen Hsueh, Yen-Jung Lu, Hsin-Pai Li, and Chia-Lung Tsai
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Supplementary Figure 2 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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- 2023
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46. Supplementary Materials and Methods from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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Yu-Sun Chang, Jau-Song Yu, Ka-Po Tse, Sai Wah Tsao, Chi-Long Chen, Ying Liang, Chuen Hsueh, Yen-Jung Lu, Hsin-Pai Li, and Chia-Lung Tsai
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Supplementary Materials and Methods from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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- 2023
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47. Supplementary Figure 1 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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Yu-Sun Chang, Jau-Song Yu, Ka-Po Tse, Sai Wah Tsao, Chi-Long Chen, Ying Liang, Chuen Hsueh, Yen-Jung Lu, Hsin-Pai Li, and Chia-Lung Tsai
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Supplementary Figure 1 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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- 2023
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48. Supplementary Figure 3 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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Yu-Sun Chang, Jau-Song Yu, Ka-Po Tse, Sai Wah Tsao, Chi-Long Chen, Ying Liang, Chuen Hsueh, Yen-Jung Lu, Hsin-Pai Li, and Chia-Lung Tsai
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Supplementary Figure 3 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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- 2023
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49. Supplementary Figure 5 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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Yu-Sun Chang, Jau-Song Yu, Ka-Po Tse, Sai Wah Tsao, Chi-Long Chen, Ying Liang, Chuen Hsueh, Yen-Jung Lu, Hsin-Pai Li, and Chia-Lung Tsai
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Supplementary Figure 5 from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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- 2023
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50. Data from Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
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Yu-Sun Chang, Jau-Song Yu, Ka-Po Tse, Sai Wah Tsao, Chi-Long Chen, Ying Liang, Chuen Hsueh, Yen-Jung Lu, Hsin-Pai Li, and Chia-Lung Tsai
- Abstract
EBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH2-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IκB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor–associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor κB and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1. (Cancer Res 2006; 66(24): 11668-76)
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- 2023
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