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Elgenidy A, Alomari O, Hesn MM, Khaled A, Nada SA, Elsayed M, Mahmoud A, Al-kurdi MAM, Afifi AM, Cholankeril G. Relative Survival, Conditional Survival, and Causes of Death in Patients with Early Gastric Cancer, with a Focus on Differences Between Cardia and Non-Cardia Cancer. Cancers (Basel) 2024; 16:4262. [PMID: 39766160 PMCID: PMC11674421 DOI: 10.3390/cancers16244262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/11/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Many researchers believe that cardia (CGC) and non-cardia (NCGC) are two different types of tumors, having different features like incidence rate, risk factors, geographical location, and socioeconomic status. This study aims to investigate the causes of death (COD) survival rates among early gastric cancer patients with a focus on differences between CGC and NCGC. Methods: This retrospective study employed SEER*stat software (version 8.3.92) to analyze the SEER 17 plus dataset (2000-2019). Standardized mortality ratios (SMR) were computed. Relative survival and conditional survival post-diagnosis were calculated using R software (version 4.1.0) among the different subgroups. Results: Within the follow-up period, 55.4% (5381) died, predominantly within the initial year post-diagnosis. Esophageal cancer was the leading non-gastric cancer cause in CGC, while miscellaneous tumors dominated in NCGC. The 1-year and 5-year relative survival for CGC patients were 76.4% and 48.9% respectively, while for NCGC were 80.4% and 63.9%. The 3-year conditional survival after 1 year and 5e years of survival for CGC were 68.7% and 88.8%, respectively, while for NCGC were 82.2% and 93.5%, respectively. This means that the longer a person has survived after diagnosis with cancer, the greater the likelihood that person will survive for another 3 years. Conclusions: This study sheds light on the substantial impact of non-cancer COD in GC patients, underscoring the necessity of considering comorbidities in their comprehensive management and follow-up. Impact: This study contributes valuable insights for clinical decision-making and informs future research directions regarding CGC and NCGC.
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Affiliation(s)
- Anas Elgenidy
- Department of Neurology, Cairo University, Cairo 11652, Egypt;
| | - Omar Alomari
- Hamidiye International School of Medicine, University of Health Sciences, 34668 Istanbul, Turkey;
| | - Mohamed Marey Hesn
- Damietta Faculty of Medicine, Al-Azhar University, Damietta 34517, Egypt; (M.M.H.); (A.K.)
| | - Anas Khaled
- Damietta Faculty of Medicine, Al-Azhar University, Damietta 34517, Egypt; (M.M.H.); (A.K.)
| | - Sarah A. Nada
- Faculty of Medicine, Menofia University, Shebin El-Kom 32861, Egypt;
| | - Mostafa Elsayed
- Faculty of Medicine, Zagazig University, Zagazig 44691, Egypt;
| | - Ali Mahmoud
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA;
| | | | - Ahmed M. Afifi
- University of Toledo Medical Center, Toledo, OH 43614, USA
| | - George Cholankeril
- Section of Gastroenterology and Hepatology, Margaret M. and Albert B. Alkek Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA;
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Boicean A, Boeras I, Birsan S, Ichim C, Todor SB, Onisor DM, Brusnic O, Bacila C, Dura H, Roman-Filip C, Ognean ML, Tanasescu C, Hasegan A, Bratu D, Porr C, Roman-Filip I, Neamtu B, Fleaca SR. In Pursuit of Novel Markers: Unraveling the Potential of miR-106, CEA and CA 19-9 in Gastric Adenocarcinoma Diagnosis and Staging. Int J Mol Sci 2024; 25:7898. [PMID: 39063140 PMCID: PMC11277351 DOI: 10.3390/ijms25147898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Gastric cancer stands as the fourth leading cause of cancer-related deaths globally, primarily comprising adenocarcinomas, categorized by anatomic location and histologic type. Often diagnosed at advanced stages, gastric cancer prognosis remains poor. To address the critical need for accurate tumoral markers for gastric cancer diagnosis, we conducted a study to assess classical markers like CEA and CA-19-9 alongside the novel marker miR-106. Our investigation revealed distinct dynamics of these markers compared to non-cancerous groups, although no disparities were observed across different disease stages. Univariable and multivariable logistic regression analyses demonstrated that elevated levels of miR-106, CEA and CA 19-9 were predictive of a positive histopathological exam, with the respective odds ratios of 12.032 (95% CI: 1.948-74.305), 30 (95% CI: 3.141-286.576), and 55.866 (95% CI: 4.512-691.687). Subsequently, we utilized predicted probabilities from regression models to construct receiver operating characteristic (ROC) curves, identifying CA 19-9 as the optimal predictor for gastric adenocarcinoma diagnosis when considering age and gender, with an area under the curve (AUC) of 0.936 (p < 0.001). Hence, classical markers exhibit superior performance compared to the novel marker miR-106 in predicting gastric adenocarcinoma.
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Affiliation(s)
- Adrian Boicean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Ioana Boeras
- Molecular Biology Laboratory of the Applied Ecology Research Center, Faculty of Sciences, Lucian Blaga University of Sibiu, 550012 Sibiu, Romania
- Faculty of Social Sciences, Lucian Blaga University of Sibiu, 550012 Sibiu, Romania
| | - Sabrina Birsan
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Cristian Ichim
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Samuel Bogdan Todor
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Danusia Maria Onisor
- Department of Gastroenterology, University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Târgu Mures, Romania; (D.M.O.); (O.B.)
| | - Olga Brusnic
- Department of Gastroenterology, University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Târgu Mures, Romania; (D.M.O.); (O.B.)
| | - Ciprian Bacila
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Horatiu Dura
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Corina Roman-Filip
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Maria Livia Ognean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Ciprian Tanasescu
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Adrian Hasegan
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Dan Bratu
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Corina Porr
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania
| | - Iulian Roman-Filip
- Department of Neurology, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology, 540136 Targu Mures, Romania
| | - Bogdan Neamtu
- Pediatric Research Department, Pediatric Clinical Hospital Sibiu, 550166 Sibiu, Romania;
| | - Sorin Radu Fleaca
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
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Romańczyk M, Osmola M, Link A, Druet A, Hémont C, Martin J, Chapelle N, Matysiak-Budnik T. Non-Invasive Markers for the Detection of Gastric Precancerous Conditions. Cancers (Basel) 2024; 16:2254. [PMID: 38927959 PMCID: PMC11202181 DOI: 10.3390/cancers16122254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Gastric cancer (GC) is still one of the most prevalent cancers worldwide, with a high mortality rate, despite improvements in diagnostic and therapeutic strategies. To diminish the GC burden, a modification of the current diagnostic paradigm, and especially endoscopic diagnosis of symptomatic individuals, is necessary. In this review article, we present a broad review and the current knowledge status on serum biomarkers, including pepsinogens, gastrin, Gastropanel®, autoantibodies, and novel biomarkers, allowing us to estimate the risk of gastric precancerous conditions (GPC)-atrophic gastritis and gastric intestinal metaplasia. The aim of the article is to emphasize the role of non-invasive testing in GC prevention. This comprehensive review describes the pathophysiological background of investigated biomarkers, their status and performance based on available data, as well as their clinical applicability. We point out future perspectives of non-invasive testing and possible new biomarkers opportunities.
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Affiliation(s)
- Marcin Romańczyk
- Department of Gastroenterology, Academy of Silesia, 40-555 Katowice, Poland
- H-T. Medical Center, 43-100 Tychy, Poland
| | | | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Amaury Druet
- IMAD, Hepato-Gastroenterology & Digestive Oncology, University Hospital of Nantes, F-44093 Nantes, France
| | - Caroline Hémont
- CHU de Nantes, Laboratoire d’Immunologie, Center for ImmunoMonitoring Nantes-Atlantique (CIMNA), F-44000 Nantes, France
| | - Jerome Martin
- CHU de Nantes, Laboratoire d’Immunologie, Center for ImmunoMonitoring Nantes-Atlantique (CIMNA), F-44000 Nantes, France
- University of Nantes, INSERM, Centre de Recherche Translationnel en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Nicolas Chapelle
- IMAD, Hepato-Gastroenterology & Digestive Oncology, University Hospital of Nantes, F-44093 Nantes, France
- University of Nantes, INSERM, Centre de Recherche Translationnel en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Tamara Matysiak-Budnik
- IMAD, Hepato-Gastroenterology & Digestive Oncology, University Hospital of Nantes, F-44093 Nantes, France
- University of Nantes, INSERM, Centre de Recherche Translationnel en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
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Bilan F, Amini M, Doustvandi MA, Tohidast M, Baghbanzadeh A, Hosseini SS, Mokhtarzadeh A, Baradaran B. Simultaneous suppression of miR-21 and restoration of miR-145 in gastric cancer cells; a promising strategy for inhibition of cell proliferation and migration. BIOIMPACTS : BI 2023; 14:27764. [PMID: 38505672 PMCID: PMC10945301 DOI: 10.34172/bi.2023.27764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 06/13/2023] [Accepted: 06/25/2023] [Indexed: 03/21/2024]
Abstract
Introduction Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. microRNAs are a group of regulatory non-coding RNAs that are involved in GC progression. miR-145 as a tumor suppressor and miR-21 as an oncomiR were shown to be dysregulated in many cancers including GC. This research aimed to enhance the expression of miR-145 while reducing the expression of miR-21 and examine their impact on the proliferation, apoptosis, and migration of GC cells. Methods KATO III cells with high expression levels of miR-21-5p and low expression of miR-145-5p were selected. These cells were then transfected with either miR-145-5p mimics or anti-miR-21-5p, alone or in combination. Afterward, the cell survival rate was determined using the MTT assay, while apoptosis induction was investigated through V-FITC/PI and DAPI staining. Additionally, cell migration was examined using the wound healing assay, and cell cycle progression was analyzed through flow cytometry. Furthermore, gene expression levels were quantified utilizing the qRT-PCR technique. Results The study's findings indicated that the co-replacement of miR-145-5p and anti-miR-21-5p led to a decrease in cell viability and the induction of apoptosis in GC cells. This was achieved via modulating the expression of Bax and Bcl-2, major cell survival regulators. Additionally, the combination therapy significantly increased sub-G1 cell cycle arrest and reduced cell migration by downregulating MMP-9 expression as an epithelial-mesenchymal transition marker. This study provides evidence for the therapeutic possibility of the combination of miR-145-5p and anti-miR-21-5p and also suggests that they could inhibit cell proliferation by modulating the PTEN/AKT1 signaling pathway. Conclusion Our research revealed that utilizing miR-145-5p and anti-miR-21-5p together could be a promising therapeutic approach for treating GC.
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Affiliation(s)
- Farzaneh Bilan
- Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Maryam Tohidast
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Choi JM, Kim SG. Effect of Helicobacter pylori Eradication on Epigenetic Changes in Gastric Cancer-related Genes. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2021.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is known that gastric carcinogenesis results from the progressive changes from chronic gastritis to gastric atrophy, intestinal metaplasia, dysplasia, and invasive carcinoma. Several genetic and epigenetic alterations are involved in this process, and Helicobacter pylori (H. pylori) infection is believed to induce the initiation and progression of these steps. From an epigenetic point of view, H. pylori induces hypermethylation of genes involved in the development of gastric cancer and regulates the expression of various microRNAs (miRNAs). These H. pylori-related epigenetic changes are accumulated not only at the site of neoplasm but also in the adjacent non-cancerous gastric mucosa. Thereby, a state vulnerable to gastric cancer known as an epigenetic field defect is formed. H. pylori eradication can have an effective chemopreventive effect in gastric carcinogenesis. However, the molecular biological changes that occur in the stomach environment during H. pylori eradication have not yet been established. Several studies have reported that H. pylori eradication can restore infection-related changes, especially epigenetic alterations in gastric cancer-related genes, but some studies have shown otherwise. Simply put, it appears that the recovery of methylated gastric cancer-related genes and miRNAs during H. pylori eradication may vary among genes and may also differ depending on the histological subtype of the gastric mucosa. In this review, we will discuss the potential mechanism of gastric cancer prevention by H. pylori eradication, mainly from an epigenetic perspective.
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Mei D, Qi Y, Xia Y, Ma J, Hu H, Ai J, Chen L, Wu N, Liao D. Microarray profile analysis identifies ETS1 as potential biomarker regulated by miR-23b and modulates TCF4 in gastric cancer. World J Surg Oncol 2021; 19:311. [PMID: 34686186 PMCID: PMC8540102 DOI: 10.1186/s12957-021-02417-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 10/03/2021] [Indexed: 12/30/2022] Open
Abstract
Background Gastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide. Early detection of GC has a significant impact on clinical outcomes. The aim of this study was to identify potential GC biomarkers. Methods In this study, we conducted a multi-step analysis of expression profiles in GC clinical samples downloaded from TCGA database to identify differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs). Potential prognostic biomarkers from the available DEMs were then established using the Cox regression method. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological role of the predicted target genes of the miRNA biomarkers. Then, the prognostic DEM-mediated regulatory network was constructed based on transcription factor (TF)–miRNA–target interaction. Subsequently, the consensus genes were further determined based on the overlap between DEGs and these target genes of DEMs. Besides, expression profile, co-expression analysis, immunity, and prognostic values of these prognostic genes were also investigated to further explore the roles in the mechanism of GC tumorigenesis. Results We got five miRNAs, including miR-23b, miR-100, miR-143, miR-145, and miR-409, which are associated with the overall survival of GC patients. Subsequently, enrichment analysis of the target genes of the miRNA biomarkers shown that the GO biological process terms were mainly enriched in mRNA catabolic process, nuclear chromatin, and RNA binding. In addition, the KEGG pathways were significantly enriched in fatty acid metabolism, extracellular matrix (ECM) receptor interaction, and proteoglycans in cancer pathways. The transcriptional regulatory network consisting of 68 TFs, 4 DEMs, and 58 targets was constructed based on the interaction of TFs, miRNAs, and targets. The downstream gene ETS1 of miR-23b and TCF4 regulated by ETS1 were obtained by the regulatory network construction and co-expression analysis. High expression of ETS1 and TCF4 indicated poor prognosis in GC patients, particularly in the advanced stages. The expression of ETS1 and TCF4 was correlated with CD4+ T cells, CD8+ T cells, and B cells. Conclusions miR-23b, ETS1, and TCF4 were identified as the prognostic biomarkers. ETS1 and TCF4 had potential immune function in GC, which provided a theoretical basis for molecular-targeted combined immunotherapy in the future.
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Affiliation(s)
- Dinglian Mei
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Yalong Qi
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Yuanyuan Xia
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Jun Ma
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Hao Hu
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Jun Ai
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Liqiang Chen
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Ning Wu
- Department of Oncology, Shanghai Pudong New Area Gongli Hospital, Shanghai, 200135, People's Republic of China
| | - Daixiang Liao
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China.
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Yang J, Yan Z, Wang Y, Xu J, Li R, Li C, Liu S, Shi L, Yao Y. Association study of relationships of polymorphisms in the miR-21, miR-26b, miR-221/222 and miR-126 genes with cervical intraepithelial neoplasia and cervical cancer. BMC Cancer 2021; 21:997. [PMID: 34488676 PMCID: PMC8422721 DOI: 10.1186/s12885-021-08743-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 08/28/2021] [Indexed: 01/15/2023] Open
Abstract
Background miR-21, miR-26b, miR-221/222 and miR-126 play crucial roles in cervical cancer development. Studies have shown that polymorphisms in miRNA genes can affect miRNA expression, which might be associated with cancer development. Methods Ten single-nucleotide polymorphisms (SNPs) in the miR-21, miR-26b, miR-221/222 and miR-126 genes (rs1292037, rs13137 in miR-21; rs2227255, rs2227258 in miR-26b; rs2858061, rs34678647, rs2858060, rs2745709 in miR-221/222; rs2297537, rs2297538 in miR-126) were selected, and genotyped in a total of 2176 individuals, including 435 patients with cervical intraepithelial neoplasia (CIN), 743 patients with cervical cancer (CC) and 998 healthy persons using TaqMan assays, and their associations with CIN and CC were evaluated. Results Our results showed significant differences for the rs2297538 genotypes between the CIN and CC groups (P = 0.001). In addition, our results also showed significant differences for the rs2297537 alleles between the CIN and CC groups (P = 0.003), and the C allele of rs2297537 might be associated with a decreased risk of CC (OR = 0.72, 95%CI: 0.58–0.90). At the inheritance analysis, between the CIN and control groups, the T/T-T/C genotype in rs1292037 and A/A-A/T genotype in rs13137 might be associated with an increased risk of CIN in the recessive model (OR = 1.61, 95% CI: 1.17–2.20 and OR = 1.58, 95% CI: 1.15–2.15). In addition, the C/C-T/T genotype of rs2745709 might be associated with a decreased risk of CIN in the overdominant model (OR = 0.66, 95% CI: 0.52–0.82). Between, CIN and CC group, the T/T-C/C genotype in rs1292037 and A/A-T/T genotype in rs13137 might be associated with an increased risk of CC in the overdominant model (OR = 1.43, 95% CI: 1.12–1.81 and OR = 1.42, 95% CI: 1.12–1.80). The rs2297538 G/G-A/G genotype might be associated with an increased risk of CC in the recessive model (OR = 2.83, 95% CI: 1.52–5.25). The rs2297537 2C/C + C/G genotype might be associated with a decreased risk of CC (OR = 0.71, 95% CI: 0.57–0.89) in the log-additive model. The rs2745709 T/T-C/C genotype might be associated with an increased risk of CC (OR = 1.44, 95% CI: 1.13–1.83) in the overdominant model. Conclusion Our results indicate that rs2297538 and rs2297537 in miR-126, rs1292037 and rs13137 in miR-21, and rs2745709 in miR-221/222, may have important roles in the development of CIN or CC.
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Affiliation(s)
- Jia Yang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, Yunnan, China
| | - Zhiling Yan
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, 650118, China
| | - Yingying Wang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, Yunnan, China
| | - Jinmei Xu
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, 650118, China
| | - Rui Li
- Department of Obstetrics and Gynaecologic, Kunming Yan'an Hospital, Kunming, 650051, China
| | - Chuanyin Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, Yunnan, China
| | - Shuyuan Liu
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, Yunnan, China
| | - Li Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, Yunnan, China.
| | - Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, Yunnan, China. .,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, 650118, Yunnan, China.
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Jonaitis P, Kupcinskas L, Kupcinskas J. Molecular Alterations in Gastric Intestinal Metaplasia. Int J Mol Sci 2021; 22:ijms22115758. [PMID: 34071181 PMCID: PMC8199079 DOI: 10.3390/ijms22115758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC.
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Vasapolli R, Venerito M, Schirrmeister W, Thon C, Weigt J, Wex T, Malfertheiner P, Link A. Inflammatory microRNAs in gastric mucosa are modulated by Helicobacter pylori infection and proton-pump inhibitors but not by aspirin or NSAIDs. PLoS One 2021; 16:e0249282. [PMID: 33857171 PMCID: PMC8049315 DOI: 10.1371/journal.pone.0249282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/15/2021] [Indexed: 12/21/2022] Open
Abstract
Gastric carcinogenesis is associated with alterations of microRNAs (miRNAs) and reversal of these alterations may be a crucial element in cancer prevention. Here we evaluate the influence of H. pylori eradication, low-dose aspirin (LDA), non-steroidal anti-inflammatory drugs (NSAIDs) and proton-pump inhibitors (PPI) on modification of inflammatory mucosal miRNAs miR-155 and miR-223 in Helicobacter pylori-infected and non-infected subjects. The study was performed in two parts: 1) interventional study in 20 healthy subjects with and without H. pylori infection or following eradication (each n = 10) where LDA (100 mg) was given daily for 7 days; 2) prospective case-control observational study (n = 188). MiR-155 and miR-223 expression was strongly linked to H. pylori-infection and in short-term view showed a trend for reversal after eradication. Daily LDA as well as regular NSAIDs showed no influence on miRNAs expression both in healthy subjects and patients, while regular PPI intake was associated with lower miR-155 expression in antrum of patients with chronic gastritis independent of density of neutrophils and mononuclear infiltrate. In summary, PPI but not LDA or NSAIDs were associated with modification of inflammatory miRNAs miR-155 and miR-223 in an H. pylori dependent manner. The functional role of inflammatory miR-155 and miR-223 in understanding of H. pylori-related diseases needs further evaluation.
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Affiliation(s)
- Riccardo Vasapolli
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
- Department of Internal Medicine II, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Wiebke Schirrmeister
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Jochen Weigt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
- Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, Department of Molecular Genetics, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
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10
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Li Y, Li C, Liu S, Yang J, Shi L, Yao Y. The associations and roles of microRNA single-nucleotide polymorphisms in cervical cancer. Int J Med Sci 2021; 18:2347-2354. [PMID: 33967611 PMCID: PMC8100648 DOI: 10.7150/ijms.57990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 03/26/2021] [Indexed: 11/05/2022] Open
Abstract
Cervical cancer is one of the fourth most common gynecological malignancies and has been identified as the fourth leading cause of cancer death in women worldwide. MicroRNAs (miRNAs) are single-stranded sequences of noncoding RNAs that are approximately 22-24 nucleotides in length. They modulate posttranscriptional mRNA expression and play critical roles in cervical cancer. Single nucleotide polymorphisms (SNPs) in miRNA genes may alter miRNA expression and maturation and have been associated with various cancers. This review mainly focuses on the roles of SNPs in miRNA genes in the development of cervical cancer and summarizes the research progress of miRNA SNPs in cervical cancer and their molecular regulation mechanisms.
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Affiliation(s)
- Yaheng Li
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Chuanyin Li
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Shuyuan Liu
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Jia Yang
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Li Shi
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Yufeng Yao
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
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11
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Franck M, Thon C, Schütte K, Malfertheiner P, Link A. Circulating miR-21-5p level has limited prognostic value in patients with hepatocellular carcinoma and is influenced by renal function. World J Hepatol 2020; 12:1031-1045. [PMID: 33312427 PMCID: PMC7701966 DOI: 10.4254/wjh.v12.i11.1031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/15/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) have been suggested as biomarkers for malignant diseases including hepatocellular carcinoma (HCC). Specifically, hsa-miR-21-5p (miR-21) is among the most frequently deregulated miRNA in cancer. The diagnostic and prognostic value of miR-21 has been demonstrated in HCC tissue, mostly in the Asian population. Although the impact of various factors has been recently reported for circulating hsa-miR-122-5p (miR-122), at present only limited knowledge is available for miR-21. AIM To evaluate the value of miR-21 for the assessment of prognosis in HCC patients and to delineate the influence of clinical and preanalytical factors on miR-21 level in sera. METHODS Patients with confirmed HCC from our European cohort with predominantly alcohol-associated liver damage were included in the study. All subjects were characterized according to their clinical and laboratory work-up and overall survival data were obtained. Quantitative real-time polymerase chain reaction was performed for miR-21 and spiked-in cel-miR-39-3p. The results were compared to previously reported miR-122 data. RESULTS Survival of HCC patients was comparable between patients with low and high serum miR-21 concentration. No association was observed between miR-21 level in sera and Child-Pugh score, Barcelona Clinic Liver Cancer staging system, or etiology of HCC/liver disease. Age, gender, or pretreatment had no association with miR-21 level. A positive correlation was observed between miR-21 and aspartate aminotransferase (r = 0.2854, P = 0.0061), serum miR-122 (r = 0.2624, P = 0.0120), and the International Normalized Ratio (r = 0.2065, P = 0.0496). Negative correlation of miR-21 with serum creatinine (r = -0.2215, P = 0.0348) suggests renal function as a potential influencing factor in miR-21 biogenesis in blood. CONCLUSION The results from this work do not support clinically relevant prognostic value of circulating miR-21 in HCC patients in real-life settings. Following systematic evaluation, we identified renal function and aspartate aminotransferase as potential factors that may affect miR-21 concentration in blood. This knowledge should be considered in future miRNA-based biomarker studies not only for HCC but also for other diseases.
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Affiliation(s)
- Martin Franck
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
| | - Kerstin Schütte
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
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12
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STAT3 Pathway in Gastric Cancer: Signaling, Therapeutic Targeting and Future Prospects. BIOLOGY 2020; 9:biology9060126. [PMID: 32545648 PMCID: PMC7345582 DOI: 10.3390/biology9060126] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 12/11/2022]
Abstract
Molecular signaling pathways play a significant role in the regulation of biological mechanisms, and their abnormal expression can provide the conditions for cancer development. The signal transducer and activator of transcription 3 (STAT3) is a key member of the STAT proteins and its oncogene role in cancer has been shown. STAT3 is able to promote the proliferation and invasion of cancer cells and induces chemoresistance. Different downstream targets of STAT3 have been identified in cancer and it has also been shown that microRNA (miR), long non-coding RNA (lncRNA) and other molecular pathways are able to function as upstream mediators of STAT3 in cancer. In the present review, we focus on the role and regulation of STAT3 in gastric cancer (GC). miRs and lncRNAs are considered as potential upstream mediators of STAT3 and they are able to affect STAT3 expression in exerting their oncogene or onco-suppressor role in GC cells. Anti-tumor compounds suppress the STAT3 signaling pathway to restrict the proliferation and malignant behavior of GC cells. Other molecular pathways, such as sirtuin, stathmin and so on, can act as upstream mediators of STAT3 in GC. Notably, the components of the tumor microenvironment that are capable of targeting STAT3 in GC, such as fibroblasts and macrophages, are discussed in this review. Finally, we demonstrate that STAT3 can target oncogene factors to enhance the proliferation and metastasis of GC cells.
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13
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Chen DD, Cheng JT, Chandoo A, Sun XW, Zhang L, Lu MD, Sun WJ, Huang YP. microRNA-33a prevents epithelial-mesenchymal transition, invasion, and metastasis of gastric cancer cells through the Snail/Slug pathway. Am J Physiol Gastrointest Liver Physiol 2019; 317:G147-G160. [PMID: 30943047 DOI: 10.1152/ajpgi.00284.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Invasion and metastasis are responsible for the majority of deaths in gastric cancer (GC). microRNA-33a (miR-33a) might function as a tumor suppressor in multiple cancers. Here, we describe the regulation and function of miR-33a in GC and mechanisms involved in epithelial-mesenchymal transition (EMT) and metastasis. First, GC tissues and adjacent normal tissues were collected. miR-33a upregulation or SNAI2 depletion on GC cells were introduced to assess the detailed regulatory mechanism of them. We assessed the expression of miR-33a, SNAI2, Snail/Slug signaling pathway-related genes, and EMT-related markers in GC tissues and cells. miR-33a distribution in GC tissues and adjacent normal tissues was measured. Cell proliferation, migration and invasion, and cell cycle distribution were assessed. In nude mice, GC tumor growth and lymph node metastasis were observed. Furthermore, the predicative value of miR-33a in the prognosis of GC patients was evaluated. The obtained results indicated that lowly expressed miR-33a, highly expressed SNAI2, activated Snail/Slug, and increased EMT were identified in GC tissues. miR-33a was located mainly in the cytoplasm. miR-33a targeted and negatively regulated SNAI2. MKN-45 and MKN-28 cell lines were selected for in vitro experiments. Upregulated miR-33a expression or siRNA-mediated silencing of SNAI2 suppressed the activation of Snail/Slug, whereby GC cell proliferation, invasion and migration, EMT, tumor growth, and lymph node metastasis were inhibited. High expression of miR-33a was a protective factor influencing the prognosis of GC. This study suggests that miR-33a inhibited EMT, invasion, and metastasis of GC through the Snail/Slug signaling pathway by modulating SNAI2 expression.NEW & NOTEWORTHY miR-33a targets and inhibits the expression of SNAI2, overexpression of SNAI2 activates the Snail/Slug signaling pathway, the Snail/Slug signaling pathway promotes GC cell proliferation, invasion, and metastasis, and overexpression of miR-33a inhibits cell proliferation, invasion, and metastasis. This study provides a new therapeutic target for the treatment of GC.
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Affiliation(s)
- Di-Di Chen
- Department of Radiotherapy and Chemotherapy, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | | | - Arvine Chandoo
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiang-Wei Sun
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Zhang
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Dong Lu
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei-Jian Sun
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ying-Peng Huang
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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14
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Bhat SA, Majid S, Rehman MU. Scenario and future prospects of microRNAs in gastric cancer: A review. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2019; 22:345-352. [PMID: 31168337 PMCID: PMC6535194 DOI: 10.22038/ijbms.2019.32399.7765] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 12/11/2018] [Indexed: 12/19/2022]
Abstract
Carcinoma of the stomach is one of the major prevalent and principal causes of cancer-related deaths worldwide. Current advancement in technology has improved the understanding of the pathogenesis and pathology of gastric cancers (GC). But, high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate novel early diagnostic/prognostic markers and therapeutic targets for GC, which are sufficiently sensitive to GC. Current biomedical investigations have explored several budding GC biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray, and RNA/DNA-Seq. Recently, small non-coding microRNAs (miRNAs) are becoming vital regulators in oncogenesis pathways and can act as handy clinical biomarkers. The newly introduced class of biomarkers is rising as new molecules for cancer diagnosis and prognosis. For better understanding of the gastric carcinogenesis, miRNAs may help to elucidate the mechanisms of tumor growth and can help to discover novel untimely potent markers for early detection of GC. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic/prognostic tools and therapeutic targets. Thus, here we introduce potential future treatment strategies for gastrointestinal (GI) cancers, which indicate the practicality and clinical applications of miRNAs in GC.
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Affiliation(s)
- Showkat Ahmad Bhat
- Department of Biochemistry, Govt. Medical College, Srinagar Jammu & Kashmir, India
| | - Sabhiya Majid
- Department of Biochemistry, Govt. Medical College, Srinagar Jammu & Kashmir, India
| | - Muneeb U Rehman
- Department of Biochemistry, Govt. Medical College, Srinagar Jammu & Kashmir, India
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15
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Link A, Kupcinskas J. MicroRNAs as non-invasive diagnostic biomarkers for gastric cancer: Current insights and future perspectives. World J Gastroenterol 2018; 24:3313-3329. [PMID: 30122873 PMCID: PMC6092583 DOI: 10.3748/wjg.v24.i30.3313] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/10/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Non-invasive diagnostic biomarkers may contribute to an early identification of gastric cancer (GC) and improve the clinical management. Unfortunately, no sensitive and specific screening biomarkers are available yet and the currently available approaches are limited by the nature of the disease. GC is a heterogenic disease with various distinct genetic and epigenetic events that occur during the multifactorial cascade of carcinogenesis. MicroRNAs (miRNAs) are commonly deregulated in gastric mucosa during the Helicobacter pylori infection and in stepwise manner from chronic gastritis, through preneoplastic conditions such as atrophic gastritis and intestinal metaplasia, to early dysplasia and invasive cancer. Identification of miRNAs in blood in 2008 led to a great interest on miRNA-based diagnostic, prognostic biomarkers in GC. In this review, we provide the most recent systematic review on the existing studies related to miRNAs as diagnostic biomarkers for GC. Here, we systematically evaluate 75 studies related to differential expression of circulating miRNAs in GC patients and provide novel view on various heterogenic aspects of the existing data and summarize the methodological differences. Finally, we highlight several important aspects crucial to improve the future translational and clinical research in the field.
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Affiliation(s)
- Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg 39120, Germany
| | - Juozas Kupcinskas
- Institute for Digestive Research and Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas LT-44307, Lithuania
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16
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Zhang L, Liu Q, Wang F. Association Between miR-149 Gene rs2292832 Polymorphism and Risk of Gastric Cancer. Arch Med Res 2018; 49:270-277. [DOI: 10.1016/j.arcmed.2018.09.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023]
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17
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Chen W, Yu Y, Yang N, Zhu J, Li K, Li R, Su W, Luo L, Hu L, Chen G, Deng H. Effects of Yangzheng Sanjie Decoction-containing serum mediated by microRNA-7 on cell proliferation and apoptosis in gastric cancer. Oncol Lett 2018; 15:3621-3629. [PMID: 29467883 PMCID: PMC5796316 DOI: 10.3892/ol.2018.7757] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/16/2017] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is one of the most common types of cancer and a leading cause of cancer-associated mortality. MicroRNAs (miRNAs/miRs) are demonstrated to function as oncomiRs or tumor-suppressor-miRs in GC. miR-7 has been identified to be a tumor suppressor of GC by targeting epidermal growth factor receptor (EGFR). In our previous study, Yangzheng Sanjie Decoction (YZSJD), a traditional Chinese formula, was identified to be effective in alleviating the symptoms and even postponing turnover of precancerous lesions. To elucidate the mechanism of YZSJD, the present study evaluated the effects of YZSJD of the GC MKN-45 cell line and investigated the underlying molecular mechanisms using YZSJD-containing serum (YCS). The expression of miR-7 in GC, normal and adjacent tissue samples was examined. The results demonstrated that YCS inhibited proliferation by inducing cell cycle arrest at the S phase, and significantly induced apoptosis compared with the control group. miR-7 was significantly downregulated in GC tissues compared with the matched ones. Using reverse transcription-quantitative polymerase chain reaction and western blot analysis, the expression of miR-7 was inversely associated with EGFR. This indicates that YCS inhibits proliferation and induces apoptosis of GC cells mediated by miR-7 targeting EGFR, which may be one of the mechanisms whereby YZSJD exerts its effects on GC.
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Affiliation(s)
- Wanqun Chen
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China.,Discipline of Integrated Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China.,Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Yaya Yu
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China.,Discipline of Integrated Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Naikun Yang
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Jingli Zhu
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Ke Li
- Pharmaceutical Research Institute, Hunan Academy of Chinese Medicine, Changsha, Hunan 410013, P.R. China
| | - Ruocun Li
- Pharmaceutical Research Institute, Hunan Academy of Chinese Medicine, Changsha, Hunan 410013, P.R. China
| | - Wenqiao Su
- Pharmaceutical Research Institute, Hunan Academy of Chinese Medicine, Changsha, Hunan 410013, P.R. China
| | - Lina Luo
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China.,Discipline of Integrated Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Ling Hu
- Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Gengxin Chen
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China.,Discipline of Integrated Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Haixia Deng
- Academy of Chinese Medical Sciences, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
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18
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Xu Q, Wu YF, Li Y, He CY, Sun LP, Liu JW, Yuan Y. SNP-SNP interactions of three new pri-miRNAs with the target gene PGC and multidimensional analysis of H. pylori in the gastric cancer/atrophic gastritis risk in a Chinese population. Oncotarget 2018; 7:23700-14. [PMID: 26988755 PMCID: PMC5029657 DOI: 10.18632/oncotarget.8057] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 02/29/2016] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is a multistep complex disease involving multiple genes, and gene–gene interactions have a greater effect than a single gene in determining cancer susceptibility. This study aimed to explore the interaction of the let-7e rs8111742, miR-365b rs121224, and miR-4795 rs1002765 single nucleotide polymorphisms (SNPs) with SNPs of the predicted target gene PGC and Helicobacter pylori status in GC and atrophic gastritis (AG) risk. Three miRNA SNPs and seven PGC SNPs were detected in 2448 cases using the Sequenom MassArray platform. Two pairwise combinations of miRNA and PGC SNPs were associated with increased AG risk (let-7e rs8111742 – PGC rs6458238 and miR-4795 rs1002765 – PGC rs9471643). Singly, miR-365b rs121224 and PGC rs6912200 had no effect individually but in combination they demonstrated an epistatic interaction associated with AG risk. Similarly, let-7e rs8111742 and miR-4795 rs1002765 SNPs interacted with H. pylori infection to increase GC risk (rs8111742: Pinteraction = 0.024; rs1002765: Pinteraction = 0.031, respectively). A three-dimensional interaction analysis found miR-4795 rs1002765, PGC rs9471643, and H. pylori infection positively interacted to increase AG risk (Pinteraction = 0.027). Also, let-7e rs8111742, PGC rs6458238, and H. pylori infection positively interacted to increase GC risk (Pinteraction = 0.036). Furthermore, both of these three-dimensional interactions had a dosage–effect correspondence (Ptrend < 0.001) and were verified by MDR. In conclusion, the miRNAs SNPs (let-7e rs8111742 and miR-4795 rs1002765) might have more superior efficiency when combined with PGC SNPs and/or H. pylori for GC or AG risk than a single SNP on its own.
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Affiliation(s)
- Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Ye-Feng Wu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Ying Li
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Cai-Yun He
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Li-Ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jing-Wei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
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19
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Kupcinskas J. Small Molecules in Rare Tumors: Emerging Role of MicroRNAs in GIST. Int J Mol Sci 2018; 19:E397. [PMID: 29385688 PMCID: PMC5855619 DOI: 10.3390/ijms19020397] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 01/24/2018] [Accepted: 01/24/2018] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of gastrointestinal tract. GISTs have very different clinical phenotypes and underlying molecular characteristics that are not yet completely understood. microRNAs (miRNAs) have been shown to participate in carcinogenesis pathways through post-transcriptional regulation of gene expression in different tumors. Over the last years emerging evidence has highlighted the role of miRNAs in GISTs. This review provides an overview of original research papers that analyze miRNA deregulation patterns, functional role, diagnostic, therapeutic and prognostic implications in GIST as well as provides directions for further research in the field.
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Affiliation(s)
- Juozas Kupcinskas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Eiveniu str. 2, LT-50009 Kaunas, Lithuania.
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, Eiveniu str. 2, LT-50009 Kaunas, Lithuania.
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20
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miR-375 is involved in Hippo pathway by targeting YAP1/TEAD4-CTGF axis in gastric carcinogenesis. Cell Death Dis 2018; 9:92. [PMID: 29367737 PMCID: PMC5833783 DOI: 10.1038/s41419-017-0134-0] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 11/06/2017] [Accepted: 11/09/2017] [Indexed: 02/08/2023]
Abstract
miR-375 is a tumor-suppressive microRNA (miRNA) in gastric cancer (GC). However, its molecular mechanism remains unclear. The aim of this study is to comprehensively investigate how miR-375 is involved in Hippo pathway by targeting multiple oncogenes. miR-375 expression in gastric cancer cell lines and primary GC was investigated by qRT-PCR. The regulation of YAP1, TEAD4, and CTGF expression by miR-375 was evaluated by qRT-PCR, western blot, and luciferase reporter assays, respectively. The functional roles of the related genes were examined by siRNA-mediated knockdown or ectopic expression assays. The clinical significance and expression correlation analysis of miR-375, YAP1, and CTGF were performed in primary GCs. TCGA cohort was also used to analyze the expression correlation of YAP1, TEAD4, CTGF, and miR-375 in primary GCs. miR-375 was down-regulated in GC due to promoter methylation and histone deacetylation. miR-375 downregulation was associated with unfavorable outcome and lymph node metastasis. Ectopic expression of miR-375 inhibited tumor growth in vitro and in vivo. Three components of Hippo pathway, YAP1, TEAD4 and CTGF, were revealed to be direct targets of miR-375. The expression of three genes showed a negative correlation with miR-375 expression and YAP1 re-expression partly abolished the tumor-suppressive effect of miR-375. Furthermore, CTGF was confirmed to be the key downstream of Hippo-YAP1 cascade and its knockdown phenocopied siYAP1 or miR-375 overexpression. YAP1 nuclear accumulation was positively correlated with CTGF cytoplasmic expression in primary GC tissues. Verteporfin exerted an anti-oncogenic effect in GC cell lines by quenching CTGF expression through YAP1 degradation. In short, miR-375 was involved in the Hippo pathway by targeting YAP1-TEAD4-CTGF axis and enriched our knowledge on the miRNA dysregulation in gastric tumorigenesis.
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21
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Wu C, Zheng X, Li X, Fesler A, Hu W, Chen L, Xu B, Wang Q, Tong A, Burke S, Ju J, Jiang J. Reduction of gastric cancer proliferation and invasion by miR-15a mediated suppression of Bmi-1 translation. Oncotarget 2018; 7:14522-36. [PMID: 26894855 PMCID: PMC4924733 DOI: 10.18632/oncotarget.7392] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 01/12/2016] [Indexed: 12/14/2022] Open
Abstract
B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays important roles in gastric cancer, but the epigenetic regulatory mechanism by microRNA (miRNA) and the functional significance of Bmi-1 inhibition in gastric cancer remains elusive. In this study, we systematically investigated the functional roles of miRNA mediated Bmi-1 suppression in gastric cancer. Our results show that the expression of miR-15a is significantly reduced in gastric cancer and the protein expression levels of Bmi-1 are inversely correlated with miR-15a (P = 0.034) in gastric cancer patient samples. Functional studies revealed that ectopic expression of miR-15a decreased Bmi-1 in gastric cancer cell lines with reduced proliferation and tumor invasion. High levels of Bmi-1 in gastric cancer patients are significantly associated with better overall survival (P = 0.024) based on the Kaplan-Meier survival analysis.
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Affiliation(s)
- Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Xiao Zheng
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.,Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.,Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Andrew Fesler
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Lujun Chen
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Bin Xu
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Qi Wang
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | | | - Stephanie Burke
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Jingfang Ju
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Jingting Jiang
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
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22
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Wang G, Fang X, Han M, Wang X, Huang Q. MicroRNA-493-5p promotes apoptosis and suppresses proliferation and invasion in liver cancer cells by targeting VAMP2. Int J Mol Med 2018; 41:1740-1748. [PMID: 29328362 DOI: 10.3892/ijmm.2018.3358] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 12/15/2017] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to explore the role of miR‑493-5p in liver cancer tissues and cell lines, and its effect on cell behavioral characteristics. The expression of miR-493-5p was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in liver cancer tissues and cell lines (hepatic cell line HL-7702 and the liver cancer cell lines HCCC-9810, HuH-7 and HepG2). In addition, the mechanism by which miR-493-5p mediates its effects was analyzed via the transfection of miR-493-5p mimic and negative control miRNA into HepG2 cells. The viability, proliferation, apoptosis and invasion of the cells were analyzed using MTT assay, flow cytometry and Transwell chamber experiments. Furthermore, the effect of miR-493-5p on the expression of vesicle associated membrane protein 2 (VAMP2) was assayed using a dual-luciferase reporter system, and VAMP2 protein levels were determined by western blot analysis. In addition, following the cotransfection of HepG2 cells with pcDNA3.1‑VAMP2 plasmid and miR‑493-5p mimic, the role of miR-493-5p as a regulator of VAMP2 was evaluated using MTT assay, flow cytometry and Transwell chamber experiments. RT-qPCR analysis indicated that the expression of miR-493-5p in liver cancer tissues and cell lines was decreased significantly compared with that in adjacent normal liver tissues and normal liver cell lines, respectively. Compared with the control group, the cells transfected with miR-493-5p mimic (the miR-493-5p overexpression group) exhibited reduced cell viability, a reduced percentage of cells in the S phase and an increased percentage of apoptotic cells. In addition, fewer cells passed through the Transwell membrane in the miR-493-5p overexpression group compared with the control group. In the dual-luciferase reporter assay, luciferase activity in the miR‑493-5p overexpression group was attenuated compared with that in the control group. In addition, western blot analysis indicated that the VAMP2 protein levels in the miR‑493-5p overexpression group were lower than those in the control group. Furthermore, in cells overexpressing miR-493-5p and VAMP2 simultaneously, the biological behavior of the cells, including cell viability, cell cycle and cell invasiveness, was significantly rescued compared with that of the control group transfected with miR‑493-5p alone. In conclusion, miR-493-5p is indicated to be a tumor suppressor gene, and is downregulated in human liver cancer. miR-493-5p overexpression promotes cell apoptosis and inhibits the proliferation and migration of liver cancer cells by negatively regulating the expression of VAMP. These observations suggest the potential of treating liver cancer by the overexpression of microRNA-493-5p.
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Affiliation(s)
- Guannan Wang
- Department of Pancreato-Biliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230001, P.R. China
| | - Xiaosan Fang
- Department of Hepatobiliary Surgery, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Meng Han
- Department of Hepatobiliary Surgery, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Qiang Huang
- Department of Pancreato-Biliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230001, P.R. China
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Zhang X, Yao J, Guo K, Huang H, Huai S, Ye R, Niu B, Ji T, Han W, Li J. The functional mechanism of miR-125b in gastric cancer and its effect on the chemosensitivity of cisplatin. Oncotarget 2017; 9:2105-2119. [PMID: 29416757 PMCID: PMC5788625 DOI: 10.18632/oncotarget.23249] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 12/05/2017] [Indexed: 12/11/2022] Open
Abstract
Numerous studies have shown drug resistance of gastric cancer cells could be modulated by abnormal expression of microRNAs. Cisplatin (DDP) is one of the most commonly used drugs for chemotherapy of gastric cancer. In this study, the potential function of miR-125b on DDP resistance in gastric cancer cells was investigated. Sixteen miRNAs significantly differential expressed in gastric tumor tissues and adjacent tissues were characterized and their corresponding putative target genes were also screened. MiR-125b was selected as our focus for its evident down-regulated expression among candidate genes. Real-time polymerase chain reaction assay indicated that miR-125b was significantly down-regulated in gastric cancer tissues and various cell lines. HER2 was identified as a target gene of miR-125b by dual luciferase reporter assay and Western blot. Moreover, miR-125b overexpression inhibited not only the proliferation, migration, and invasion abilities of HGC-27 and MGC-803 cells, but also in vivo tumor growth of MGC-803 cells by an intratumoral delivery approach. Notably, we observed up-regulated miR-125b contributed to the chemosensitivity of DDP in HGC-27 and MGC-803 cells at different concentrations and also possessed sensibilization for DDP at different times. MiR-125b expression was found to be related to lymph node metastasis, HER2 expression and overall survival of patients through correlation analysis. Collectively, these results indicate miR-125b may regulate DDP resistance as a promising therapeutic target for gastric cancer treatment in future.
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Affiliation(s)
- Xinyue Zhang
- Department of Radiotherapy, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jie Yao
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Kai Guo
- Department of Gastroenterology, The 161th Hospital of PLA, Wuhan 430010, P.R. China
| | - Hu Huang
- Department of Oncology, The 161th Hospital of PLA, Wuhan 430010, P.R. China
| | - Siyuan Huai
- Department of Radiotherapy, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Rui Ye
- Department of Radiotherapy, Chinese PLA General Hospital, Beijing 100853, P.R. China.,Department of Oncology, Beidaihe Sanatorium of Beijing Military Command, Qinhuangdao 066100, P.R. China
| | - Baolong Niu
- Department of Radiotherapy, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Tiannan Ji
- Department of Radiotherapy, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Weidong Han
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jianxiong Li
- Department of Radiotherapy, Hainan Branch of Chinese PLA General Hospital, Sanya 572000, P.R. China
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Zhang X, Ma G, Liu J, Zhang Y. MicroRNA-182 promotes proliferation and metastasis by targeting FOXF2 in triple-negative breast cancer. Oncol Lett 2017; 14:4805-4811. [PMID: 29085483 PMCID: PMC5649577 DOI: 10.3892/ol.2017.6778] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 08/11/2017] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer (BC), is characterized as high proliferation, young age and poor prognosis. MicroRNA-182 (miR-182) was reported to have oncogenic potential in many cancers. We aimed to elucidate pathobiological effects of miR-182 expression by targeting forkhead-box F2 (FOXF2) in TNBC. In this study, we explored the functional role of miR-182 expression in TNBC. Quantitative real-time PCR (qRT-PCR) was applied to evaluate the expression of miR-182 in cell lines and tissues. A series of in vitro and in vivo assays were performed in the MCF-7 and MDA-MB-231 cell lines with miR-182 overexpression. Luciferase reporter assays and western blot analysis were used to identify FOXF2 as the direct and functional target of miR-182. In TNBC tissues and cell lines, we found that miR-182 was significantly upregulated. Transwell assay showed that re-expression of miR-182 increased cell migration and invasion abilities and MTT assay showed that it promoted cell growth in vitro. In vivo assay, re-expression of miR-182 significantly increase tumor volume and enhanced instant metastasis in the lungs of mice. Besides, FOXF2 was identified as a direct and functional target of miR-182. These results indicated that miR-182 plays an important role in the initiation and progression of TNBC by targeting FOXF2 and the miR-182/FOXF2 axis may present a new therapeutic strategy for TNBC in the future.
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Affiliation(s)
- Xingzeng Zhang
- Department of General Surgery, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Genshun Ma
- Department of General Surgery, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Jianchao Liu
- Department of General Surgery, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Yajun Zhang
- Department of General Surgery, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
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25
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Petkevicius V, Salteniene V, Juzenas S, Wex T, Link A, Leja M, Steponaitiene R, Skieceviciene J, Kupcinskas L, Jonaitis L, Kiudelis G, Malfertheiner P, Kupcinskas J. Polymorphisms of microRNA target genes IL12B, INSR, CCND1 and IL10 in gastric cancer. World J Gastroenterol 2017; 23:3480-3487. [PMID: 28596683 PMCID: PMC5442083 DOI: 10.3748/wjg.v23.i19.3480] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 02/23/2017] [Accepted: 03/21/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate associations between miRNA target genes IL12B, INSR, CCND1 and IL10 polymorphisms and gastric cancer (GC) in European population. METHODS Gene polymorphisms were analyzed in 508 controls and 474 GC patients from 3 tertiary centers in Germany, Lithuania and Latvia. Controls were patients from the out-patient departments, who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy. Gastric cancer (GC) patients had histopathological verification of gastric adenocarcinoma. Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells. IL12B T>G (rs1368439), INSR T>C (rs1051690), CCND1 A>C (rs7177) and IL10 T>C (rs3024498) SNPs were genotyped by the real-time polymerase chain reaction. Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex, age and country of birth. RESULTS We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690. The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls (23.26% and 19.19% respectively, P = 0.028). CT genotype was also more prevalent in patients compared to control group (38.48% and 30.12% respectively, P < 0.021). Logistic regression analysis revealed that only one polymorphism (rs1051690 in INSR gene) was associated with increased risk of GC. Carriers of CT genotype had higher odds of GC when compared to CC genotype (OR = 1.45, 95%PI: 1.08-1.95, P = 0.01). Similar association was observed in a dominant model for INSR gene, where comparison of TT+CT vs CC genotypes showed an increased risk of GC (OR = 1.44, 95%PI: 1.08-1.90, P = 0.01). Other analyzed SNPs were not associated with the presence of GC. CONCLUSION INSR rs1051690 SNP is associated with increased risk of GC, while polymorphisms in IL12B, CCND1 and IL10 genes are not linked with the presence of GC.
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26
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Wang Q, Yu J. MiR-129-5p suppresses gastric cancer cell invasion and proliferation by inhibiting COL1A1. Biochem Cell Biol 2017; 96:19-25. [PMID: 28482162 DOI: 10.1139/bcb-2016-0254] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is one of the most lethal cancers worldwide. In this study, we aimed to explore the role of miR-129-5p, a newly identified miR-129 member, in GC cells as well as the potential mechanism of action. The results of reverse transcription - qualitative polymerase chain reaction (RT-qPCR) and Western Blot showed that miR-129 was downregulated in GC cells compared with normal ones. Using MTT, colony formation, wound healing assay, and a Transwell assay, we evaluated the proliferation, migration, and invasion abilities of transfected cells, and confirmed miR-129-5p as a tumor suppressor in GC. After a microarray analysis comparing different gene expressions in miR-129-5p transfected SGC-7901 cells, COL1A1 was selected for biggest fold-change and potential target of miR-129-5p predicted by TargetScan. Measured by RT-qPCR and Western blot, COL1A1 turned out to be upregulated in GC tissues and cells. We further confirmed the targeting relationship between miR-129-5p and COL1A1 by dual luciferase assay. By manipulating the expression of COL1A1 in SGC-7901 cells, cell proliferation, migration, and invasion were examined and the tumor-promoting function of COL1A1 was validated. Moreover, co-transfection of miR-129-5p mimics and COL1A1 attenuated the tumor-promoting effects induced by a single-transfection of COL1A1, and miR-129-5p inhibitor counteracted the tumor-suppressing effects of COL1A1 siRNA. Collectively, the data demonstrate the important functions of the miR-129-5p-COL1A1 axis in GC: miR-129-5p suppresses GC cell proliferation, migration, and invasion, by selectively inhibiting COL1A1. This study provides new therapeutic targets for the clinical treatment of GC.
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Affiliation(s)
- Quan Wang
- Department of Gastrointestinal Surgery, the First Hospital of Jilin University, Changchun 130021, Jilin, China.,Department of Gastrointestinal Surgery, the First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Jinhai Yu
- Department of Gastrointestinal Surgery, the First Hospital of Jilin University, Changchun 130021, Jilin, China.,Department of Gastrointestinal Surgery, the First Hospital of Jilin University, Changchun 130021, Jilin, China
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27
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Biersack B. Interactions between anticancer active platinum complexes and non-coding RNAs/microRNAs. Noncoding RNA Res 2017; 2:1-17. [PMID: 30159416 PMCID: PMC6096430 DOI: 10.1016/j.ncrna.2016.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/07/2016] [Accepted: 10/07/2016] [Indexed: 12/13/2022] Open
Abstract
Platinum(II) complexes such as cisplatin, carboplatin and oxaliplatin are clinically approved for the therapy of various solid tumors. Challenging pathogenic properties of cancer cells and the response of cancers towards platinum-based drugs are strongly influenced by non-coding small RNA molecules, the microRNAs (miRNAs). Both increased platinum activity and formation of tumor resistance towards platinum drugs are controlled by miRNAs. This review gives an overview of the interactions between platinum-based drugs and miRNAs, and their influence on platinum activity in various cancer types is discussed.
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Key Words
- 5-FU, 5-fluorouracil
- Anticancer drugs
- CBDCA, cyclobutane-1,1-dicarboxylate
- Carboplatin
- Cisplatin
- DACH, 1,2-diaminocyclohexane
- DDP, cisplatin
- EGCG, (−)-epigallocatechin-3-gallate
- EOX, epirubicin/oxaliplatin/xeloda
- FOLFOX, folinate/5-FU/oxaliplatin
- GC, gemcitabine/cisplatin, gastric cancer
- LNA, locked nucleic acid
- MVAC, methotrexate/vinblastine/adriamycin/cisplatin
- MicroRNA
- Oxaliplatin
- Platinum complexes
- XELOX, xeloda/oxaliplatin
- dTTP, deoxythymidine triphosphate
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28
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Xu Q, Chen TJ, He CY, Sun LP, Liu JW, Yuan Y. MiR-27a rs895819 is involved in increased atrophic gastritis risk, improved gastric cancer prognosis and negative interaction with Helicobacter pylori. Sci Rep 2017; 7:41307. [PMID: 28150722 PMCID: PMC5288699 DOI: 10.1038/srep41307] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 12/19/2016] [Indexed: 12/15/2022] Open
Abstract
MiR-27a rs895819 is a loop-stem structure single nucleotide polymorphism affecting mature miR-27a function. In this study, we performed a comprehensive analysis about the association of rs895819 with gastric cancer risk and prognosis, atrophic gastritis risk, as well as the interactions with environmental factors. A total of 939 gastric cancer patients, 1,067 atrophic gastritis patients and 1,166 healthy controls were screened by direct sequencing and MALDI-TOF-MS. The association of rs895819 with clinical pathological parameters and prognostic survival in 357 gastric cancer patients was also been analyzed. The rs895819 variant genotype increased the risk for atrophic gastritis (1.58-fold) and gastric cancer (1.24-fold). While in stratified analysis, the risk effect was demonstrated more significantly in the female, age >60y, Helicobacter pylori (H. pylori) negative and non-drinker subgroups. Rs895819 and H. pylori showed an interaction effect for atrophic gastritis risk. In the survival analysis, the rs895819 AG heterozygosis was associated with better survival than the AA wild-type in the TNM stage I–II subgroup. In vitro study by overexpressing miR-27a, cells carrying polymorphic-type G allele expressed lower miR-27a than wild-type A allele. In conclusion, miR-27a rs895819 is implicated as a biomarker for gastric cancer and atrophic gastritis risk, and interacts with H. pylori in gastric carcinogenesis.
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Affiliation(s)
- Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Tie-Jun Chen
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Cai-Yun He
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Li-Ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jing-Wei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
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29
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Shi ZW, Wang JL, Zhao N, Guan Y, He W. Single nucleotide polymorphism of hsa-miR-124a affects risk and prognosis of osteosarcoma. Cancer Biomark 2017; 17:249-57. [PMID: 27540978 DOI: 10.3233/cbm-160637] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To study the correlation between single nucleotide polymorphism (SNP) of hsa-miR-124a and risk and prognosis of osteosarcoma (OS). METHODS OS patients (n = 174) hospitalized at The Second Affiliated Hospital of Harbin Medical University from January 2010 to March 2012 were selected as case group by inclusion and exclusion criteria, and healthy people (n = 150) receiving physical examination at the same duration were recruited as control group. Polymerase chain reaction-ligase detection reaction (PCR-LDR) was performed for genotyping of hsa-miR-124a rs531564. RESULTS There were significant differences in the frequency distribution of genotypes and alleles of hsa-miR-124a rs531564 in the case and control group (all P < 0.05); the individuals carrying with CG + GG genotype showed significantly decreased risk for OS. The clinical pathological characteristics were significantly different in the patients with CC genotype and CG + GG genotype, including tumor size, tumor differentiation grading, Enneking staging, operation manner, time of chemotherapy and metastasis (all P < 0.05). The 5-year survival rate of the cases with CC genotype was significantly lower than that of the ones with CG + GG genotype (P < 0.05). CG + GG genotype, Enneking staging and operation manner were independent risk factors for prognosis of OS (all P < 0.05). CONCLUSIONS CG +$ GG genotype of hsa-miR-124a rs531564 had decreased risk for OS and affected prognosis of OS.
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Affiliation(s)
- Zuo-Wei Shi
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jing-Lu Wang
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ning Zhao
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ying Guan
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Wen He
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Lee SW, Park KC, Kim JG, Moon SJ, Kang SB, Lee DS, Sul HJ, Ji JS, Jeong HY. Dysregulation of MicroRNA-196b-5p and MicroRNA-375 in Gastric Cancer. J Gastric Cancer 2016; 16:221-229. [PMID: 28053808 PMCID: PMC5206312 DOI: 10.5230/jgc.2016.16.4.221] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 09/09/2016] [Accepted: 09/22/2016] [Indexed: 12/15/2022] Open
Abstract
Purpose Dysregulated microRNAs (miRNAs) can contribute to cancer development by leading to abnormal proliferation of cells, apoptosis, and differentiation. Although several miRNAs that are related to gastric cancer have been identified, the reported results have been inconsistent. The aim of this study was to determine miRNA expression profiles and validate miRNAs up- and down-regulated in gastric cancer. Materials and Methods We evaluated 34 primary gastric cancer tissues and paired adjacent nontumorous gastric tissues. Total RNA was extracted, and low-molecular-weight RNAs (<200 nucleotides) were isolated for further analysis. Two pairs of tissues were processed for GeneChip microarray analysis, and the identified up- and down-regulated miRNAs were validated by real-time quantitative polymerase chain reaction (qPCR). Results In the set of differentially expressed miRNAs, 5 were overexpressed by more than 2 fold, and 5 were reduced by 2 fold or less in gastric cancer tissues compared with normal gastric tissues. Four of these miRNAs (miR-196b-5p, miR-375, miR-483-5p, and miR-486-5p) were then validated by qPCR, and the relative expression levels of 2 miRNAs (miR-196b-5p and miR-375) were significantly different between cancer and normal tissues. Conclusions Our results revealed that the expression of miR-196b-5p and miR-375 significantly correlates with gastric cancer. These miRNAs could therefore serve as diagnostic biomarkers of gastric cancer.
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Affiliation(s)
- Seung Woo Lee
- Division of Gastroenterology, Department of Internal Medicine, Daejeon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Ki Cheol Park
- Clinical Research Institute, Daejeon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Jeong Goo Kim
- Department of General Surgery, Daejeon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Sung Jin Moon
- Division of Gastroenterology, Department of Internal Medicine, Daejeon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Sang Bum Kang
- Division of Gastroenterology, Department of Internal Medicine, Daejeon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Dong Soo Lee
- Division of Gastroenterology, Department of Internal Medicine, Daejeon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Hae Joung Sul
- Department of Pathology, Daejeon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Jeong Seon Ji
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Hyun Yong Jeong
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
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Taniguchi H, Moriya C, Igarashi H, Saitoh A, Yamamoto H, Adachi Y, Imai K. Cancer stem cells in human gastrointestinal cancer. Cancer Sci 2016; 107:1556-1562. [PMID: 27575869 PMCID: PMC5132287 DOI: 10.1111/cas.13069] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 08/24/2016] [Accepted: 08/27/2016] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) are thought to be responsible for tumor initiation, drug and radiation resistance, invasive growth, metastasis, and tumor relapse, which are the main causes of cancer-related deaths. Gastrointestinal cancers are the most common malignancies and still the most frequent cause of cancer-related mortality worldwide. Because gastrointestinal CSCs are also thought to be resistant to conventional therapies, an effective and novel cancer treatment is imperative. The first reported CSCs in a gastrointestinal tumor were found in colorectal cancer in 2007. Subsequently, CSCs were reported in other gastrointestinal cancers, such as esophagus, stomach, liver, and pancreas. Specific phenotypes could be used to distinguish CSCs from non-CSCs. For example, gastrointestinal CSCs express unique surface markers, exist in a side-population fraction, show high aldehyde dehydrogenase-1 activity, form tumorspheres when cultured in non-adherent conditions, and demonstrate high tumorigenic potential in immunocompromised mice. The signal transduction pathways in gastrointestinal CSCs are similar to those involved in normal embryonic development. Moreover, CSCs are modified by the aberrant expression of several microRNAs. Thus, it is very difficult to target gastrointestinal CSCs. This review focuses on the current research on gastrointestinal CSCs and future strategies to abolish the gastrointestinal CSC phenotype.
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Affiliation(s)
- Hiroaki Taniguchi
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Chiharu Moriya
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Hisayoshi Igarashi
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Anri Saitoh
- The Center for Antibody and Vaccine TherapyResearch HospitalThe Institute of Medical ScienceThe University of TokyoTokyoJapan
| | - Hiroyuki Yamamoto
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineSt. Marianna University School of MedicineKawasakiJapan
| | - Yasushi Adachi
- Department of Gastroenterology, Rheumatology, and Clinical ImmunologySapporo Medical University School of MedicineSapporoJapan
| | - Kohzoh Imai
- The Institute of Medical ScienceThe University of TokyoTokyoJapan
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Li WJ, Wang Y, Gong Y, Tu C, Feng TB, Qi CJ. MicroRNA-124 rs531564 Polymorphism and Cancer Risk: A Meta-analysis. Asian Pac J Cancer Prev 2016; 16:7905-9. [PMID: 26625819 DOI: 10.7314/apjcp.2015.16.17.7905] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Several studies reported there was a polymorphism (rs531564 C > G) in miR-124 gene. To investigate the MiR-124 rs531564 polymorphism and cancer risk. We conducted a literature search of the Medline, Embase and Wangfang Medicine databases to identify all relevant studies for this meta-analysis. We determined that the miR-124 rs531564 polymorphism was significantly associated with decreased risks of cancers in the allelic model (G vs C, OR=0.71, 95% CI=0.53-0.94, P=0.02), homozygote model (GG vs CC, OR=0.42, 95% CI=0.26-0.66, P=0.0002), dominant model (GG/GC vs CC, OR=0.71, 95% CI=0.51-0.98, P=0.04) and recessive model (GG vs GC/CC, OR=0.43, 95% CI=0.27-0.69, P=0.0004). In an analysis stratified by cervical cancer group, significant associations were observed in the allelic model (G vs C, OR=0.46, 95% CI=0.32-0.66, P<0.0001), and dominant model (GG/GC vs CC, OR=0.45, 95% CI=0.3-0.66, P<0.0001). Subgroup analysis also revealed a decreased risk for esophageal squamous cell carcinoma in the homozygote model (GG vs CC, OR=0.45, 95% CI=0.27-0.75, P=0.002) and recessive model (GG vs GC/CC, OR=0.46, 95% CI=0.28-0.75, P=0.002). This meta-analysis suggests that the miR-124 rs531564 C > G polymorphism is an important risk factor for cancers among the Chinese population.
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Affiliation(s)
- Wen-Jing Li
- Medical Research Center, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou, China E-mail :
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Li Z, Yu X, Wang Y, Shen J, Wu WKK, Liang J, Feng F. By downregulating TIAM1 expression, microRNA-329 suppresses gastric cancer invasion and growth. Oncotarget 2016; 6:17559-69. [PMID: 25654811 PMCID: PMC4627328 DOI: 10.18632/oncotarget.2755] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 11/16/2014] [Indexed: 01/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide. Emerging evidence has shown that abnormal microRNAs (miRNAs) expression is involved in tumorigenesis. MiR-329 was previously reported to act as a tumor suppressor or oncogene in some types of cancer. However, its function in gastric cancer (GC) is unclear. Here, we found that miR-329 was down-regulated in GC compared with adjacent controls. Enforced expression of miR-329 inhibited proliferation, migration and invasion of gastric cancer cells in vitro. We identified T lymphoma invasion and metastasis 1 (TIAM1) gene as potential target of miR-329. MiR-329 levels inversely correlated with TIAM1 expression in GC. Importantly, TIAM1 rescued the miR-329-mediated inhibition of cell invasion and proliferation. Finally, reintroduction of miR-329 significantly inhibited tumor formation of GC in the xenograft mice. Our findings suggest that miR-329 is a tumor suppressor and potential therapeutic target of GC
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Affiliation(s)
- Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Yu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Wang
- Department of Abdominal Surgery, Cancer Institute and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jianxiong Shen
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Jinqian Liang
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fan Feng
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Acupuncture Decreases NF-κB p65, miR-155, and miR-21 and Increases miR-146a Expression in Chronic Atrophic Gastritis Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:9404629. [PMID: 27293468 PMCID: PMC4887647 DOI: 10.1155/2016/9404629] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 04/04/2016] [Accepted: 04/13/2016] [Indexed: 02/08/2023]
Abstract
Acupuncture has been used to treat chronic atrophic gastritis (CAG) in traditional Chinese medicine (TCM) for centuries. In this study, we evaluated the effect of acupuncture at Zusanli (ST36), Zhongwan (CV12), and Pishu (BL20) acupoints on weight changes of rats, histological changes of gastric glands, and expressions changes of nuclear factor-kappa B (NF-κB) p65, microRNA- (miR-) 155, miR-21, and miR-146a in CAG rats induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) combined with irregular diet. Consequently, we found that acupuncture treatment elevated body weight of rats significantly when compared to the model group. By observing histological changes, we found that the acupuncture group showed better improvement of gastric mucosa injury than the model group. Our results also demonstrated upregulation of NF-κB p65, miR-155, and miR-21 in gastric tissue of CAG rats and a positive correlation between miR-155 and miR-21. Relatively, expression of miR-146a was downregulated and negative correlation relationships between miR-146a and miR-155/miR-21 in CAG rats were observed. Additionally, expressions of NF-κB p65, miR-155, and miR-21 were downregulated and miR-146a was upregulated after acupuncture treatment. Taken together, our data imply that acupuncture can downregulate NF-κB p65, miR-155, and miR-21 and upregulate miR-146a expression in CAG rats. NF-κB p65, miR-155, miR-21, and miR-146a may play important roles in therapeutic effect of acupuncture in treating CAG.
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Steponaitiene R, Kupcinskas J, Langner C, Balaguer F, Venclauskas L, Pauzas H, Tamelis A, Skieceviciene J, Kupcinskas L, Malfertheiner P, Link A. Epigenetic silencing of miR-137 is a frequent event in gastric carcinogenesis. Mol Carcinog 2016; 55:376-386. [PMID: 25663388 DOI: 10.1002/mc.22287] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 12/09/2014] [Accepted: 12/18/2014] [Indexed: 12/14/2022]
Abstract
MicroRNAs (miRNA) are involved in posttranscriptional regulation of gene expression and are dysregulated during carcinogenesis. CpG island methylation of miR-137 is a common event in different cancers; however, the role of miR-137 in gastric cancer (GC) remains largely unexplored. In this study we aimed to characterize the epigenetic alterations of miR-137 in gastric carcinogenesis. We analyzed total 295 tissues including paired primary gastric cancer (T-GC) with corresponding adjacent gastric mucosa (N-GC), paired primary colorectal cancer (CRC) tissues with corresponding non-tumorous mucosa, gastric tissues from controls (N), and patients with chronic/atrophic gastritis (CG) with and without Helicobacter pylori infection. Bisulfite pyrosequencing and TaqMan RT-PCR were used to analyze miR-137 methylation and expression, respectively. Survival differences were evaluated using Kaplan-Meier analyses. miR-137 CpG island methylation was more frequent in tumorous compared to non-tumorous conditions and higher in CRC than in GC. In comparison to N-GC, miR 137 methylation level was lower in N and CG tissues, which correlates with Correas cascade. MiR-137 methylation inversely correlates with global LINE-1 methylation and miR-137 expression. miR-137 methylation was higher in intestinal type GC compared to diffuse one, and higher in antrum compared to cardia and corpus, however, miR-137 methylation was associated with worse prognosis in diffuse, but not in intestinal type of GC. The expression in colon was significantly higher compared to any gastric tissues suggesting functional difference. In summary, miR-137 methylation is a frequent event in gastrointestinal cancers which occurs early in stepwise manner during gastric carcinogenesis and inversely correlates with global methylation. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Ruta Steponaitiene
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Juozas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Cosima Langner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Francesc Balaguer
- Department of Gastroenterology, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Catalonia, Spain
| | - Linas Venclauskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Henrikas Pauzas
- Department of Surgery, Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Algimantas Tamelis
- Department of Surgery, Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Limas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Shafiee M, Aleyasin SA, Mowla SJ, Vasei M, Yazdanparast SA. The Effect of MicroRNA-375 Overexpression, an Inhibitor of Helicobacter pylori-Induced Carcinogenesis, on lncRNA SOX2OT. Jundishapur J Microbiol 2016; 9:e23464. [PMID: 27800139 PMCID: PMC5081003 DOI: 10.5812/jjm.23464] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 02/09/2015] [Accepted: 02/15/2015] [Indexed: 02/07/2023] Open
Abstract
Background Helicobacter pylori is a major human pathogenic bacterium in gastric mucosa. Although the association between gastric cancer and H. pylori has been well-established, the molecular mechanisms underlying H. pylori-induced carcinogenesis are still under investigation. MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression at the posttranscriptional level. Recently, studies have revealed that miRNAs are involved in immune response and host cell response to bacteria. Also, microRNA-375 (miR-375) is a key regulator of epithelial properties that are necessary for securing epithelium-immune system cross-talk. It has been recently reported that miR-375 acts as an inhibitor of H. pylori-induced gastric carcinogenesis. There are few reports on miRNA-mediated targeting long noncoding RNAs (lncRNAs). Objectives This study aimed to examine the possible effect of miR-375 as an inhibitor of H. pylori-induced carcinogenesis on the expression of lncRNA SOX2 overlapping transcript (SOX2OT) and SOX2, a master regulator of pluripotency of cancer stem cells. Materials and Methods In a model cell line, NT-2 was transfected with the constructed expression vector pEGFP-C1 contained miR-375. The RNA isolations and cDNA synthesis were performed after 48 hours of transformation. Expression of miR-375 and SOX2OT and SOX2 were quantified using real-time polymerase chain reaction and compared with control cells transfected with pEGFP-C1-Mock clone. Cell cycle modification was also compared after transfections using the flow cytometry analysis. Results Following ectopic expression of miR-375, SOX2OT and SOX2 expression analysis revealed a significant decrease in their expression level (P < 0.05) in NT-2 cells compared to the control. Cell cycle analysis following ectopic expression of miR-375 in the NT-2 cells using propidium iodine staining revealed significant extension in sub-G1 cell cycle. Conclusions This is the first report to show down-regulation of SOX2OT and SOX2 following induced expression of miR-375. This finding may suggest expression regulation potential between different classes of ncRNAs, for example between miR-375 and SOX2OT. This data not only extends our understanding of possible ncRNA interactions in cancers but also may open novel investigation lines towards elucidation of molecular mechanisms controlling H. pylori inflammation and carcinogenesis.
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Affiliation(s)
- Mohammad Shafiee
- National Institute of Genetic Engineering and Biotechnology, Tehran, IR Iran
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Seyed Ahmad Aleyasin
- National Institute of Genetic Engineering and Biotechnology, Tehran, IR Iran
- Corresponding author: Seyed Ahmad Aleyasin, National Institute of Genetic Engineering and Biotechnology, Tehran, IR Iran. Tel: +98-2144580302, Fax: +98-2144580395, E-mail:
| | - Seyed Javad Mowla
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, IR Iran
| | - Mohammad Vasei
- Department of Pathology, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Amir Yazdanparast
- Department of Medical Parasitology and Mycology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, IR Iran
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Skierucha M, Milne ANA, Offerhaus GJA, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016; 22:2460-2474. [PMID: 26937134 PMCID: PMC4768192 DOI: 10.3748/wjg.v22.i8.2460] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
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Bellissimo F, Pinzone MR, Cacopardo B, Nunnari G. Diagnostic and therapeutic management of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12003-12021. [PMID: 26576088 PMCID: PMC4641121 DOI: 10.3748/wjg.v21.i42.12003] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 08/03/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an increasing health problem, representing the second cause of cancer-related mortality worldwide. The major risk factor for HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemo-embolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines.
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Abstract
Helicobacter pylori infection plays a crucial role in gastric carcinogenesis. H pylori exerts oncogenic effects on gastric mucosa through complex interaction between bacterial virulence factors and host inflammatory responses. On the other hand, gastric cancer develops via stepwise accumulation of genetic and epigenetic alterations in H pylori-infected gastric mucosa. Recent comprehensive analyses of gastric cancer genomes indicate a multistep process of genetic alterations as well as possible molecular mechanisms of gastric carcinogenesis. Both genetic processes of gastric cancer development and molecular oncogenic pathways related to H pylori infection are important to completely understand the pathogenesis of H pylori-related gastric cancer.
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Juzėnas S, Saltenienė V, Kupcinskas J, Link A, Kiudelis G, Jonaitis L, Jarmalaite S, Kupcinskas L, Malfertheiner P, Skieceviciene J. Analysis of Deregulated microRNAs and Their Target Genes in Gastric Cancer. PLoS One 2015; 10:e0132327. [PMID: 26172537 PMCID: PMC4501563 DOI: 10.1371/journal.pone.0132327] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 06/13/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are widely studied non-coding RNAs that modulate gene expression. MiRNAs are deregulated in different tumors including gastric cancer (GC) and have potential diagnostic and prognostic implications. The aim of our study was to determine miRNA profile in GC tissues, followed by evaluation of deregulated miRNAs in plasma of GC patients. Using available databases and bioinformatics methods we also aimed to evaluate potential target genes of confirmed differentially expressed miRNA and validate these findings in GC tissues. METHODS The study included 51 GC patients and 51 controls. Initially, we screened miRNA expression profile in 13 tissue samples of GC and 12 normal gastric tissues with TaqMan low density array (TLDA). In the second stage, differentially expressed miRNAs were validated in a replication cohort using qRT-PCR in tissue and plasma samples. Subsequently, we analyzed potential target genes of deregulated miRNAs using bioinformatics approach, determined their expression in GC tissues and performed correlation analysis with targeting miRNAs. RESULTS Profiling with TLDA revealed 15 deregulated miRNAs in GC tissues compared to normal gastric mucosa. Replication analysis confirmed that miR-148a-3p, miR-204-5p, miR-223-3p and miR-375 were consistently deregulated in GC tissues. Analysis of GC patients' plasma samples showed significant down-regulation of miR-148a-3p, miR-375 and up-regulation of miR-223-3p compared to healthy subjects. Further, using bioinformatic tools we identified targets of replicated miRNAs and performed disease-associated gene enrichment analysis. Ultimately, we evaluated potential target gene BCL2 and DNMT3B expression by qRT-PCR in GC tissue, which correlated with targeting miRNA expression. CONCLUSIONS Our study revealed miRNA profile in GC tissues and showed that miR-148a-3p, miR-223-3p and miR-375 are deregulated in GC plasma samples, but these circulating miRNAs showed relatively weak diagnostic performance as sole biomarkers. Target gene analysis demonstrated that BCL2 and DNMT3B expression in GC tissue correlated with their targeting miRNA expression.
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Affiliation(s)
- Simonas Juzėnas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Violeta Saltenienė
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Juozas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, Magdeburg, Germany
| | - Gediminas Kiudelis
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Laimas Jonaitis
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Sonata Jarmalaite
- Division of Human Genome Research Centre, Faculty of Natural Sciences, Vilnius University, Vilnius, Lithuania
| | - Limas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, Magdeburg, Germany
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Liu Z, Xu Y, Long J, Guo K, Ge C, Du R. microRNA-218 suppresses the proliferation, invasion and promotes apoptosis of pancreatic cancer cells by targeting HMGB1. Chin J Cancer Res 2015; 27:247-57. [PMID: 26157321 DOI: 10.3978/j.issn.1000-9604.2015.04.07] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 03/24/2015] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE To detect the expression profiles of microRNA-218 (miR-218) in human pancreatic cancer tissue (PCT) and cells and their effects on the biological features of human pancreatic cancer cell line PANC-1 and observe the effect of miR-218 on the expression of the target gene high mobility group box 1 (HMGB1), with an attempt to provide new treatment methods and strategies for pancreatic cancer. METHODS The expressions of miR-218 in PCT and normal pancreas tissue as well as in various pancreatic cancer cell lines including AsPC-1, BxPC-3, and PANC-1 were determined with quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The change of miR-218 expression in PANC-1 cells was detected using qRT-PCT after the transfection of miR-218 mimic for 48 h. Cell Counting Kit-8 (CCK-8) was applied for detecting the effect of miR-218 on the activity of PANC-1 cells. The effects of miR-218 on the proliferation and apoptosis of PANC-1 cells were analyzed using the flow cytometry. The effect of miR-218 on the migration of PANC-1 cells was detected using the Trans-well migration assay. The HMGB1 was found to be a target gene of miR-218 by luciferase reporter assay, and the effect of miR-218 on the expression of HMGB1 protein in cells were determined using Western blotting. RESULTS As shown by qRT-PCR, the expressions of miR-218 in PCT and in pancreatic cancer cell line significantly decreased when compared with the normal pancreatic tissue (NPT) (P<0.01). Compared with the control group, the miR-218 expression significantly increased in the PANC-1 group after the transfection of miR-218 mimic for 48 h (P<0.01). Growth curve showed that the cell viability significantly dropped after the overexpression of miR-218 in the PANC-1 cells for two days (P<0.05). Flow cytometry showed that the S-phase fraction significantly dropped after the overexpression of miR-218 (P<0.01) and the percentage of apoptotic cells significantly increased (P<0.01). As shown by the Trans-well migration assay, the enhanced miR-218 expression was associated with a significantly lower number of cells that passed through a Transwell chamber (P<0.01). Luciferase reporter assay showed that, compared with the control group, the relative luciferase activity significantly decreased in the miR-218 mimic group (P<0.01). As shown by the Western blotting, compared with the control group, the HMGB1 protein expression significantly decreased in the PANC-1 group after the transfection of miR-218 mimic for 48 h (P<0.01). CONCLUSIONS The miR-218 expression decreases in human PCT and cell lines. miR-218 can negatively regulate the HMGB1 protein expression and inhibit the proliferation and invasion of pancreatic cancer cells. A treatment strategy by enhancing the miR-218 expression may benefit the patients with pancreatic cancer.
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Affiliation(s)
- Zhe Liu
- 1 Department of Pancreatic Surgery, First Hospital of China Medical University, Shenyang 110000, China ; 2 Department of Otorhinolaryngology, Fengtian Hospital, Shenyang Medical University, Shenyang 110024, China
| | - Yuanhong Xu
- 1 Department of Pancreatic Surgery, First Hospital of China Medical University, Shenyang 110000, China ; 2 Department of Otorhinolaryngology, Fengtian Hospital, Shenyang Medical University, Shenyang 110024, China
| | - Jin Long
- 1 Department of Pancreatic Surgery, First Hospital of China Medical University, Shenyang 110000, China ; 2 Department of Otorhinolaryngology, Fengtian Hospital, Shenyang Medical University, Shenyang 110024, China
| | - Kejian Guo
- 1 Department of Pancreatic Surgery, First Hospital of China Medical University, Shenyang 110000, China ; 2 Department of Otorhinolaryngology, Fengtian Hospital, Shenyang Medical University, Shenyang 110024, China
| | - Chunlin Ge
- 1 Department of Pancreatic Surgery, First Hospital of China Medical University, Shenyang 110000, China ; 2 Department of Otorhinolaryngology, Fengtian Hospital, Shenyang Medical University, Shenyang 110024, China
| | - Ruixia Du
- 1 Department of Pancreatic Surgery, First Hospital of China Medical University, Shenyang 110000, China ; 2 Department of Otorhinolaryngology, Fengtian Hospital, Shenyang Medical University, Shenyang 110024, China
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Effects of Two Common Polymorphisms rs2910164 in miR-146a and rs11614913 in miR-196a2 on Gastric Cancer Susceptibility. Gastroenterol Res Pract 2015; 2015:764163. [PMID: 25983750 PMCID: PMC4423019 DOI: 10.1155/2015/764163] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 10/25/2014] [Indexed: 12/12/2022] Open
Abstract
Background. Single nucleotide polymorphisms (SNPs) in genes encoding microRNAs may play important role in the development of gastric cancer. It has been reported that common SNPs rs2910164 in miR-146a and rs11614913 in miR-196a2 are associated with susceptibility to gastric cancer. The published results remain inconclusive or even controversial. A meta-analysis was conducted to quantitatively assess potential association between the two common SNPs and gastric cancer risk. Methods. A comprehensive literature search was performed in multiple internet-based electronic databases. Data from 12 eligible studies were extracted to estimate pooled odds ratios (ORs) and 95% confidence intervals (95% CI). Results. C allele of rs2910164 is associated with reduced gastric cancer risk in heterozygote model and dominant model whereas rs11614913 indicates no significant association. Subgroup analysis demonstrates that C allele of rs2910164 and rs11614913 may decrease susceptibility to diffuse type gastric cancer in dominant model and recessive model, respectively, while rs11614913 increased intestinal type gastric cancer in dominant model. Conclusion. SNPs rs2910164 and rs11614913 might have effect on gastric cancer risk in certain genetic models and specific types of cancer. Further well-designed studies should be considered to validate the potential effect.
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Zhang Y, Han T, Wei G, Wang Y. Inhibition of microRNA-17/20a suppresses cell proliferation in gastric cancer by modulating UBE2C expression. Oncol Rep 2015; 33:2529-36. [PMID: 25760688 DOI: 10.3892/or.2015.3835] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 01/07/2015] [Indexed: 12/17/2022] Open
Abstract
microRNAs (miRNAs) are small non-coding RNAs that potentially play a critical role in carcinogenesis. Increasing evidence indicates that the miR-17/20 cluster is upregulated in numerous types of human cancers including gastric cancer which suggests that the miR-17/20 cluster may play an important role in tumorigenesis. However, its role in gastric cancer carcinogenesis remains poorly defined due to the lack of target gene information. The aim of the present study was to investigate the target genes of the miR-17/20 cluster and their role in the tumor growth of gastric cancer. We found that both miR-17 and miR-20a (miR-17/20a) target the UBE2C gene in gastric cancer cells. Luciferase assay, qRT-PCR and western blot analysis confirmed that UBE2C is a direct target of miR‑17/20a in gastric cancer cells. Our results showed that the expression of UBE2C was positively regulated by miR-17/20a at both the mRNA and protein levels. Moreover, miR-17/20a was upregulated and positively associated with UBE2C in the gastric cancer tissues when compared to the adjacent nontumor tissues. Inhibition of miR-17/20a in gastric cancer cells was statistically correlated with a decrease in cell growth. These results demonstrate that upregulation of miR-17/20a promotes gastric cancer cell growth by targeting UBE2C and inhibition of their levels is a potentially promising therapeutic strategy for gastric cancer.
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Affiliation(s)
- Yingyi Zhang
- Department of Oncology, Changhai Hospital, Shanghai 200433, P.R. China
| | - Ting Han
- Department of General Surgery, Changhai Hospital, Shanghai 200433, P.R. China
| | - Guo Wei
- Department of General Surgery, Changhai Hospital, Shanghai 200433, P.R. China
| | - Yajie Wang
- Department of Oncology, Changhai Hospital, Shanghai 200433, P.R. China
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Schütte K, Schulz C, Link A, Malfertheiner P. Current biomarkers for hepatocellular carcinoma: Surveillance, diagnosis and prediction of prognosis. World J Hepatol 2015; 7:139-149. [PMID: 25729470 PMCID: PMC4342597 DOI: 10.4254/wjh.v7.i2.139] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 11/21/2014] [Accepted: 12/03/2014] [Indexed: 02/06/2023] Open
Abstract
Biomarkers for surveillance, diagnosis and prediction of prognosis in patients with hepatocellular carcinoma (HCC) are currently not ready for introduction into clinical practice because of limited sensitivity and specificity. Especially for the early detection of small HCC novel biomarkers are needed to improve the current effectiveness of screening performed by ultrasound. The use of high-throughput technologies in hepatocellular research allows to identify molecules involved in the complex pathways in hepatocarcinogenesis. Several invasive and non-invasive biomarkers have been identified already and have been evaluated in different clinical settings. Gene signatures with prognostic potential have been identified by gene expression profiling from tumor tissue. However, a single "all-in-one" biomarker that fits all-surveillance, diagnosis, prediction of prognosis-has not been found so far. The future of biomarkers most probably lies in a combination of non-invasive biomarkers, imaging and clinical parameters in a surveillance setting. Molecular profiling of tumorous and non-tumorous liver tissue may allow a prediction of prognosis for the individual patient and hopefully clear the way for individual treatment approaches. This article gives an overview on current developments in biomarker research in HCC with a focus on currently available and novel biomarkers, in particular on microRNA.
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Affiliation(s)
- Kerstin Schütte
- Kerstin Schütte, Christian Schulz, Alexander Link, Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, 39120 Magdeburg, Germany
| | - Christian Schulz
- Kerstin Schütte, Christian Schulz, Alexander Link, Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, 39120 Magdeburg, Germany
| | - Alexander Link
- Kerstin Schütte, Christian Schulz, Alexander Link, Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, 39120 Magdeburg, Germany
| | - Peter Malfertheiner
- Kerstin Schütte, Christian Schulz, Alexander Link, Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, 39120 Magdeburg, Germany
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45
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Kang W, Tong JHM, Lung RWM, Dong Y, Zhao J, Liang Q, Zhang L, Pan Y, Yang W, Pang JCS, Cheng ASL, Yu J, To KF. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer 2015; 14:52. [PMID: 25743273 PMCID: PMC4342823 DOI: 10.1186/s12943-015-0323-3] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 02/16/2015] [Indexed: 12/13/2022] Open
Abstract
Background MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. In this study, the role of miR-15a and miR-16-1 in gastric adenocarcinoma (GAC) was investigated. Methods The expression of miR-15a and miR-16-1 in cell lines and primary tumors was examined by miRNA qRT-PCR. Proliferative assays, colony formation, cell invasion and migration, flow cytometry analysis and in vivo study were performed by ectopic expression of miR-15a and miR-16-1. The putative target genes of miR-15a and miR-16-1 were explored by TargetScan and further validated. Results We found that miR-15a and miR-16-1 were down-regulated in GAC cell lines and primary tumor samples compared with normal gastric epithelium. Functional study demonstrated that ectopic expression of miR-15a and miR-16-1 suppressed cell proliferation, monolayer colony formation, invasion and migration, and xenograft formation in vivo. In addition, miR-15a and miR-16-1 induced G0/G1 cell cycle arrest which was further confirmed by Western blot and qRT-PCR of related cell cycle regulators. YAP1 was confirmed to be a functional target of miR-15a and miR-16-1 in GAC. YAP1 re-expression partly abrogated the inhibitory effect of miR-15a and miR-16-1 in GAC cells. In clinical samples, YAP1 protein expression shows negative correlation with miR-15a and miR-16-1 expression. Conclusion In conclusion, targeting YAP1 by tumor suppressor miRNA miR-15a and miR-16-1 plays inhibitory effect and this might have a therapeutic potential in GAC. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0323-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
| | - Joanna H M Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Raymond W M Lung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Yujuan Dong
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Junhong Zhao
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Qiaoyi Liang
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Li Zhang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Yi Pan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China.
| | - Jesse C S Pang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Alfred S L Cheng
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. .,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China.
| | - Jun Yu
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. .,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, PR China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
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Link A, Schirrmeister W, Langner C, Varbanova M, Bornschein J, Wex T, Malfertheiner P. Differential expression of microRNAs in preneoplastic gastric mucosa. Sci Rep 2015; 5:8270. [PMID: 25652892 PMCID: PMC4317705 DOI: 10.1038/srep08270] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 01/14/2015] [Indexed: 12/14/2022] Open
Abstract
Gastric carcinogenesis is a multifactorial H.pylori-triggered dynamic process that goes through a cascade of preneoplastic conditions. The expression of miRNAs in the stomach with regard to preneoplastic precursor conditions and H.pylori infection has not been investigated systematically. In this prospective proof-of-principle study, we evaluated the miRNA expression in gastric antrum and corpus mucosa from patients with chronic non-atrophic gastritis (CNAG), atrophic gastritis (AG), and GC compared to controls. Gastric normal mucosa shows a unique expression pattern for miR-21, miR-155 and miR-223, which is specific for different regions. In correlation with progression of Correa's cascade and H.pylori infection, we observed a gradual increase in miR-155 and miR-223 both in corpus and antrum and miR-21 only in the antrum mucosa. Using miRNA expression we calculated a score that allowed us to discriminate patients with AG from subjects with normal mucosa with high diagnostic accuracy in testing and validation cohorts reproducibly. In summary, the expression pattern of miRNAs in the gastric mucosa is gradually increased with progression of Correa's cascade and H.pylori infection, suggesting miRNAs as potential biomarkers for preneoplastic precursor conditions. However, differences of miRNA expression between the gastric antrum and the corpus need to be considered in future studies.
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Affiliation(s)
- Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Wiebke Schirrmeister
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Cosima Langner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Mariya Varbanova
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Jan Bornschein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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Gao Y, Liu Y, Liu GL, Ran LK, Zeng F, Wu JY, Song FZ. Association between the pre-mir-218 polymorphism and cancer risk in the Chinese population: a meta-analysis. Asian Pac J Cancer Prev 2015; 15:2517-22. [PMID: 24761857 DOI: 10.7314/apjcp.2014.15.6.2517] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Several recent studies have explored associations between pre-mir-218 polymorphism (rs11134527) and cancer risk. However, published data are still inconclusive. To obtain a more precise estimation of the relationship in the Chinese population, we carried out a meta-analysis for the first time. MATERIALS AND METHODS Through retrieval from the PubMed, Medline, Embase, Web of Science databases, China National Knowledge Infrastructure and the Chinese BioMedical Literature Database, a total of four studies were analyzed with 3,561 cases and 3,628 controls for SNP pre-mir-218 rs11134527. We calculated odds ratios (ORs) and 95% confidence intervals (95%CIs) to explore the strength of associations. RESULTS The results showed that the rs11134527 polymorphism was associated with decreased cancer risk in GG versus AA and GG versus AA+AG models tested ( GG vs AA: OR=0.82, 95%CI: 0.71-0.94; GG vs AA+AG: OR=0.84, 95%CI: 0.74-0.96), and significantly decreased cervical cancer risk was observed in GG versus AA and GG versus AA+AG models (GG vs AA: OR=0.79, 95%CI: 0.66-0.94; GG vs AA+AG: OR=0.80, 95%CI: 0.68-0.94). However, no significant association between the rs11134527 polymorphism and hepatocellular carcinoma risk was observed in all comparison models tested (AG vs AA: OR=0.94, 95%CI: 0.79-1.11; GG vs AA: OR=0.88, 95%CI: 0.70-1.10; GG+AG vs AA: OR=0.92, 95%CI: 0.79-1.08; GG vs AA+AG: OR=0.91, 95%CI: 0.75-1.11). CONCLUSION The findings suggest that pre-miR-218 rs11134527 polymorphism may have some relation to cancer development in Chinese. However, well-designed studies with larger sample size and more detailed data are needed to confirm these conclusions.
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Affiliation(s)
- Yue Gao
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China E-mail :
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Leja M, You W, Camargo MC, Saito H. Implementation of gastric cancer screening - the global experience. Best Pract Res Clin Gastroenterol 2014; 28:1093-106. [PMID: 25439074 PMCID: PMC5847270 DOI: 10.1016/j.bpg.2014.09.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 08/31/2014] [Accepted: 09/15/2014] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is still an important global healthcare problem, and in absolute figures it is going to remain at the present level in foreseeable future. In general, survival of patients with GC is poor mainly due to advanced-stage diagnosis. Early-stage GC can be cured by endoscopic resection or less invasive surgical treatment. Unfortunately, there is no appropriate screening strategy available for global application. This article provides a description of established national and regional GC screening programs and the screening modalities used. This review also summarizes current approaches to develop cancer-screening biomarkers. Although candidates with initial promising results have been suggested, moving discovery into clinical practice is still a major challenge. Well-designed biomarker studies, with systematic validation steps, are needed to decrease the burden of this fatal disease.
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Affiliation(s)
- Mārcis Leja
- Faculty of Medicine, University of Latvia, 6 Linezera iela, LV1006 Riga, Latvia.
| | - Weicheng You
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
| | - Hiroshi Saito
- Cancer Screening Assessment & Management Division, Research Center for Cancer Prevention & Detection, National Cancer Center, Tokyo 104-0045, Japan.
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Abstract
Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers; the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review.
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Affiliation(s)
- Mairi H McLean
- National Cancer Institute, Laboratory of Molecular Immunoregulation, Cancer &Inflammation Program, 1050 Boyles Street, Frederick, MD 21702-1201, USA
| | - Emad M El-Omar
- Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB51 5ER, UK
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Pasechnikov V, Chukov S, Fedorov E, Kikuste I, Leja M. Gastric cancer: prevention, screening and early diagnosis. World J Gastroenterol 2014; 20:13842-62. [PMID: 25320521 PMCID: PMC4194567 DOI: 10.3748/wjg.v20.i38.13842] [Citation(s) in RCA: 297] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 04/28/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer continues to be an important healthcare problem from a global perspective. Most of the cases in the Western world are diagnosed at late stages when the treatment is largely ineffective. Helicobacter pylori (H. pylori) infection is a well-established carcinogen for gastric cancer. While lifestyle factors are important, the efficacy of interventions in their modification, as in the use of antioxidant supplements, is unconvincing. No organized screening programs can be found outside Asia (Japan and South Korea). Although several screening approaches have been proposed, including indirect atrophy detection by measuring pepsinogen in the circulation, none of them have so far been implemented, and more study data is required to justify any implementation. Mass eradication of H. pylori in high-risk areas tends to be cost-effective, but its adverse effects and resistance remain a concern. Searches for new screening biomarkers, including microRNA and cancer-autoantibody panels, as well as detection of volatile organic compounds in the breath, are in progress. Endoscopy with a proper biopsy follow-up remains the standard for early detection of cancer and related premalignant lesions. At the same time, new advanced high-resolution endoscopic technologies are showing promising results with respect to diagnosing mucosal lesions visually and targeting each biopsy. New histological risk stratifications (classifications), including OLGA and OLGIM, have recently been developed. This review addresses the current means for gastric cancer primary and secondary prevention, the available and emerging methods for screening, and new developments in endoscopic detection of early lesions of the stomach.
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