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Cook SR, Hugen S, Hayward JJ, Famula TR, Belanger JM, McNiel E, Fieten H, Oberbauer AM, Leegwater PA, Ostrander EA, Mandigers PJ, Evans JM. Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.14.604426. [PMID: 39372775 PMCID: PMC11451740 DOI: 10.1101/2024.08.14.604426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3, that have not been associated with human GC.
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Affiliation(s)
- Shawna R. Cook
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Sanne Hugen
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jessica J. Hayward
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Thomas R. Famula
- Department of Animal Science, University of California, Davis, CA, USA
| | | | - Elizabeth McNiel
- Cummings School of Veterinary Medicine, Tufts University, Grafton, Massachusetts, USA
| | - Hille Fieten
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | | | - Peter A.J. Leegwater
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Elaine A. Ostrander
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Center, National Institutes of Health, Bethesda, MD, USA
| | - Paul J.J. Mandigers
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jacquelyn M. Evans
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
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Li J, Yan Y, Wang G, Huang Z. Hypoxia-inducible factor-2α and its missense mutations: potential role in HCC diagnosis, progression, and prognosis and underlying mechanism. ONCOLOGY AND TRANSLATIONAL MEDICINE 2022; 8:267-275. [DOI: 10.1007/s10330-022-0598-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 12/01/2022] [Indexed: 01/04/2025]
Abstract
Abstract
Objective
This study aims to gain further the potential mechanisms of HIF-2α in tumor progression and tumorigenesis.
Methods
Mined The Cancer Genome Atlas (TCGA) dataset. In total, 421 participants were enrolled in the TCGAHepatocellular Carcinoma (HCC) study, comprising 371 patients with cancer and 50 healthy controls. From the 371 tumor samples, three samples containing the missense mutation of the HIF-2α gene were compared with 368 wild-type samples to identify differentially expressed genes (DEGs).
Results
After filtering, univariate Cox regression and multivariate Cox regression analyses showed that the differentially expressed genes (DEGs) progestagen-associated endometrial protein (PAEP) PNLIPRP2, MIR147B, and pregnancy zone protein (PZP) were significantly correlated with the survival times of patients with HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8 database to detect the functional annotation of these four DEGs as well as hub genes obtained from protein-protein interaction (PPI) network analysis using the STRING v10 database. Our analysis focused on the PAEP and PZP genes, whose protein expressions were downregulated in samples with HIF-2α missense mutation. The hub genes of PAEP and PZP were identified using PPI network analysis. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that PAEP and its hub genes were highly enriched in the TGF-β pathway, which is consistent with the analysis of PZP.
Conclusion
Our study proved that the missense mutation of HIF-2α induces the upregulation of PAEP, which is positively related to the poor prognosis of patients with HCC, as it may upregulate the TGF-β pathway. In contrast, PZP downregulation showed the opposite phenomenon, as it may downregulate the TGF-β pathway.
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Affiliation(s)
- Jun Li
- Emergency Department, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Yibo Yan
- Division of Cardiology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Ganxin Wang
- Division of Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zaozao Huang
- Yangchunhu Community Hospital, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
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Sznurkowska MK, Aceto N. The gate to metastasis: key players in cancer cell intravasation. FEBS J 2021; 289:4336-4354. [PMID: 34077633 PMCID: PMC9546053 DOI: 10.1111/febs.16046] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/19/2021] [Accepted: 06/01/2021] [Indexed: 02/06/2023]
Abstract
Metastasis is a leading cause of cancer‐related death and consists of a sequence of events including tumor expansion, intravasation of cancer cells into the circulation, survival in the bloodstream, extravasation at distant sites, and subsequent organ colonization. Particularly, intravasation is a process whereby cancer cells transverse the endothelium and leave the primary tumor site, pioneering the metastatic cascade. The identification of those mechanisms that trigger the entry of cancer cells into the bloodstream may reveal fundamentally novel ways to block metastasis at its start. Multiple factors have been implicated in cancer progression, yet, signals that unequivocally provoke the detachment of cancer cells from the primary tumor are still under investigation. Here, we discuss the role of intrinsic properties of cancer cells, tumor microenvironment, and mechanical cues in the intravasation process, outlining studies that suggest the involvement of various factors and highlighting current understanding and open questions in the field.
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Affiliation(s)
- Magdalena K Sznurkowska
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Switzerland
| | - Nicola Aceto
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Switzerland.,Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
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King R, Hayes C, Donohoe CL, Dunne MR, Davern M, Donlon NE. Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers. World J Gastrointest Oncol 2021; 13:312-331. [PMID: 34040696 PMCID: PMC8131902 DOI: 10.4251/wjgo.v13.i5.312] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/24/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The malfeasant role of the hypoxic tumour microenvironment (TME) in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be elucidated. Gastroesophageal cancers (GOCs) represent a major burden of worldwide disease, responsible for the deaths of over 1 million people annually. Disentangling the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these diseases. This review discusses the underlying principles and processes of the hypoxic response and the effect of hypoxia in promoting the hallmarks of cancer in the context of GOCs. We focus on its bidirectional influence on inflammation and how it drives angiogenesis, innate and adaptive immune evasion, metastasis, and the reprogramming of cellular bioenergetics. The contribution of the hypoxic GOC TME to treatment resistance is examined and a brief overview of the pharmacodynamics of hypoxia-targeted therapeutics is given. The principal methods that are used in measuring hypoxia and how they may enhance prognostication or provide rationale for individually tailored management in the case of tumours with significant hypoxic regions are also discussed.
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Affiliation(s)
- Ross King
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Conall Hayes
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Claire L Donohoe
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Margaret R Dunne
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Maria Davern
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Noel E Donlon
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
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Yao X, Ajani JA, Song S. Molecular biology and immunology of gastric cancer peritoneal metastasis. Transl Gastroenterol Hepatol 2020; 5:57. [PMID: 33073052 DOI: 10.21037/tgh.2020.02.08] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/03/2020] [Indexed: 12/24/2022] Open
Abstract
Peritoneal metastases occur in 55-60% of patients with gastric cancer (GC) and are associated with a 2% 5-year overall survival rate. There are limited treatment options for these patients, and no targeted therapy or immunotherapy is available. Rational therapeutic targets remain to be found. In this review, we present the published literature and our own recent experience in molecular biology to identify important molecules and signaling pathways as well as cellular immunity involved in the peritoneal metastasis of GC. We also suggest potential novel strategies for improving the outcomes of GC patients with peritoneal metastasis.
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Affiliation(s)
- Xiaodan Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Li Y, Wang Q, Ning N, Tang F, Wang Y. Bioinformatic analysis reveals MIR502 as a potential tumour suppressor in ovarian cancer. J Ovarian Res 2020; 13:77. [PMID: 32660514 PMCID: PMC7359466 DOI: 10.1186/s13048-020-00683-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/07/2020] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Ovarian cancer (OC) is a major cause of death among women due to the lack of early screening methods and its complex pathological progression. Increasing evidence has indicated that microRNAs regulate gene expression in tumours by interacting with mRNAs. Although the research regarding OC and microRNAs is extensive, the vital role of MIR502 in OC remains unclear. METHODS We integrated two microRNA expression arrays from GEO to identify differentially expressed genes. The Kaplan-Meier method was used to screen for miRNAs that had an influence on survival outcome. Upstream regulators of MIR502 were predicted by JASPAR and verified by ChIP-seq data. The LinkedOmics database was used to study genes that were correlated with MIR502. Gene Set Enrichment Analysis (GSEA) was conducted for functional annotation with GO and KEGG pathway enrichment analyses by using the open access WebGestalt tool. We constructed a PPI network by using STRING to further explore the core proteins. RESULTS We found that the expression level of MIR502 was significantly downregulated in OC, which was related to poor overall survival. NRF1, as an upstream regulator of MIR502, was predicted by JASPAR and verified by ChIP-seq data. In addition, anti-apoptosis and pro-proliferation genes in the Hippo signalling pathway, including CCND1, MYC, FGF1 and GLI2, were negatively regulated by MIR502, as shown in the GO and KEGG pathway enrichment results. The PPI network further demonstrated that CCND1 and MYCN were at core positions in the development of ovarian cancer. CONCLUSIONS MIR502, which is regulated by NRF1, acts as a tumour suppressor gene to accelerate apoptosis and suppress proliferation by targeting the Hippo signalling pathway in ovarian cancer.
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Affiliation(s)
- Yan Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang, China
| | - Qi Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang, China
| | - Ning Ning
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang, China
| | - Fanglan Tang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang, China
| | - Yan Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang, China.
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Guo F, Xue J. MicroRNA‑628‑5p inhibits cell proliferation and induces apoptosis in colorectal cancer through downregulating CCND1 expression levels. Mol Med Rep 2020; 21:1481-1490. [PMID: 32016467 PMCID: PMC7003041 DOI: 10.3892/mmr.2020.10945] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 11/22/2019] [Indexed: 12/17/2022] Open
Abstract
MicroRNA (miR)-628-5p serves as an antitumor gene in a variety of cancers; however, the role of miR-628-5p in colorectal cancer remains largely unclear. The purpose of this study was to investigate the role and mechanism of miR-628-5p in colorectal cancer. Reverse transcription-quantitative PCR (RT-qPCR), colony formation assays and flow cytometric analysis were used to determine the expression levels of miR-628-5p in colorectal cancer tissues and cell lines, and the proliferative ability of colorectal cancer cells. TargetScan version 7.2 and dual-luciferase reporter assay were performed to predict and confirm miR-628-5p target genes. The expression levels of cyclin D1 (CCND1) and related genes were determined using RT-qPCR or/and western blotting analysis. miR-628-5p mimics and CCND1 plasmids were used to overexpress miR-628-5p and CCND1; it was demonstrated that the expression levels of miR-628-5p were significantly downregulated in colorectal cancer tissues and cell lines. miR-628-5p mimic-transfected cells inhibited the proliferation and induced apoptosis of HT-29 cells. CCND1, a downstream effector of miR-628-5p, promoted the proliferation and suppressed apoptosis of HT-29 cells, and the effects were reversed by miR-628-5p mimics. In conclusion, the present study suggested that colorectal cancer progression may be regulated through the miR-628-5p/CCND1 axis, and miR-628-5p could be used as a potential diagnostic and prognostic biomarker for colorectal cancer.
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Affiliation(s)
- Fei Guo
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075061, P.R. China
| | - Jun Xue
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075061, P.R. China
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Luo D, Liu H, Lin D, Lian K, Ren H. The Clinicopathologic and Prognostic Value of Hypoxia-Inducible Factor-2α in Cancer Patients: A Systematic Review and Meta-Analysis. Cancer Epidemiol Biomarkers Prev 2018; 28:857-866. [PMID: 30591590 DOI: 10.1158/1055-9965.epi-18-0881] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/12/2018] [Accepted: 12/04/2018] [Indexed: 01/12/2023] Open
Abstract
Hypoxia-inducible factor-2α (HIF2α) plays an important role in the development of tumors. However, the clinicopathologic and prognostic significance of HIF2α in cancer patients remains controversial. Therefore, we performed a meta-analysis to investigate the relationship between the HIF2α status and clinical outcome in human cancer. Studies were screened online using electronic databases. The pooled risk ratios or hazard ratios (HR) with their 95% confidence intervals (CI) were calculated from available publications. Subgroup analysis, sensitivity analysis, heterogeneity, and publication bias were also conducted. A total of 854 studies with 4,345 patients were obtained in this meta-analysis. The results indicated that the increased expression of HIF2α could predict unfavorable overall survival of cancer patients on both univariate analysis (HR, 1.64; 95% CI, 1.41-1.92, P < 0.001) and multivariate analysis (HR, 2.21; 95% CI, 1.70-2.87, P < 0.001). Moreover, HIF2α overexpression was associated closely with tumor differentiation, tumor-node-metastasis stage, and lymph metastasis. In addition, there was no obvious evidence for significant publication bias in this meta-analysis. Our study indicated that HIF2α might be an indicator of poor prognosis and clinicopathologic features of tumors and could serve as a novel biomarker in human cancer.
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Affiliation(s)
- Deqing Luo
- Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China
| | - Hui Liu
- Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China
| | - Dasheng Lin
- Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China
| | - Kejian Lian
- Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China
| | - Hongyue Ren
- Department of Pathology, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China.
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Tang LR, Wu JX, Cai SL, Huang YX, Zhang XQ, Fu WK, Zhuang QY, Li JL. Prolyl hydroxylase domain 3 influences the radiotherapy efficacy of pancreatic cancer cells by targeting hypoxia-inducible factor-1α. Onco Targets Ther 2018; 11:8507-8515. [PMID: 30555241 PMCID: PMC6278705 DOI: 10.2147/ott.s187615] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Purpose Pancreatic cancer is characterized by a hypoxic microenvironment and resistance to most currently available treatment modalities. Prolyl hydroxylase domain 3 (PHD3) is a rate-limiting enzyme that regulates the degradation of hypoxia-inducible factors (HIFs) and is deregulated in pancreatic cancer cells. Whether such alteration of PHD3 expression contributes to the sustained growth and radioresistance of pancreatic cancer cells remains largely unknown. Materials and methods PHD3 was overexpressed in pancreatic cancer Mia-paca2 cells via lentiviral expression. Cell cycle progression and apoptosis were assayed by flow cytometry. HIF-1α, EGFR, and PHD3 protein expression was assessed by Western blotting. Cell survival was determined in a colony formation assay. Results PHD3 overexpression suppressed HIF-1α protein expression and EGFR phosphorylation and enhanced the 2 Gy irradiation-mediated reductions in HIF-1α and phosphorylated (p)-EGFR under either normoxic or hypoxic conditions. PHD3 overexpression inhibited the growth and colony formation of Mia-paca2 cells in response to irradiation under either normoxic or hypoxic conditions. PHD3 overexpression exacerbated irradiation-induced apoptosis, with a greater effect under hypoxia than normoxia. Cell cycle distribution analysis demonstrated that PHD3 overexpression resulted in further shortened S phase and lengthened G2/M phase in response to irradiation. Conclusion PHD3 expression may contribute to the radiotherapy efficacy of pancreatic cancer cells and serve as a novel biomarker for improving radiotherapy efficacy in pancreatic cancer.
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Affiliation(s)
- Li-Rui Tang
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China,
| | - Jun-Xin Wu
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China,
| | - Shao-Li Cai
- Key Laboratories of Innate Immune Biology of Fujian Province, Biomedical Research Center of South China, Fujian Normal University, Fuzhou, China
| | - Yun-Xia Huang
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China,
| | - Xue-Qing Zhang
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China,
| | - Wan-Kai Fu
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China,
| | - Qing-Yang Zhuang
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China,
| | - Jin-Luan Li
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China,
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Araos J, Sleeman JP, Garvalov BK. The role of hypoxic signalling in metastasis: towards translating knowledge of basic biology into novel anti-tumour strategies. Clin Exp Metastasis 2018; 35:563-599. [DOI: 10.1007/s10585-018-9930-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 08/13/2018] [Indexed: 02/06/2023]
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Li N, Han M, Zhou N, Tang Y, Tang XS. MicroRNA-495 Confers Increased Sensitivity to Chemotherapeutic Agents in Gastric Cancer via the Mammalian Target of Rapamycin (mTOR) Signaling Pathway by Interacting with Human Epidermal Growth Factor Receptor 2 (ERBB2). Med Sci Monit 2018; 24:5960-5972. [PMID: 30147110 PMCID: PMC6122272 DOI: 10.12659/msm.909458] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In recent years, the incidence of gastric cancer (GC) has been increasing worldwide. Emerging evidence shows that microRNAs (miRs) may be involved in the pathogenesis of GC. Thus, this study explored the mediatory role of miR-495 in GC chemosensitivity, and investigated the mechanism by which it affects the biological behaviors of GC cells via the mTOR signaling pathway. MATERIAL AND METHODS After GC and paracancerous tissue collection, the positive rate of ERBB2 and mTOR was evaluated by immunohistochemistry. Subsequently, the expression of miR-495, ERBB2, and mTOR was determined by RT-qPCR and Western blot analysis. Next, the targeting relationship between miR-495 and ERBB2 was confirmed by dual-luciferase reporter gene assay. In addition, chemosensitivity and proliferation were detected by MTT assay and apoptosis was assessed by flow cytometry. RESULTS We found higher positive rates of ERBB2 and mTOR and decreased expression of miR-495 in GC tissues and showed that ERBB2 is the target gene of miR-495. Furthermore, we determined that overexpression of miR-495 and silencing of ERBB2 enhanced GC cell chemosensitivity and apoptosis, but inhibited GC cell proliferation. We also found that the effect of miR-495 inhibition was lost when ERBB2 was suppressed. CONCLUSIONS The key findings of our study demonstrate that the miR-495 exerts promotive effects on GC chemosensitivity via inactivation of the mTOR signaling pathway by suppressing ERBB2. The study provides reliable evidence supporting the use of miR-495 as a novel potential target in the chemotherapy of GC.
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12
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Murugesan T, Rajajeyabalachandran G, Kumar S, Nagaraju S, Jegatheesan SK. Targeting HIF-2α as therapy for advanced cancers. Drug Discov Today 2018; 23:1444-1451. [DOI: 10.1016/j.drudis.2018.05.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 03/27/2018] [Accepted: 05/02/2018] [Indexed: 12/14/2022]
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Moreno Roig E, Yaromina A, Houben R, Groot AJ, Dubois L, Vooijs M. Prognostic Role of Hypoxia-Inducible Factor-2α Tumor Cell Expression in Cancer Patients: A Meta-Analysis. Front Oncol 2018; 8:224. [PMID: 29942795 PMCID: PMC6004384 DOI: 10.3389/fonc.2018.00224] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/30/2018] [Indexed: 12/21/2022] Open
Abstract
Hypoxia-inducible factor-2α (HIF-2α) plays an important role in tumor progression and metastasis. A number of studies have evaluated the correlation between HIF-2α overexpression and clinical outcome in cancer patients but yielded inconsistent results. To comprehensively and quantitatively summarize the evidence on the capability of HIF-2α to predict the prognosis of cancer patients with solid tumors, a meta-analysis was carried out. Renal cell carcinoma (CC-RCC) was separately analyzed due to an alternative mechanism of regulation. Systematic literature searches were performed in PubMed and Embase databases for relevant original articles until February 2018. Forty-nine studies with 6,052 patients were included in this study. The pooled hazard ratios (HRs) with corresponding confidence intervals were calculated to assess the prognostic value of HIF-2α protein expression in tumor cells. The meta-analysis revealed strong significant negative associations between HIF-2α expression and five endpoints: overall survival [HR = 1.69, 95% confidence interval (95% CI) 1.39-2.06], disease-free survival (HR = 1.87, 95% CI 1.2-2.92), disease-specific survival (HR = 1.57, 95% CI 1.06-2.34), metastasis-free survival (HR = 2.67, 95% CI 1.32-5.38), and progression-free survival (HR = 2.18, 95% CI 1.25-3.78). Subgroup analyses revealed similar associations in the majority of tumor sites. Overall, these data demonstrate a negative prognostic role of HIF-2α in patients suffering from different types of solid tumors.
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Affiliation(s)
- Eloy Moreno Roig
- Department of Radiotherapy (MAASTRO)/GROW - School for Developmental Biology and Oncology, Maastricht University, Maastricht, Netherlands
| | - Ala Yaromina
- Department of Radiotherapy (MAASTRO)/GROW - School for Developmental Biology and Oncology, Maastricht University, Maastricht, Netherlands
| | - Ruud Houben
- Department of Radiation Oncology, MAASTRO Clinic, Maastricht, Netherlands
| | - Arjan J Groot
- Department of Radiotherapy (MAASTRO)/GROW - School for Developmental Biology and Oncology, Maastricht University, Maastricht, Netherlands
| | - Ludwig Dubois
- Department of Radiotherapy (MAASTRO)/GROW - School for Developmental Biology and Oncology, Maastricht University, Maastricht, Netherlands
| | - Marc Vooijs
- Department of Radiotherapy (MAASTRO)/GROW - School for Developmental Biology and Oncology, Maastricht University, Maastricht, Netherlands
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Harashima N, Takenaga K, Akimoto M, Harada M. HIF-2α dictates the susceptibility of pancreatic cancer cells to TRAIL by regulating survivin expression. Oncotarget 2018; 8:42887-42900. [PMID: 28476028 PMCID: PMC5522113 DOI: 10.18632/oncotarget.17157] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 03/20/2017] [Indexed: 11/25/2022] Open
Abstract
Cancer cells develop resistance to therapy by adapting to hypoxic microenvironments, and hypoxia-inducible factors (HIFs) play crucial roles in this process. We investigated the roles of HIF-1α and HIF-2α in cancer cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) using human pancreatic cancer cell lines. siRNA-mediated knockdown of HIF-2α, but not HIF-1α, increased susceptibility of two pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL in vitro under normoxic and hypoxic conditions. The enhanced sensitivity to TRAIL was also observed in vivo. This in vitro increased TRAIL sensitivity was observed in other three pancreatic cancer cell lines. An array assay of apoptosis-related proteins showed that knockdown of HIF-2α decreased survivin expression. Additionally, survivin promoter activity was decreased in HIF-2α knockdown Panc-1 cells and HIF-2α bound to the hypoxia-responsive element in the survivin promoter region. Conversely, forced expression of the survivin gene in HIF-2α shRNA-expressing Panc-1 cells increased resistance to TRAIL. In a xenograft mouse model, the survivin suppressant YM155 sensitized Panc-1 cells to TRAIL. Collectively, our results indicate that HIF-2α dictates the susceptibility of human pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL by regulating survivin expression transcriptionally, and that survivin could be a promising target to augment the therapeutic efficacy of death receptor-targeting anti-cancer therapy.
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Affiliation(s)
- Nanae Harashima
- Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
| | - Keizo Takenaga
- Department of Life Science, Shimane University Faculty of Medicine, Shimane, Japan
| | - Miho Akimoto
- Department of Life Science, Shimane University Faculty of Medicine, Shimane, Japan
| | - Mamoru Harada
- Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
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15
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Liu X, Wang Y, Sun L, Min J, Liu J, Chen D, Zhang H, Zhang H, Zhang H, Zhou Y, Liu L. Long noncoding RNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia. Cancer Sci 2018; 109:988-1000. [PMID: 29383777 PMCID: PMC5891181 DOI: 10.1111/cas.13519] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 01/10/2018] [Accepted: 01/22/2018] [Indexed: 01/03/2023] Open
Abstract
Hypoxia plays a critical role in the metastasis of gastric cancer (GC), yet the underlying mechanism remains largely unclear. It is also not known whether long, noncoding RNAs (lncRNAs) are involved in the contribution of hypoxia to GC metastasis. In the present study, we found that lncRNA BC005927 can be induced by hypoxia in GC cells and mediates hypoxia-induced GC cell metastasis. Furthermore, BC005927 is frequently upregulated in GC samples and increased BC005927 expression was correlated with a higher tumor-node-metastasis stage. GC patients with higher BC005927 expression had poorer prognoses than those with lower expression. Additional experiments showed that BC005927 expression is induced by hypoxia inducible factor-1 alpha (HIF-1α); ChIP assay and luciferase reporter assays confirmed that this lncRNA is a direct transcriptional target of HIF-1α. Next, we found that EPHB4, a metastasis-related gene, is regulated by BC005927 and that the expression of EPHB4 was positively correlated with that of BC005927 in the clinical GC samples assessed. Intriguingly, EPHB4 expression was also increased under hypoxia, and its upregulation by BC005927 resulted in hypoxia-induced GC cell metastasis. These results advance the current understanding of the role of BC005927 in the regulation of hypoxia signaling and offer new avenues for the development of therapeutic interventions against cancer progression.
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Affiliation(s)
- Xiangqiang Liu
- Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.,Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the PLA, Guangzhou, China
| | - Yafang Wang
- Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Li Sun
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Jie Min
- Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jiaming Liu
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Di Chen
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Hongbo Zhang
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Hongwei Zhang
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Helong Zhang
- Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yongan Zhou
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Lili Liu
- Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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16
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Jiang L, Liu QL, Liang QL, Zhang HJ, Ou WT, Yuan GL. Association of PHD3 and HIF2α gene expression with clinicopathological characteristics in human hepatocellular carcinoma. Oncol Lett 2017; 15:545-551. [PMID: 29375719 DOI: 10.3892/ol.2017.7302] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 09/15/2017] [Indexed: 02/07/2023] Open
Abstract
Egl-9 family hypoxia-inducible factor (HIF)3/prolyl hydroxylase 3 (EGLN3/PHD3) serves a role in the progression and prognosis of cancer. PHD3 is able to induce apoptosis in HepG2 cells. In the present study, the protein levels of PHD3 and HIF2α were analyzed by western blot analysis and immunohistochemistry in 84 paired hepatocellular carcinoma (HCC) tissues and adjacent non-tumor liver tissues. The mRNA levels of PHD3 and HIF2α were analyzed by reverse transcription-quantitative polymerase chain reaction. PHD3 was overexpressed in HCC tissues compared with adjacent liver tissues (mRNA expression: P<0.001; protein expression: P=0.003; immunohistochemistry positive rate: P=0.001). The high level of expression of PHD3 in HCC tissues was associated with good differentiation (mRNA expression: P=0.002; protein expression: P<0.001) and small tumor size (mRNA expression: P<0.001; protein expression: P=0.002). In addition, HIF2α expression was lower in HCC tissues compared with adjacent liver tissues (mRNA expression: P<0.001; protein expression: P=0.002; immunohistochemistry positive rate: P=0.002). No statistically significant associations were identified between HIF2α expression and clinicopathological characteristics. Pearson's and Spearman's correlation coefficients revealed no correlation between HIF2α and PHD3 expression in HCC. In conclusion, PHD3 expression acts as a favorable prognostic marker for patients with HCC. There is no correlation between PHD3 and HIF2α expression in HCC.
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Affiliation(s)
- Liang Jiang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Qiu-Long Liu
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Qi-Lian Liang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Hui-Jie Zhang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Wen-Ting Ou
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Gao-Le Yuan
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
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17
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Yang YL, Gong WY, Chen FF, Chen LC, Chen YT. pPe Op from Omphalia lapidescens Schroet induces cell cycle arrest and inhibits the migration of MC-4 gastric tumor cells. Oncol Lett 2017; 14:533-540. [PMID: 28693202 PMCID: PMC5494755 DOI: 10.3892/ol.2017.6207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 01/19/2017] [Indexed: 12/16/2022] Open
Abstract
The aim of the present study was to investigate the effect of purified Omphalia lapidescens protein (pPeOp) extracted by polyvinylpyrrolidone from the fungus Omphalia lapidescens Schroet on the proliferation and cell cycle progression of MC-4 human gastric tumor cells. Using polyvinylpyrrolidone, pPeOp was extracted from O. lapidescens Schroet. MC-4 cells were cultured with 30, 60 or 90 µg/ml pPeOp, with 5-fluorouracil used as a positive control. Survival rates of treated cells were significantly decreased compared with those of the untreated control group in a dose-dependent manner. Using flow cytometric analysis, cells treated with pPeOp were demonstrated to arrest in S phase and exhibit abnormal G0/G1 and G2/M phase cell cycle distribution. In addition, a wound healing assay demonstrated that pPeOp significantly inhibited the migration of MC-4 cells. The mRNA and protein expression levels of cyclin D1/cyclin-dependent kinase (CDK) 4, cyclin B/CDK1, cyclin A/CDK2, matrix metalloproteinase (MMP)-2 and MMP-9 were determined using reverse transcription-quantitative polymerase chain reaction analysis and western blotting. The mRNA expression level of CDK4 and cyclin A was significantly increased compared with the untreated control; however, cyclin D1, CDK1, CDK2, cyclin B, MMP-2, and MMP-9 exhibited a significantly decreased mRNA expression level, indicating that there is a negative association between concentration and cyclin D1 expression levels. The expression of the cycle arrest-associated proteins and migration-associated proteins examined were similar to the observed mRNA expression levels. In conclusion, pPeOp was identified to inhibit migration of and cause S phase cell cycle arrest in MC-4 cells.
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Affiliation(s)
- Yong-Le Yang
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Wei-Yao Gong
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Fei-Fei Chen
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Lu-Chao Chen
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Yi-Tao Chen
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
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18
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Li W, He X, Xue R, Zhang Y, Zhang X, Lu J, Zhang Z, Xue L. Combined over-expression of the hypoxia-inducible factor 2α gene and its long non-coding RNA predicts unfavorable prognosis of patients with osteosarcoma. Pathol Res Pract 2016; 212:861-866. [PMID: 27623205 DOI: 10.1016/j.prp.2016.06.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 06/16/2016] [Accepted: 06/24/2016] [Indexed: 01/16/2023]
Abstract
BACKGROUND LncRNA hypoxia-inducible factor-2α (HIF-2α) promoter upstream transcript (HIF2PUT) functions as a novel regulatory factor of osteosarcoma stem cells partly by controlling HIF-2α expression. The aim of this study was to investigate the clinical significance of HIF-2α and HIF2PUT in human osteosarcoma. MATERIALS AND METHODS Quantitative real-time PCR was performed to detect the expression levels of HIF-2α mRNA and HIF2PUT in 82 surgical specimens of primary osteosarcoma and matched non-cancerous bone tissues. Then, the associations of HIF-2α and/or HIF2PUT expression with various clinicopathological features of osteosarcoma patients were statistically analyzed. Moreover, their prognostic value was further evaluated. RESULTS Compared with non-cancerous bone tissues, HIF-2α mRNA and HIF2PUT expression were both significantly upregulated in osteosarcoma tissues (all P<0.001). Interestingly, the expression levels of HIF-2α mRNA in osteosarcoma tissues were positively correlated with those of HIF2PUT (r=0.28, P=0.009). Additionally, osteosarcoma patients with HIF-2α mRNA and/or HIF2PUT over-expression more frequently had large tumor size (all P<0.05), advanced clinical stage (all P<0.01) and positive distant metastasis (all P<0.01). Moreover, osteosarcoma patients with HIF-2α mRNA and/or HIF2PUT over-expression had a significantly shorter overall and disease-free survival (all P<0.05). Furthermore, Cox multivariate analysis identified that HIF-2α mRNA and/or HIF2PUT expression, clinical stage and distant metastasis were all independent and significant prognostic factors for both overall and disease-free survival (all P<0.05). CONCLUSIONS HIF-2α and HIF2PUT upregulation may be a common feature in human osteosarcomas with aggressive potency. The over-expression of the two molecules, alone or combined, may predict poor prognosis in osteosarcoma patients.
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Affiliation(s)
- Wei Li
- Department of Orthopedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xijing He
- Department of Orthopedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
| | - Rongliang Xue
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Ying Zhang
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xiaoqin Zhang
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Jianrui Lu
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Zhenni Zhang
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Li Xue
- Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
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Zheng F, Du F, Zhao J. Clinicopathological Differences and Prognostic Value of Hypoxia-Inducible Factor-2α Expression for Gastric Cancer: Evidence From Meta-Analysis. Medicine (Baltimore) 2016; 95:e2871. [PMID: 26886654 PMCID: PMC4998654 DOI: 10.1097/md.0000000000002871] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Published literatures have reported the relationship between hypoxic-inducible factor-2α (HIF-2α) expression and clinicopathological features in gastric cancer (GC), but the evaluated conclusions remain controversial. A meta-analysis was carried to examine the clinicopathological features and prognostic values of HIF-2α in patients with GC. Systematic detailed searches were performed to Pub Med, Cochrane Library, and EBSCO until to August 2015. Six studies (508 specimens) were included in this meta-analysis. HIF-2α-positive expression indicates an unfavorable prognosis value and advanced clinicopathological differences for the available patient dates with GC. Further multivariate meta-analysis revealed that HIF-2α-positive expression in gastric cancer associated with deeper tumor infiltration (OR = 3.08; 95%CI: 1.18-8.04), higher rates of lymphatic metastasis (OR = 3.26; 95%CI: 1.10-9.63), higher TNM stage (III+IV) (OR = 2.61; 95%CI: 1.40-4.84), and much lower 5-year overall survival (OR = 2.08; 95%CI: 1.21-3.58). Nevertheless, there is no association between HIF-2α-positive expression and worse tumor differentiation (OR = 2.03; 95%CI: 0.73-5.64). In addition, by this subgroup analysis, HIF-2α-positive expression associated with deeper tumor infiltration (OR = 3.81; 95%CI: 1.03-14.08), higher lymphatic metastasis (OR = 4.71; 95%CI: 1.08-20.50), higher TNM stage (OR = 3.21; 95%CI: 1.57-6.57), worse tumor differentiation (OR = 3.08; 95%CI: 1.51-6.31), and lower 5-year overall survival (OR = 2.34; 95%CI: 1.15-4.79). Our results indicate that HIF-2α overexpression can potently predict the poor prognosis and may be a potential therapeutic target for gastric carcinoma, according to the limited evidence. Meanwhile, further studies are needed to elucidate the accuracy of these results.
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Affiliation(s)
- Fangchao Zheng
- From the Affiliated Hospital of Qinghai University (FZ, JZ), Qinghai University, Xining; and Department of Medical Oncology (FD, JZ), Cancer Institute & Hospital, Peking Union Medical College, Beijing, China
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20
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The tumor promoting roles of HSP60 and HIF2α in gastric cancer cells. Tumour Biol 2016; 37:9849-54. [DOI: 10.1007/s13277-015-4783-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 12/29/2015] [Indexed: 12/29/2022] Open
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21
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Tong GH, Tong WW, Qin XS, Lu LP, Liu Y. DBD-F induces apoptosis in gastric cancer-derived cells through suppressing HIF2α expression. Cell Oncol (Dordr) 2015; 38:479-84. [PMID: 26526811 DOI: 10.1007/s13402-015-0253-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2015] [Indexed: 01/29/2023] Open
Abstract
PURPOSE Gastric cancer is the third leading cause of cancer-related death in China. Accumulating evidence indicates that HIF2α may affect the aggressiveness of gastric cancer. It has also been found that HIF2α C-terminal PAS domains can form complexes with inactive benzoxadiazole antagonists. Here, the anti-tumor effect of 4-(N,Ndimethylaminosulphonyl)-7-fluoro-1,2,3-benzoxadiazole (DBD-F) on human gastric cancer cells was examined using both in vitro and in vivo assays. METHODS AND RESULTS We found that DBD-F can induce apoptosis and inhibit the mobility of MKN28 and MKN45 gastric cancer-derived cells in vitro. We also found that DBD-F can suppress tumor growth in established gastric cancer-derived xenograft models in vivo. Finally, we found that DBD-F can inhibit HIF2α expression in gastric cancer-derived cells. CONCLUSIONS From our findings we conclude that DBD-F (i) is cytotoxic to gastric cancer-derived cells and (ii) can induce apoptosis in these cells via the MEK/ERK signaling pathway. In addition, our findings strongly indicate that DBD-F can inhibit HIF2α expression by affecting the phosphorylation status of MEK/ERK in gastric cancer-derived cells.
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Affiliation(s)
- Guang-Hui Tong
- Department of Laboratory Medicine, ShengJing Affiliated Hospital, China Medical University, Shenyang, 110004, China
| | - Wei-Wei Tong
- Department of Laboratory Medicine, ShengJing Affiliated Hospital, China Medical University, Shenyang, 110004, China
| | - Xiao-Song Qin
- Department of Laboratory Medicine, ShengJing Affiliated Hospital, China Medical University, Shenyang, 110004, China
| | - Li-Ping Lu
- Department of Laboratory Medicine, ShengJing Affiliated Hospital, China Medical University, Shenyang, 110004, China
| | - Yong Liu
- Department of Laboratory Medicine, ShengJing Affiliated Hospital, China Medical University, Shenyang, 110004, China.
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Zhang Y, Guo X, Li Z, Li B, Li Z, Li R, Guo Q, Xiong L, Yu L, Zhao J, Lin N. A systematic investigation based on microRNA-mediated gene regulatory network reveals that dysregulation of microRNA-19a/Cyclin D1 axis confers an oncogenic potential and a worse prognosis in human hepatocellular carcinoma. RNA Biol 2015; 12:643-57. [PMID: 25985117 DOI: 10.1080/15476286.2015.1022702] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) contribute to a wide variety of human diseases by regulating gene expression, leading to imbalances in gene regulatory networks. To discover novel hepatocellular carcinoma (HCC)-related miRNA-target axes and to elucidate their functions, we here performed a systematic investigation combining biological data acquisition and integration, miRNA-target prediction, network construction, functional assay and clinical validation. As a result, a total of 117 HCC differentially expressed miRNAs were identified, and 728 high confident target genes of these miRNAs were collected. Then, the interaction network of target genes was constructed and 221 key nodes with topological importance in the network were identified according to their topological features including degree, node-betweenness, closeness and K-coreness. Among these key nodes, Cyclin D1 had the highest node-betweenness, implying its bottleneck role in the network. Luciferase reporter assay confirmed that miRNA-19a, which was one of HCC downregulated miRNAs, directly targeted Cyclin D1 in HCC cells. Moreover, miR-19a might play inhibitory roles in HCC malignancy via regulating Cyclin D1 expression. Further clinical evidence also highlighted the prognostic potential of miR-19a/Cyclin D1 axis in HCC. In conclusion, this systematic investigation provides a framework to identify featured miRNAs and their target genes which are potent effectors in the occurrence and development of HCC. More importantly, miR-19a/Cyclin D1 axis might have promising applications as a therapeutic target and a prognostic marker for patients with HCC.
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Affiliation(s)
- Yanqiong Zhang
- a Institute of Chinese Materia Medica; China Academy of Chinese Medical Sciences ; Beijing , China
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