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A Pan-Cancer Analysis on the Systematic Correlation of MutS Homolog 2 (MSH2) to a Malignant Tumor. JOURNAL OF ONCOLOGY 2022; 2022:9175402. [PMID: 35368899 PMCID: PMC8970884 DOI: 10.1155/2022/9175402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/02/2022] [Accepted: 03/04/2022] [Indexed: 11/18/2022]
Abstract
MutS homolog 2 (MSH2) is a crucial participant in human DNA repair, and lots of the studies functionally associated with it were begun with hereditary nonpolyposis colorectal cancer (HNPCC). MSH2 has also been reported to take part in the progresses of various tumors' formation. With the help of GTEx, CCLE, and TCGA pan-cancer databases, the analysis of MSH2 gene distribution in both tumor tissues and normal control tissues was carried out. Kaplan-Meyer survival plots and COX regression analysis were conducted for the assessment into the MSH2's impact on tumor patients' clinical prognosis. In an investigation to the association of MSH2 expression with immune infiltration level of various tumors and a similar study on tumor immune neoantigens, microsatellite instability was subsequently taken. It was found that high expression of MSH2 is prevalent in most cancers. MSH2's efficacy on clinical prognosis as well as immune infiltration in tumor patients revealed a fact that expression of MSH2 in prostate adenocarcinoma (PRAD), brain lower-grade glioma (LGG), breast-invasive carcinoma (BRCA), and head and neck squamous cell carcinoma (HNSC) posed a significant correlation with the immune cell infiltration level of patients. Likewise as above, MSH2's expression comes in a similar trend with tumor immune neoantigens and microsatellite instability. MSH2's expression in the majority of tumors is a direct factor to the activation of tumor-associated pathways as well as immune-associated pathways. MSH2's early screening or even therapeutic target role for sarcoma (SARC) diagnosis is contributing to the efficiency of early screening and overall survival in SARC patients.
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Gao Y, Luo XD, Yang XL, Tu D. Clinical significance of breast cancer susceptibility gene 1 expression in resected non-small cell lung cancer: A meta-analysis. World J Clin Cases 2021; 9:9090-9100. [PMID: 34786391 PMCID: PMC8567518 DOI: 10.12998/wjcc.v9.i30.9090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/25/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The clinical significance of breast cancer susceptibility gene 1 (BRCA1) in non-small cell lung cancer (NSCLC) patients undergoing surgery remains unclear up to now.
AIM To explore the relation of BRCA1 expression with clinicopathological characteristics and survival in patients with resected NSCLC.
METHODS EMBASE, PubMed, Web of Science, and The Cochrane Library databases were searched to identify the relevant articles. To assess the correlation between the expression of BRCA1 and clinicopathological characteristics and prognosis of patients with resected NSCLC patients, the combined relative risks or hazard ratios (HRs) with their corresponding 95% confidence intervals [CIs] were estimated.
RESULTS Totally, 11 articles involving 1041 patients were included in the meta-analysis. The results indicated that the expression of BRCA1 was significantly correlated with prognosis of resected NSCLC. Positive BRCA1 expression signified a shorter overall survival (HR = 1.60, 95%CI: 1.25-2.05; P < 0.001) and disease-free survival (HR = 1.78, 95%CI: 1.42-2.23; P < 0.001). However, no significant association of BRCA1 expression with any clinicopathological parameters was observed.
CONCLUSION BRCA1 expression indicates a poor prognosis in resected NSCLC patients. BRCA1 might serve as an independent biomarker to predict clinical outcomes and help to customize optimal adjuvant chemotherapy for NSCLC patients who had received surgical therapy.
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Affiliation(s)
- Yang Gao
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Xiao-Di Luo
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Xiao-Li Yang
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Dong Tu
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
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Montazeri V, Ghahremani MH, Montazeri H, Hasanzad M, Safavi DM, Ayati M, Chehrazi M, Arefi Moghaddam B, Ostad SN. A Preliminary Study of NER and MMR Pathways Involved in Chemotherapy Response in Bladder Transitional Cell Carcinoma: Impact on progression-free survival. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2020; 19:355-365. [PMID: 32922493 PMCID: PMC7462481 DOI: 10.22037/ijpr.2020.112646.13878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
One of the main genotoxic drugs used in bladder cancer chemotherapy is cisplatin. While it is applied in most types of cancers, resistance to cisplatin is wildly common. In order to overcome drug resistance, it is necessary to determine a predictive marker. This study was conducted to provide basic data for selecting and designing a gene profile for further cohort and RCT studies in the future to improve response to treatment in bladder cancer. The expression levels of ERCC1, MLH1, MSH2, and CTR1 mRNA were determined in the tumor tissue using real-time q-PCR. Progression-free survival (PFS) was analyzed in term of the level of genes expression. The results revealed that the level of ERCC1 mRNA expression was higher in the recurrence (R) group compared to the no recurrence (NR) group. Moreover, the PFS time was increased in the patients with an ERCC1 expression level of below 1.57. The level of MLH1 and MSH2 mRNA expression was lower in the R group compared to the NR group; therefore, PFS time was increased in the patients with MLH1 and MSH2 gene expression levels above the cutoff point. While the level of CTR1 mRNA expression was higher in the R group versus the NR group, the PFS time was longer in the patients with CTR1 expression levels of below 1.265 compared to the patients with high levels of CTR1 expression. It can be concluded that the level of ERCC1, MLH1, MSH2, and CTR1 mRNA expression may be associated with PFS time as possible therapeutic targets for decreasing cisplatin resistance.
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Affiliation(s)
- Vahideh Montazeri
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Montazeri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Mandana Hasanzad
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - D Majid Safavi
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Ayati
- Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Chehrazi
- Department of Biostatistics and Epidemiology, School of Public Health, Babol University of Medical Sciences, Babol, Iran
| | | | - Seyed Nasser Ostad
- Toxicology and Poisoning Research Centre, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Identification of PDL1-Related Biomarkers to Select Lung Adenocarcinoma Patients for PD1/PDL1 Inhibitors. DISEASE MARKERS 2020; 2020:7291586. [PMID: 32587640 PMCID: PMC7303743 DOI: 10.1155/2020/7291586] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 03/15/2020] [Accepted: 05/25/2020] [Indexed: 12/23/2022]
Abstract
PD1/PDL1 inhibitors have been adopted for the treatment of advanced non-small-cell lung cancer, and PDL1 expression has been investigated as a predictive biomarker for PD1/PDL1 inhibitor therapy. However, PDL1 lacks diagnostic accuracy in differentiating patients who are likely or unlikely to benefit. So, it is urgent and clinically significant to identify other associated predictive biomarkers for PD1/PDL1 inhibitor therapy. Our work was to identify PDL1-related biomarkers that could improve the patient selection for PD1/PDL1 inhibitor treatment. We obtained 500 genes coexpressed with PDL1 in lung adenocarcinoma from the TCGA database. Then, we identified 125 out of 500 genes differentially expressed in lung adenocarcinoma. A total of 39 genes were distinguished with prognostic value and associated with overall survival. Median survival time analysis based on gene expression level, protein-protein interaction analysis, GO and KEGG enrichment analyses, and significant GO and KEGG function consistency analyses were conducted to screen candidate biomarkers. Three candidate genes, BRCA1, BRIP1, and EREG, were identified to be functionally significantly coexpressed with PDL1. Functional enrichment analysis and protein-protein interaction networks further showed that these genes mainly participated in immune response and cell activation. Additionally, to find potential adjuvant therapeutic targets in PD1/PDL1 inhibitor treatment, we performed transcription factor prediction analysis. A group of negative differential expression but PDL1-related biomarkers has been identified, which might help to assess the clinical management of lung cancer patients. A combination of potential biomarkers and adjuvant therapeutic targets with PDL1 will predict the response to PD1/PDL1 inhibitors more accurately and help with the patient selection for more personalized immune checkpoint inhibitor treatment.
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Dubois F, Keller M, Hoflack J, Maille E, Antoine M, Westeel V, Bergot E, Quoix E, Lavolé A, Bigay-Game L, Pujol JL, Langlais A, Morin F, Zalcman G, Levallet G. Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial. Cancers (Basel) 2019; 11:cancers11121835. [PMID: 31766357 PMCID: PMC6966477 DOI: 10.3390/cancers11121835] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/12/2019] [Accepted: 11/19/2019] [Indexed: 12/27/2022] Open
Abstract
RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Cancérologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models (HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP-1. Wound-healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of RASSF1 gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemo-sensitivity in lung cancer.
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Affiliation(s)
- Fatéméh Dubois
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, 14074 Caen, France; (F.D.); (M.K.); (E.M.); (E.B.)
- Department of Pathology, CHU de Caen, 14033 Caen, France
| | - Maureen Keller
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, 14074 Caen, France; (F.D.); (M.K.); (E.M.); (E.B.)
- Normandie Université, UNICAEN, UPRES-EA2608, 14032 Caen, France
| | - Julien Hoflack
- Normandie Université, UNICAEN, UPRES-EA2608, 14032 Caen, France
| | - Elodie Maille
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, 14074 Caen, France; (F.D.); (M.K.); (E.M.); (E.B.)
- Normandie Université, UNICAEN, INSERM UMR 1086 ANTICIPE, 14032 Caen, France
| | - Martine Antoine
- Department of Pathology, Hôpital Tenon, AP-HP, 75020 Paris, France;
| | - Virginie Westeel
- Department of Pneumology, University Hospital of Besançon, University Bourgogne Franche-Comté, 25000 Besançon, France;
| | - Emmanuel Bergot
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, 14074 Caen, France; (F.D.); (M.K.); (E.M.); (E.B.)
- Department of Pulmonology & Thoracic Oncology, CHU de Caen, 14033 Caen, France
| | - Elisabeth Quoix
- Department of Pneumology, University Hospital, 67000 Strasbourg, France;
| | - Armelle Lavolé
- Sorbonne Université, GRC n 04, Theranoscan, AP-HP, Service de Pneumologie, Hôpital Tenon, 75020 Paris, France;
| | - Laurence Bigay-Game
- Pneumology Department, Toulouse-Purpan, University Hospital Toulouse, 31300 Toulouse, France;
| | - Jean-Louis Pujol
- Département d’Oncologie Thoracique, CHU Montpellier, Univ. Montpellier, 34595 Montpellier, France;
| | - Alexandra Langlais
- Intergroupe Francophone de Cancérologie Thoracique (IFCT), 75009 Paris, France; (A.L.); (F.M.)
| | - Franck Morin
- Intergroupe Francophone de Cancérologie Thoracique (IFCT), 75009 Paris, France; (A.L.); (F.M.)
| | - Gérard Zalcman
- U830 INSERM “Genetics and Biology of Cancers, A.R.T Group”, Curie Institute, 75005 Paris, France
- Department of Thoracic Oncology & CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, 75018 Paris, France
- Correspondence: (G.Z.); (G.L.); Tel.: +33-(0)140-257-502 (G.Z.); +33-(0)231-063-134 (G.L.)
| | - Guénaëlle Levallet
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, 14074 Caen, France; (F.D.); (M.K.); (E.M.); (E.B.)
- Department of Pathology, CHU de Caen, 14033 Caen, France
- Correspondence: (G.Z.); (G.L.); Tel.: +33-(0)140-257-502 (G.Z.); +33-(0)231-063-134 (G.L.)
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Mao Y, Xue P, Li L, Xu P, Cai Y, Chu X, Jiang P, Zhu S. Bioinformatics analysis of mRNA and miRNA microarray to identify the key miRNA‑gene pairs in small‑cell lung cancer. Mol Med Rep 2019; 20:2199-2208. [PMID: 31257520 PMCID: PMC6691276 DOI: 10.3892/mmr.2019.10441] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 06/06/2019] [Indexed: 02/07/2023] Open
Abstract
Small-cell lung cancer (SCLC) is a type of lung cancer with early metastasis, and high recurrence and mortality rates. The molecular mechanism is still unclear and further research is required. The aim of the present study was to examine the pathogenesis and potential molecular markers of SCLC by comparing the differential expression of mRNA and microRNA (miRNA) between SCLC tissue and normal lung tissue. A transcriptome sequencing dataset (GSE6044) and a non-coding RNA sequence dataset (GSE19945) were downloaded from the Gene Expression Omnibus (GEO) database. In total, 451 differentially expressed genes (DEGs) and 134 differentially expressed miRNAs (DEMs) were identified using the R limma software package and the GEO2R tool of the GEO, respectively. The Gene Ontology function was significantly enriched for 28 terms, and the Kyoto Encyclopedia of Genes and Genomes database had 19 enrichment pathways, mainly related to ‘cell cycle’, ‘DNA replication’ and ‘oocyte meiosis mismatch repair’. The protein-protein interaction network was constructed using Cytoscape software to identify the molecular mechanisms of key signaling pathways and cellular activities in SCLC. The 1,402 miRNA-gene pairs encompassed 602 target genes of the DEMs using miRNAWalk, which is a bioinformatics platform that predicts DEM target genes and miRNA-gene pairs. There were 19 overlapping genes regulated by 32 miRNAs between target genes of the DEMs and DEGs. Bioinformatics analysis may help to better understand the role of DEGs, DEMs and miRNA-gene pairs in cell proliferation and signal transduction. The related hub genes may be used as biomarkers for the diagnosis and prognosis of SCLC, and as potential drug targets.
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Affiliation(s)
- Yun Mao
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Peng Xue
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Linlu Li
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Pengpeng Xu
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yafang Cai
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xuelei Chu
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Pengyuan Jiang
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Shijie Zhu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
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Lin XL, Sun QC, Lu Y, Han XQ, Zhao T, Zhou XH. [Proteomic analysis and verification of protein expression after upregulation of human CD99 in Hodgkin lymphoma cell line L428]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 40:490-496. [PMID: 31340622 PMCID: PMC7342398 DOI: 10.3760/cma.j.issn.0253-2727.2019.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Indexed: 11/22/2022]
Abstract
Objective: To investigate the proteins expression difference after upregulation of human CD99 in Hodgkin Lymphoma cell line, L428 cell, and verify the function of differential proteins. Methods: The differential proteins were detected by two-dimensional fluorescence difference gel electrophoresis and mass spectrometry analysis, cluster analysis was done by GOfact. Results: There were 38 proteins screened out, of which 21 proteins were positively associated with CD99, while 17 proteins were negative. Among the 38 proteins, 32 proteins participated in biological process, and 35 proteins were involved in the composition and construction. And 28 proteins participated in multifaceted biological activities including antioxidation, protein binding, catalytic activity, regulation of enzyme, signal transduction, molecular structure, regulation of translation and ion transport. Conclusions: The changes of the differential proteins, correlated with cytoskeleton, cell differentiation, signal pathway and regulating gene expression, are closely relevant to the translation between Hodgkin/Reed-Sternberg and B lymphocyte cell.
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Affiliation(s)
- X L Lin
- Department of Pathology, Southern Medical University, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, China
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Zeng Z, Li D, Yu T, Huang Y, Yan H, Gu L, Yuan J. Association and clinical implication of the USP10 and MSH2 proteins in non-small cell lung cancer. Oncol Lett 2018; 17:1128-1138. [PMID: 30655874 PMCID: PMC6312927 DOI: 10.3892/ol.2018.9702] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 10/12/2018] [Indexed: 12/22/2022] Open
Abstract
Ubiquitin-specific protease 10 (USP10) is involved in a number of biological processes by stabilizing several proteins, which have been implicated in multiple stages of tumorigenesis and progression. Previous studies have indicated that USP10 stabilizes and deubiquitinates MutS homolog 2 (MSH2) in in vitro and in vivo models. The level of MSH2 protein has been positively correlated with that of the USP10 protein in a panel of lung cancer cell lines. Furthermore, depletion of USP10 in lung cancer cells causes decreased apoptosis and increased cell survival upon treatment with DNA-damaging agents. However, the expression and clinical implication of USP10 protein in lung cancer tissues is not clear. Additionally, whether the level of MSH2 protein is positively correlated with that of the USP10 protein in lung cancer tissues also remains unresolved. Therefore, USP10 protein expression was detected in 148 human non-small cell lung cancer (NSCLC) and 139 non-cancerous lung tissues using immunohistochemistry, whereas mRNA was investigated by Gene Expression Omnibus dataset and The Cancer Genome Atlas database analyses. It was identified that USP10 protein expression was significantly downregulated in NSCLC tissues compared with in normal lung tissues (P<0.05). However, no significant difference in USP10 mRNA expression between the two tissues was identified. In addition, a positive correlation was observed between the USP10 and MSH2 proteins in NSCLC tissues (P<0.05). However, the clinicopathological features and survival analysis indicated that the USP10 and MSH2 proteins were not associated with clinical features, including age, sex, tumor size, Tumor-Node-Metastasis stage and tumor cell differentiation, along with the prognosis of NSCLC. Collectively, these results suggest that downregulation of USP10 protein serves an important function in the tumorigenesis of NSCLC, and the level of USP10 protein is positively correlated with that of MSH2 protein in NSCLC tissues, which may indicate that USP10 also stabilizes the MSH2 protein in patients with lung cancer.
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Affiliation(s)
- Zhi Zeng
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Dan Li
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Tao Yu
- Integrated Traditional Chinese and Western Medicine Ward, Oncology Department, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Yabing Huang
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Honglin Yan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jingping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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A Whole-genome CRISPR Screen Identifies a Role of MSH2 in Cisplatin-mediated Cell Death in Muscle-invasive Bladder Cancer. Eur Urol 2018; 75:242-250. [PMID: 30414698 DOI: 10.1016/j.eururo.2018.10.040] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/15/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades. OBJECTIVE To identify genes that influence cisplatin resistance in bladder cancer. DESIGN, SETTING, AND PARTICIPANTS We performed a whole-genome CRISPR screen in a bladder cancer cell line to identify genes that mediate resistance to cisplatin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Targeted validation was performed in two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset. RESULTS AND LIMITATIONS From the CRISPR screen, we identified MSH2 as the most significantly enriched gene and mismatch repair as the most significantly enriched pathway that promoted resistance to cisplatin. Bladder cancer cells with knockdown of MSH2 showed a reduction in cisplatin-mediated apoptosis. MSH2 loss did not impact the sensitivity to other chemotherapies, including the cisplatin analog oxaliplatin. Bladder tumors with low MSH2 protein levels, quantified using reverse-phase protein array, showed poorer survival when treated with cisplatin- or carboplatin-based therapy; these results require future validation using immunohistochemistry. Additionally, results are retrospective from patients with primarily high-grade tumors; thus, validation in a controlled clinical trial is needed. CONCLUSIONS We generated in vitro evidence that bladder cancer cell lines depleted of MSH2 are more resistant to cisplatin. We additionally found an association between low MSH2 in bladder tumors and poorer patient survival when treated with platinum-based chemotherapy. If successfully validated prospectively, MSH2 protein level could assist in the selection of patients for chemotherapy. PATIENT SUMMARY We report the first evidence that MSH2 protein level may contribute to chemotherapy resistance observed in muscle-invasive bladder cancer. MSH2 has potential as a biomarker predictive of response to platinum-based therapy.
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Fujii K, Miyata Y, Takahashi I, Koizumi H, Saji H, Hoshikawa M, Takagi M, Nishimura T, Nakamura H. Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer. Proteomics Clin Appl 2018; 12:e1800015. [PMID: 29888431 DOI: 10.1002/prca.201800015] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/10/2018] [Indexed: 12/15/2022]
Abstract
PURPOSE The molecular underpinnings that may prognosticate survival and increase our understanding of tumor development and progression are still poorly understood. This study aimed to define the molecular signatures for malignancy in small cell lung carcinoma (SCLC), which is known for its highly aggressive clinical features and poor prognosis. EXPERIMENTAL DESIGN Using clinical specimens, the authors perform a comparative proteomic analysis of high-grade SCLCs and low-grade pulmonary carcinoid tumors (PCTs), both of which are types of neuroendocrine tumors. A label-free LC-MS-based quantitative proteomic analysis is applied to tumor cells laser-microdissected from their formalin-fixed paraffin-embedded (FFPE) tissues obtained from six patients each. RESULTS Overall, 1991 proteins are identified from tumor cells in the FFPE tissues. Through the protein-protein interaction network analysis of 201 proteins significantly, the authors find that SCLC is functionally characterized by activation of molecular pathways for spliceosome, RNA transport, and DNA replication and cell cycle. Particularly, 11 proteins involved in tumor proliferation (MCM2, 4, 6, 7, and MSH2), metastasis (RCC2, CORO1C, CHD4, and IPO9), and cancer metabolism (PHGDH and TYMP) are identified as SCLC-specific proteins. Furthermore, their prognostic significances are demonstrated by online Kaplan-Meier survival analysis. CONCLUSIONS AND CLINICAL RELEVANCE These clinical tissue proteomic approach for SCLC reveals the proteins associated with aggressiveness and poor prognosis. The identified SCLC-specific proteins represent potential therapeutic targets. Moreover, MCMs and PHGDH can be poor prognostic factors for lung cancer.
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Affiliation(s)
- Kiyonaga Fujii
- Department of Translational Medicine Informatics, St. Marianna University School of Medicine, Kawasaki, Japan
| | | | | | - Hirotaka Koizumi
- Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Hisashi Saji
- Department of Chest Surgery, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masahiro Hoshikawa
- Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masayuki Takagi
- Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Toshihide Nishimura
- Department of Translational Medicine Informatics, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Haruhiko Nakamura
- Department of Translational Medicine Informatics, St. Marianna University School of Medicine, Kawasaki, Japan.,Department of Chest Surgery, St. Marianna University School of Medicine, Kawasaki, Japan
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Ensuring the Safety and Security of Frozen Lung Cancer Tissue Collections through the Encapsulation of Dried DNA. Cancers (Basel) 2018; 10:cancers10060195. [PMID: 29891792 PMCID: PMC6025404 DOI: 10.3390/cancers10060195] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/08/2018] [Accepted: 06/08/2018] [Indexed: 02/06/2023] Open
Abstract
Collected specimens for research purposes may or may not be made available depending on their scarcity and/or on the project needs. Their protection against degradation or in the event of an incident is pivotal. Duplication and storage on a different site is the best way to assure their sustainability. The conservation of samples at room temperature (RT) by duplication can facilitate their protection. We describe a security system for the collection of non-small cell lung cancers (NSCLC) stored in the biobank of the Nice Hospital Center, France, by duplication and conservation of lyophilized (dried), encapsulated DNA kept at RT. Therefore, three frozen tissue collections from non-smoking, early stage and sarcomatoid carcinoma NSCLC patients were selected for this study. DNA was extracted, lyophilized and encapsulated at RT under anoxic conditions using the DNAshell technology. In total, 1974 samples from 987 patients were encapsulated. Six and two capsules from each sample were stored in the biobanks of the Nice and Grenoble (France) Hospitals, respectively. In conclusion, DNA maintained at RT allows for the conservation, duplication and durability of collections of interest stored in biobanks. This is a low-cost and safe technology that requires a limited amount of space and has a low environmental impact.
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Zhu X, Wang Z, Qiu X, Wang W, Bei C, Tan C, Qin L, Ren Y, Tan S. Rs2303428 of MSH2 Is Associated with Hepatocellular Carcinoma Prognosis in a Chinese Population. DNA Cell Biol 2018; 37:634-641. [PMID: 29874113 DOI: 10.1089/dna.2018.4224] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The defects of DNA repair genes may lead to genomic instability and cancer. As an important DNA mismatch repair gene that maintains genomic stability from DNA replication errors, genetic variants of mutS homolog 2 (MSH2) are associated with some cancers. In this study, 1021 hepatocellular carcinoma (HCC) cases and 1021 non-HCC controls from Guangxi were included to explore the association between MSH2 single-nucleotide polymorphisms (SNPs) and HCC. Among the eight MSH2 SNPs, only genotype distribution of rs2303428 was significantly different from HCC and non-HCC patients (p < 0.05). Moreover, CT, TT, and CT/TT genotype of rs2303428 could increase HCC risk [OR (95% CI) = 1.758 (1.195-2.657), 1.846 (1.213-2.896), and 1.823 (1.219-2.763), respectively] and decrease the survival time of HCC patients [codominant, HR (95% CI) = 1.267 (1.046-1.535); dominant, HR (95% CI) = 1.675 (1.162-2.414)]. In addition, rs2303428 was found to interact with HBV infection and family history to increase HCC risk by gene-environment analysis (p < 0.05). Finally, multivariate COX regression analysis showed that rs2303428, tumor number, tumor staging, and metastasis had a significant influence on HCC prognosis. Our results provide MSH2 SNP, rs2303428, as a new prognostic biomarker for HCC patients.
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Affiliation(s)
- Xiaonian Zhu
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Zhigang Wang
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Xiaoqiang Qiu
- 2 Department of Epidemiology and Statistics, School of Public Health, Guangxi Medical University , Nanning, China
| | - Weiwei Wang
- 3 Department of Liver Transplantation, People's Hospital of Zhengzhou University , Zhengzhou, China
| | - Chunhua Bei
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Chao Tan
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Linyuan Qin
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Yuan Ren
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Shengkui Tan
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
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Progress in the Management of Early-Stage Non-Small Cell Lung Cancer in 2017. J Thorac Oncol 2018; 13:767-778. [PMID: 29654928 DOI: 10.1016/j.jtho.2018.04.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 04/03/2018] [Accepted: 04/04/2018] [Indexed: 12/17/2022]
Abstract
The landscape of care for early-stage non-small cell lung cancer continues to evolve. While some of the developments do not seem as dramatic as what has occurred in advanced disease in recent years, there is a continuous improvement in our ability to diagnose disease earlier and more accurately. We have an increased understanding of the diversity of early-stage disease and how to better tailor treatments to make them more tolerable without impacting efficacy. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in the care of early-stage lung cancer patients have provided focused updates across multiple areas including screening, pathology, staging, surgical techniques and novel technologies, adjuvant therapy, radiotherapy, surveillance, disparities, and quality of life. The source for information includes large academic meetings, the published literature, or novel unpublished data from other international oncology assemblies.
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Abstract
Maintaining the genetic integrity is a key process in cell viability and is enabled by a wide network of repair pathways. When this system is defective, it generates genomic instability and results in an accumulation of chromosomal aberrations and mutations that may be responsible for various clinical phenotypes, including susceptibility to develop cancer. Indeed, these defects can promote not only the initiation of cancer, but also allow the tumor cells to rapidly acquire mutations during their evolution. Several genes are involved in these damage repair systems and particular polymorphisms are predictive of the onset of cancer, the best described of them being BRCA. In addition to its impact on carcinogenesis, the DNA damage repair system is now considered as a therapeutic target of choice for cancer treatment, as monotherapy or in combination with other cytotoxic therapies, such as chemotherapies or radiotherapy. PARP inhibitors are nowadays the best known, but other agents are emerging in the field of clinical research. The enthusiasm in this area is coupled with promising results and a successful collaboration between clinicians and biologists would allow to optimize treatment plans in order to take full advantage of the DNA repair system modulation.
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