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Gholamhosseinzadeh E, Ghalehnoei H, Kazemi Veisari A, Jafari N, Goli HR. Evaluation of the Rock1 and microRNA-148a expression in biopsies collected from patients with Helicobacter pylori induced gastritis. BMC Gastroenterol 2024; 24:251. [PMID: 39112943 PMCID: PMC11308716 DOI: 10.1186/s12876-024-03347-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/01/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Helicobacter pylori infection is one of the most common chronic bacterial infections, especially in developing countries. MicroRNA-148a is involved in the regulation of various genes, including Rock1, which is altered in gastric cancer. Decreased expression of mir-148a leads to tumor metastasis and increased Rock1 gene expression in gastric cancer. This study aimed to investigate the expression of these genes in biopsies collected from patients with H. pylori induced gastritis. METHODS Informed consent forms were gotten from the studied patients with gastritis who needed endoscopy. Gastric biopsies were taken by a gastroenterologist from patients with inflammation. Rapid urease test, stool antigen detection, and histopathological staining were used to determine the H. pylori infected patients. Real time PCR was used to evaluate the miRNA and Rock1 expression levels. RESULTS The Rock1 expression level in biopsies that were positive for H. pylori was significantly increased compared to our control gastritis group that were H. pylori-negative, but the results were not statistically significant. Moreover, the mir-148a expression level in H. pylori-positive patients with gastritis was increased compared to our control group. However, the results were not statistically significant. We did not find a significant relation between the expression levels of Rock1 and mir-148a in samples with gastritis infected or uninfected by H. pylori. This result may be due to the small sample size. CONCLUSION We suggest that this test should be carried out with more samples, and the comparison should be done between biopsies with inflammation and no inflammation in a patient.
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Affiliation(s)
- Ebrahim Gholamhosseinzadeh
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Medical Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Farah Abad blv, Khazar square, Sari, Mazandaran, Iran
| | - Hossein Ghalehnoei
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Arash Kazemi Veisari
- Gut and Liver Research Center, Non-communicable Disease Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Narjes Jafari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamid Reza Goli
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Department of Medical Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Farah Abad blv, Khazar square, Sari, Mazandaran, Iran.
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2
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Li S, Hoefnagel SJM, Krishnadath KK. Molecular Biology and Clinical Management of Esophageal Adenocarcinoma. Cancers (Basel) 2023; 15:5410. [PMID: 38001670 PMCID: PMC10670638 DOI: 10.3390/cancers15225410] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) is a highly lethal malignancy. Due to its rising incidence, EAC has become a severe health challenge in Western countries. Current treatment strategies are mainly chosen based on disease stage and clinical features, whereas the biological background is hardly considered. In this study, we performed a comprehensive review of existing studies and discussed how etiology, genetics and epigenetic characteristics, together with the tumor microenvironment, contribute to the malignant behavior and dismal prognosis of EAC. During the development of EAC, several intestinal-type proteins and signaling cascades are induced. The anti-inflammatory and immunosuppressive microenvironment is associated with poor survival. The accumulation of somatic mutations at the early phase and chromosomal structural rearrangements at relatively later time points contribute to the dynamic and heterogeneous genetic landscape of EAC. EAC is also characterized by frequent DNA methylation and dysregulation of microRNAs. We summarize the findings of dysregulations of specific cytokines, chemokines and immune cells in the tumor microenvironment and conclude that DNA methylation and microRNAs vary with each different phase of BE, LGD, HGD, early EAC and invasive EAC. Furthermore, we discuss the suitability of the currently employed therapies in the clinic and possible new therapies in the future. The development of targeted and immune therapies has been hampered by the heterogeneous genetic characteristics of EAC. In view of this, the up-to-date knowledge revealed by this work is absolutely important for future EAC studies and the discovery of new therapeutics.
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Affiliation(s)
- Shulin Li
- Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
- Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
| | | | - Kausilia Krishnawatie Krishnadath
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, 2000 Antwerpen, Belgium
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3
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Islam MO, Thangaretnam K, Lu H, Peng D, Soutto M, El-Rifai W, Giordano S, Ban Y, Chen X, Bilbao D, Villarino AV, Schürer S, Hosein PJ, Chen Z. Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma. Mol Ther Oncolytics 2023; 30:286-300. [PMID: 37732296 PMCID: PMC10507159 DOI: 10.1016/j.omto.2023.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 08/24/2023] [Indexed: 09/22/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) patients have poor clinical outcomes, with an overall 5-year survival rate of 20%. Smoking is a significant risk factor for EAC. The role of WEE1, a nuclear kinase that negatively regulates the cell cycle in normal conditions, in EAC tumorigenesis and drug resistance is not fully understood. Immunohistochemistry staining shows significant WEE1 overexpression in human EAC tissues. Nicotine, nicotine-derived nitrosamine ketone, or 2% cigarette smoke extract treatment induces WEE1 protein expression in EAC, detected by western blot and immunofluorescence staining. qRT-PCR and reporter assay indicates that smoking induces WEE1 expression through miR-195-5p downregulation in EAC. ATP-Glo cell viability and clonogenic assay confirmed that WEE1 inhibition sensitizes EAC cells to docetaxel treatment in vitro. A TE-10 smoking machine with EAC patient-derived xenograft mouse model demonstrated that smoking induces WEE1 protein expression and resistance to docetaxel in vivo. MK-1775 and docetaxel combined treatment improves EAC patient-derived xenograft mouse survival in vivo. Our findings demonstrate, for the first time, that smoking-induced WEE1 overexpression through miRNA dysregulation in EAC plays an essential role in EAC drug resistance. WEE1 inhibition is a promising therapeutic method to overcome drug resistance and target treatment refractory cancer cells.
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Affiliation(s)
- Md Obaidul Islam
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Krishnapriya Thangaretnam
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Heng Lu
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Dunfa Peng
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Mohammed Soutto
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Wael El-Rifai
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL 33136, USA
| | - Silvia Giordano
- University of Torino, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo, Italy
| | - Yuguang Ban
- Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Xi Chen
- Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Daniel Bilbao
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Alejandro V. Villarino
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Stephan Schürer
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
- Institute for Data Science and Computing, University of Miami, Coral Gables, FL 33146, USA
| | - Peter J. Hosein
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
- Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Zheng Chen
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
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4
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Farasati Far B, Vakili K, Fathi M, Yaghoobpoor S, Bhia M, Naimi-Jamal MR. The role of microRNA-21 (miR-21) in pathogenesis, diagnosis, and prognosis of gastrointestinal cancers: A review. Life Sci 2023; 316:121340. [PMID: 36586571 DOI: 10.1016/j.lfs.2022.121340] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/16/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs regulating the expression of several target genes. miRNAs play a significant role in cancer biology, as they can downregulate their corresponding target genes by impeding the translation of mRNA (at the mRNA level) as well as degrading mRNAs by binding to the 3'-untranslated (UTR) regions (at the protein level). miRNAs may be employed as cancer biomarkers. Therefore, miRNAs are widely investigated for early detection of cancers which can lead to improved survival rates and quality of life. This is particularly important in the case of gastrointestinal cancers, where early detection of the disease could substantially impact patients' survival. MicroRNA-21 (miR-21 or miRNA-21) is one of the most frequently researched miRNAs, where it is involved in the pathophysiology of cancer and the downregulation of several tumor suppressor genes. In gastrointestinal cancers, miR-21 regulates phosphatase and tensin homolog (PTEN), programmed cell death 4 (PDCD4), mothers against decapentaplegic homolog 7 (SMAD7), phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT), matrix metalloproteinases (MMPs), β-catenin, tropomyosin 1, maspin, and ras homolog gene family member B (RHOB). In this review, we investigate the functions of miR-21 in pathogenesis and its applications as a diagnostic and prognostic cancer biomarker in four different gastrointestinal cancers, including colorectal cancer (CRC), pancreatic cancer (PC), gastric cancer (GC), and esophageal cancer (EC).
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammed Bhia
- Student Research Committee, Department of Pharmaceutics and Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - M Reza Naimi-Jamal
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran.
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5
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Lu H, Gomaa A, Wang-Bishop L, Ballout F, Hu T, McDonald O, Washington MK, Livingstone AS, Wang TC, Peng D, El-Rifai W, Chen Z. Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma. Cancers (Basel) 2022; 14:1401. [PMID: 35326553 PMCID: PMC8946061 DOI: 10.3390/cancers14061401] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 12/24/2022] Open
Abstract
Unfolded protein response (UPR) protects malignant cells from endoplasmic reticulum stress-induced apoptosis. We report that Aurora kinase A (AURKA) promotes cancer cell survival by activating UPR in esophageal adenocarcinoma (EAC). A strong positive correlation between AURKA and binding immunoglobulin protein (BIP) mRNA expression levels was found in EACs. The in vitro assays indicated that AURKA promoted IRE1α protein phosphorylation, activating prosurvival UPR in FLO-1 and OE33 cells. The use of acidic bile salts to mimic reflux conditions in patients induced high AURKA and IRE1α levels. This induction was abrogated by AURKA knockdown in EAC cells. AURKA and p-IRE1α protein colocalization was observed in neoplastic gastroesophageal lesions of the L2-IL1b mouse model of Barrett's esophageal neoplasia. The combined treatment using AURKA inhibitor and tunicamycin synergistically induced cancer cell death. The use of alisertib for AURKA inhibition in the EAC xenograft model led to a decrease in IRE1α phosphorylation with a significant reduction in tumor growth. These results indicate that AURKA activates UPR, promoting cancer cell survival during ER stress in EAC. Targeting AURKA can significantly reverse prosurvival UPR signaling mechanisms and decrease cancer cell survival, providing a promising approach for the treatment of EAC patients.
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Affiliation(s)
- Heng Lu
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
| | - Ahmed Gomaa
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
| | - Lihong Wang-Bishop
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA;
| | - Farah Ballout
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
| | - Tianling Hu
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
| | - Oliver McDonald
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Mary Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37235, USA;
| | - Alan S. Livingstone
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA;
| | - Dunfa Peng
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
| | - Wael El-Rifai
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
| | - Zheng Chen
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.L.); (A.G.); (F.B.); (T.H.); (A.S.L.); (W.E.-R.)
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6
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Sun Z, He Z, Liu R, Zhang Z. Cation Lipid-Assisted PEG6-PLGA Polymer Nanoparticles Encapsulated Knocking Down Long ncRNAs Reverse Non-Coding RNA of Xist Through the Support Vector Machine Model to Regulate the Molecular Mechanisms of Gastric Cancer Cell Apoptosis. J Biomed Nanotechnol 2021; 17:1305-1319. [PMID: 34446134 DOI: 10.1166/jbn.2021.3107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Gastric adenocarcinoma (GAC) is one kind of gastric cancer with a high incidence rate and mortality. It is essential to study the etiology of GAC and provide theoretical guidance for the prevention and treatment of GAC. Bioinformatics was used via differential expression analysis, weighted gene co-expression network analysis, gene set enrichment analysis, and a training support vector machine (SVM) model to construct a TSIX/mir-320a/Rad51 network as the research index of GAC disease. On the basis of CRISPR/Cas9 gene editing technology, the present study utilizes the Cation lipid-assisted PEG-6-PLGA polymer nanoparticle (CLAN) drug carrier system to prepare the target knock-out TSIX drug with CRISPR/CaS9 nucleic acid. Knocking down lncRNA TSIX restored the suppression role of miR-320a on Rad51 and inhibited the Rad51 expression. Simultaneously, this ceRNA network activated the ATF6 signaling pathway after endoplasmic reticulum stress to promote GAC cells' apoptosis and inhibit the disease. TSIX/miR-320a/Rad51 network may be a potential biological target of GAC disease and provides a new strategy for treating GAC disease.
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Affiliation(s)
- Zhengwang Sun
- Department of Orthopaedic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China
| | - Zirui He
- Department of General Surgery, Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai 200032, PR China
| | - Rujiao Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China
| | - Zhe Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, PR China
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7
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Elnaggar GN, El-Hifnawi NM, Ismail A, Yahia M, Elshimy RAA. Micro RNA-148a Targets Bcl-2 in Patients with Non-Small Cell Lung Cancer. Asian Pac J Cancer Prev 2021; 22:1949-1955. [PMID: 34181356 PMCID: PMC8418855 DOI: 10.31557/apjcp.2021.22.6.1949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/16/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Lung cancer is one of the most prevalent cancers and the leading cause of cancer-related deaths worldwide. MicroRNAs regulate more than 60% of human genes, including tumor suppressor genes and oncogenes. Accordingly, they can affect cancer risk. This study aimed to evaluate the role of serum miR-148a as a non-invasive biomarker in non-small cell lung cancer (NSCLC) patients and to assess the correlation between miR-148a and Bcl-2, as one of its target proteins. MATERIALS AND METHODS A total of 50 newly diagnosed NSCLC cases and 30 apparently healthy controls were recruited in this study. MiR-148a level was measured by TaqMan- Real time RT-PCR assay and Bcl-2 level was measured by ELISA. RESULTS Significant lower expression of serum miR-148a and higher serum Bcl-2 levels were observed in NSCLC patients as compared to the control group (p.
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Affiliation(s)
- Ghada Nabil Elnaggar
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt.
| | - Niveen M El-Hifnawi
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt.
| | - Abeer Ismail
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt.
| | - Maha Yahia
- Department of Medical Oncology, National Cancer Institute, Cairo University, Egypt.
| | - Reham A A Elshimy
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt.
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Lv Y, Wang Y, Song Y, Wang SS, Cheng KW, Zhang ZQ, Yao J, Zhou LN, Ling ZY, Cao C. LncRNA PINK1-AS promotes Gαi1-driven gastric cancer tumorigenesis by sponging microRNA-200a. Oncogene 2021; 40:3826-3844. [PMID: 33958720 DOI: 10.1038/s41388-021-01812-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/07/2021] [Accepted: 04/21/2021] [Indexed: 02/03/2023]
Abstract
Gastric cancer (GC) is one of the leading causes of human mortality around the world. We have previously shown that Gαi1 (the inhibitory subunit 1 of the heterotrimeric guanine nucleotide-binding protein) recruitment to ligand-activated receptor tyrosine kinases (RTKs) is essential for signaling. Testing its role in GC cancer-promoting functions, we found that Gαi1 is upregulated in human GC, correlating with poor overall survival. In established and primary human GC cells, Gαi1 shRNA (small hairpin RNA) or knockout produced significant anti-GC cell activity, proliferation and migration was inhibited, and apoptosis was activated. Conversely, ectopic Gαi1 overexpression promoted proliferation and migration of GC cells in vitro. By examining the tumor-suppressive miRNA microRNA-200a (miR-200a), we found that miR-200a directly silenced Gαi1 to induce anti-GC cell activity. The expression of miR-200a was downregulated in human GC, correlating with upregulation of a novel miR-200a-targeting long non-coding RNA (LncRNA), PINK1 (PTEN Induced Kinase 1)-AS. RNA immunoprecipitation, RNA-pull down, and RNA fluorescence in situ hybridization assays confirmed that PINK1-AS directly binds to miR-200a. Silencing PINK1-AS in GC cells led to miR-200a accumulation, Gαi1 downregulation, and inhibition of GC cell progression in vitro, whereas PINK1-AS upregulation produced the converse results. Significantly, anti-GC cell activity induced by PINK1-AS shRNA was ameliorated by the expression of miR-200a antisense or the 3'-UTR (untranslated region)-depleted Gαi1. In vivo, the growth of subcutaneous MGC-803 xenografts in nude mice was inhibited by PINK1-AS shRNA, but accelerated by PINK1-AS overexpression. Patient-derived GC xenograft growth in nude mice was largely inhibited after intratumoral injection of PINK1-AS shRNA lentivirus. In conclusion, PINK1-AS promotes Gαi1-driven GC progression by sponging miR-200a.
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Affiliation(s)
- Yan Lv
- Center of Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Yin Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Yu Song
- Department of Oncology, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Shu-Sheng Wang
- Department of General Surgery, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Kai-Wen Cheng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Zhi-Qing Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Jin Yao
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
| | - Li-Na Zhou
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
| | - Zhuo-Yan Ling
- Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, China.
| | - Cong Cao
- Center of Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China. .,Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China. .,North District, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
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9
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Dinneen K, Baird AM, Ryan C, Sheils O. The Role of Cancer Stem Cells in Drug Resistance in Gastroesophageal Junction Adenocarcinoma. Front Mol Biosci 2021; 8:600373. [PMID: 33628765 PMCID: PMC7897661 DOI: 10.3389/fmolb.2021.600373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 01/06/2021] [Indexed: 12/24/2022] Open
Abstract
Gastroesophageal junction adenocarcinomas (GEJA) have dramatically increased in incidence in the western world since the mid-20th century. Their prognosis is poor, and conventional anti-cancer therapies do not significantly improve survival outcomes. These tumours are comprised of a heterogenous population of both cancer stem cells (CSC) and non-CSCs, with the former playing a crucial role in tumorigenesis, metastasis and importantly drug resistance. Due to the ability of CSCs to self-replicate indefinitely, their resistance to anti-cancer therapies poses a significant barrier to effective treatment of GEJA. Ongoing drug development programmes aim to target and eradicate CSCs, however their characterisation and thus identification is difficult. CSC regulation is complex, involving an array of signalling pathways, which are in turn influenced by a number of entities including epithelial mesenchymal transition (EMT), microRNAs (miRNAs), the tumour microenvironment and epigenetic modifications. Identification of CSCs commonly relies on the expression of specific cell surface markers, yet these markers vary between different malignancies and indeed are often co-expressed in non-neoplastic tissues. Development of targeted drug therapies against CSCs thus requires an understanding of disease-specific CSC markers and regulatory mechanisms. This review details the current knowledge regarding CSCs in GEJA, with particular emphasis on their role in drug resistance.
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Affiliation(s)
- Kate Dinneen
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.,Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Anne-Marie Baird
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Ciara Ryan
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Orla Sheils
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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10
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Alabi N, Sheka D, Siddiqui A, Wang E. Methylation-Based Signatures for Gastroesophageal Tumor Classification. Cancers (Basel) 2020; 12:E1208. [PMID: 32403416 PMCID: PMC7281220 DOI: 10.3390/cancers12051208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/04/2020] [Accepted: 05/08/2020] [Indexed: 12/12/2022] Open
Abstract
Contention exists within the field of oncology with regards to gastroesophageal junction (GEJ) tumors, as in the past, they have been classified as gastric cancer, esophageal cancer, or a combination of both. Misclassifications of GEJ tumors ultimately influence treatment options, which may be rendered ineffective if treating for the wrong cancer attributes. It has been suggested that misclassification rates were as high as 45%, which is greater than reported for junctional cancer occurrences. Here, we aimed to use the methylation profiles of GEJ tumors to improve classifications of GEJ tumors. Four cohorts of DNA methylation profiles, containing ~27,000 (27k) methylation sites per sample, were collected from the Gene Expression Omnibus and The Cancer Genome Atlas. Tumor samples were assigned into discovery (nEC = 185, nGC = 395; EC, esophageal cancer; GC gastric cancer) and validation (nEC = 179, nGC = 369) sets. The optimized Multi-Survival Screening (MSS) algorithm was used to identify methylation biomarkers capable of distinguishing GEJ tumors. Three methylation signatures were identified: They were associated with protein binding, gene expression, and cellular component organization cellular processes, and achieved precision and recall rates of 94.7% and 99.2%, 97.6% and 96.8%, and 96.8% and 97.6%, respectively, in the validation dataset. Interestingly, the methylation sites of the signatures were very close (i.e., 170-270 base pairs) to their downstream transcription start sites (TSSs), suggesting that the methylations near TSSs play much more important roles in tumorigenesis. Here we presented the first set of methylation signatures with a higher predictive power for characterizing gastroesophageal tumors. Thus, they could improve the diagnosis and treatment of gastroesophageal tumors.
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Affiliation(s)
- Nikolay Alabi
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada;
| | - Dropen Sheka
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada;
| | - Ashar Siddiqui
- Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada;
| | - Edwin Wang
- Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada;
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Tang S, Cheng J, Yao Y, Lou C, Wang L, Huang X, Zhang Y. Combination of Four Serum Exosomal MiRNAs as Novel Diagnostic Biomarkers for Early-Stage Gastric Cancer. Front Genet 2020; 11:237. [PMID: 32256526 PMCID: PMC7089961 DOI: 10.3389/fgene.2020.00237] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 02/27/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality in the United States and China, there is an urgent need to discover novel non-invasive biomarkers for the early diagnosis of GC to improve the prognosis of GC patients. Exosomal miRNAs are considered promising biomarkers for cancer diagnosis. Using next-generation sequencing (NGS), bioinformatics and further validation, we identified and evaluated exosomal miRNAs in serum as early diagnostic markers for GC. NGS revealed that the average mappable reads in the RNA libraries were about 6.5 million per patient including miRNAs (73.38%), rRNAs (17.10%), snRNAs (8.83%), snoRNAs (0.65%), and tRNAs (0.04%). A total of 66 up and 13 down-regulated exosomal miRNAs were found in the screened cohort. In the validation cohort, by comparing with healthy individuals, higher levels of serum exosomal miR-92b-3p, let-7g-5p, miR-146b-5p, and miR-9-5p were found to be significantly associated with early-stage GC (p < 0.05). Diagnostic power of the combined panels of the exosomal miRNAs or the combination of exosomal miRNAs and CEA outperformed that of single exosomal miRNA marker for establishing a diagnosis of early-stage GC. The combined diagnosis of exosomal miR-92b-3p + let-7g-5p + miR-146b-5p + miR-9-5p with CEA had the most powerful efficiency with an AUC up to 0.786. In addition, serum levels of exosomal miR-92b-3p were significantly associated with poor cohesiveness (p = 0.0021), let-7g-5p and miR-146b-5p were significantly correlated with nerve infiltration (p = 0.0234 and p = 0.0126, respectively), and miR146b-5p was statistically correlated with tumor invasion depth in early-stage GC (p = 0.0089). In conclusion, serum exosomal miR-92b-3p, -146b-5p, -9-5p, and let-7g-5p may serve as potential non-invasive biomarkers for early diagnosis of GC.
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Affiliation(s)
- Shuli Tang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Jianan Cheng
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Changjie Lou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Liang Wang
- Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
| | - Xiaoyi Huang
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
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12
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Chen Z, Li Z, Soutto M, Wang W, Piazuelo MB, Zhu S, Guo Y, Maturana MJ, Corvalan AH, Chen X, Xu Z, El-Rifai WM. Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis. Gastroenterology 2019; 156:1127-1139.e8. [PMID: 30502323 PMCID: PMC6409191 DOI: 10.1053/j.gastro.2018.11.052] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 11/20/2018] [Accepted: 11/21/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS microRNAs (miRNAs) are small noncoding RNAs that bind to the 3' untranslated regions of mRNAs to promote their degradation or block their translation. Mice with disruption of the trefoil factor 1 gene (Tff1) develop gastric neoplasms. We studied these mice to identify conserved miRNA networks involved in gastric carcinogenesis. METHODS We performed next-generation miRNA sequencing analysis of normal gastric tissues (based on histology) from patients without evidence of gastric neoplasm (n = 64) and from TFF1-knockout mice (n = 22). We validated our findings using 270 normal gastric tissues (including 61 samples from patients without evidence of neoplastic lesions) and 234 gastric tumor tissues from 3 separate cohorts of patients and from mice. We performed molecular and functional assays using cell lines (MKN28, MKN45, STKM2, and AGS cells), gastric organoids, and mice with xenograft tumors. RESULTS We identified 117 miRNAs that were significantly deregulated in mouse and human gastric tumor tissues compared with nontumor tissues. We validated changes in levels of 6 miRNAs by quantitative real-time polymerase chain reaction analyses of neoplastic gastric tissues from mice (n = 39) and 3 independent patient cohorts (n = 332 patients total). We found levels of MIR135B-5p, MIR196B-5p, and MIR92A-5p to be increased in tumor tissues, whereas levels of MIR143-3p, MIR204-5p, and MIR133-3p were decreased in tumor tissues. Levels of MIR143-3p were reduced not only in gastric cancer tissues but also in normal tissues adjacent to tumors in humans and low-grade dysplasia in mice. Transgenic expression of MIR143-3p in gastric cancer cell lines reduced their proliferation and restored their sensitivity to cisplatin. AGS cells with stable transgenic expression of MIR143-3p grew more slowly as xenograft tumors in mice than control AGS cells; tumor growth from AGS cells that expressed MIR143-3p, but not control cells, was sensitive to cisplatin. We identified and validated bromodomain containing 2 (BRD2) as a direct target of MIR143-3p; increased levels of BRD2 in gastric tumors was associated with shorter survival times for patients. CONCLUSIONS In an analysis of miRNA profiles of gastric tumors from mice and human patients, we identified a conserved signature associated with the early stages of gastric tumorigenesis. Strategies to restore MIR143-3p or inhibit BRD2 might be developed for treatment of gastric cancer.
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Affiliation(s)
- Zheng Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mohammed Soutto
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Shoumin Zhu
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Yan Guo
- Bioinformatics Shared Resources, University of New Mexico Comprehensive Cancer Center, New Mexico
| | - Maria J Maturana
- Advanced Center for Chronic Diseases, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Alejandro H Corvalan
- Advanced Center for Chronic Diseases, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Xi Chen
- Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
| | - Wael M El-Rifai
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
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13
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Wang J, Zhang H, Zhou X, Wang T, Zhang J, Zhu W, Zhu H, Cheng W. Five serum-based miRNAs were identified as potential diagnostic biomarkers in gastric cardia adenocarcinoma. Cancer Biomark 2019; 23:193-203. [PMID: 30198863 DOI: 10.3233/cbm-181258] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Circulating microRNAs (miRNAs) have been implicated as novel biomarkers for various types of cancers. The aim of the study is to identify serum miRNAs with potential in detecting gastric cardia adenocarcinoma (GCA). METHODS A three-phase study was designed with 102 GCA patients and 84 cancer-free controls. In the screening phase (3 GCA pools vs. 1 normal control (NC) pool), a total of 35 miRNAs were identified using quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel. Subsequently, these miRNAs were further assessed by qRT-PCR in the training phase (30 GCAs vs. 30 NCs) and testing phase (72 GCAs vs. 54 NCs). Finally, the expression levels of the identified miRNAs were assessed in GCA tissues and exosomes. RESULTS Five up-regulated miRNAs (miR-200a-3p, miR-296-5p, miR-132-3p, miR-485-3p and miR-22-5p) were identified in serum of the GCA patients compared with NCs. The areas under the receiver operating characteristic curve (AUCs) of the five-miRNA panel were 0.766 and 0.724 for the training and testing phases, respectively. In addition, miR-200a-3p, miR-296-5p, miR-485-3p and miR-22-5p were significantly up-regulated in GCA tissues. However, none of the miRNAs in the exosomes showed different expression between GCA patients and NCs. CONCLUSIONS We identified a five-miRNA panel in peripheral serum samples as a non-invasive biomarker in detection of GCA.
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Affiliation(s)
- Juan Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.,Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Huo Zhang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.,Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.,Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Tongshan Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - JinYing Zhang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Hong Zhu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Wenfang Cheng
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
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14
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Stojanovic J, Tognetto A, Tiziano DF, Leoncini E, Posteraro B, Pastorino R, Boccia S. MicroRNAs expression profiles as diagnostic biomarkers of gastric cancer: a systematic literature review. Biomarkers 2018; 24:110-119. [DOI: 10.1080/1354750x.2018.1539765] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Jovana Stojanovic
- Sezione di Igiene, Istituto di Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Alessia Tognetto
- Sezione di Igiene, Istituto di Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Danilo Francesco Tiziano
- Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Roma, Italia
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia
| | - Emanuele Leoncini
- Sezione di Igiene, Istituto di Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Brunella Posteraro
- Sezione di Igiene, Istituto di Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italia
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia
| | - Roberta Pastorino
- Sezione di Igiene, Istituto di Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Stefania Boccia
- Sezione di Igiene, Istituto di Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italia
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia
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15
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Optimizing miRNA-module diagnostic biomarkers of gastric carcinoma via integrated network analysis. PLoS One 2018; 13:e0198445. [PMID: 29879180 PMCID: PMC5991748 DOI: 10.1371/journal.pone.0198445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/18/2018] [Indexed: 12/17/2022] Open
Abstract
Several microRNAs (miRNAs) have been suggested as novel biomarkers for diagnosing gastric cancer (GC) at an early stage, but the single-marker strategy may ignore the co-regulatory relationships and lead to low diagnostic specificity. Thus, multi-target modular diagnostic biomarkers are urgently needed. In this study, a Zsummary and NetSVM-based method was used to identify GC-related hub miRNAs and activated modules from clinical miRNA co-expression networks. The NetSVM-based sub-network consisting of the top 20 hub miRNAs reached a high sensitivity and specificity of 0.94 and 0.82. The Zsummary algorithm identified an activated module (miR-486, miR-451, miR-185, and miR-600) which might serve as diagnostic biomarker of GC. Three members of this module were previously suggested as biomarkers of GC and its 24 target genes were significantly enriched in pathways directly related to cancer. The weighted diagnostic ROC AUC of this module was 0.838, and an optimized module unit (miR-451 and miR-185) obtained a higher value of 0.904, both of which were higher than that of individual miRNAs. These hub miRNAs and module have the potential to become robust biomarkers for early diagnosis of GC with further validations. Moreover, such modular analysis may offer valuable insights into multi-target approaches to cancer diagnosis and treatment.
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16
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miR-133b, a particular member of myomiRs, coming into playing its unique pathological role in human cancer. Oncotarget 2018; 8:50193-50208. [PMID: 28422730 PMCID: PMC5564843 DOI: 10.18632/oncotarget.16745] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 03/21/2017] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs, a family of single-stranded and non-coding RNAs, play a crucial role in regulating gene expression at posttranscriptional level, by which it can mediate various types of physiological and pathological process in normal developmental progress and human disease, including cancer. The microRNA-133b originally defined as canonical muscle-specific microRNAs considering their function to the development and health of mammalian skeletal and cardiac muscles, but new findings coming from our group and others revealed that miR-133b have frequently abnormal expression in various kinds of human cancer and its complex complicated regulatory networks affects the tumorigenicity and development of malignant tumors. Very few existing reviews on miR-133b, until now, are principally about its role in homologous cluster (miR-1, −133 and -206s), however, most of constantly emerging new researches now are focused mainly on one of them, so In this article, to highlight the unique pathological role of miR-133b playing in tumor, we conduct a review to summarize the current understanding about one of the muscle-specific microRNAs, namely miR-133b, acting in human cancer. The review focused on the following four aspects: the overview of miR-133b, the target genes of miR-133b involved in human cancer, the expression of miR-133b and regulatory mechanisms leading to abnormal expression of miR-133b.
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17
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Wang W, Du M, Li Z, Zhang L, Li Q, Xu Z, Li B, Wang L, Li F, Zhang D, Xu H, Yang L, Gong W, Qiang F, Zhang Z, Xu Z. A Genetic Variant Located in miR-146b Promoter Region Is Associated with Prognosis of Gastric Cancer. Cancer Epidemiol Biomarkers Prev 2018; 27:822-828. [PMID: 29685895 DOI: 10.1158/1055-9965.epi-17-1054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 02/13/2018] [Accepted: 04/17/2018] [Indexed: 11/16/2022] Open
Abstract
Background: SNPs in the promoter region of miRNAs have been reported to be associated with cancer prognosis. Our previous study found that miR-146b had a strong correlation with the stage classification of gastric cancer and contributed to tumor progression. The current study was aimed at investigating whether an SNP located in the promoter region of miR-146b could affect the survival rate of gastric cancer.Methods: Using bioinformatics tools, we identified one SNP (rs1536309) that is located in the miR-146b promoter. We genotyped this SNP site to assess its association with gastric cancer prognosis in 940 cases.Results: We found that the dominant model of miR-146b rs1536309 was associated with a higher survival rate of gastric cancer. The association remained significant in the subgroup analysis by age (≤60), sex (male), tumor size (≤5 cm), histologic type (diffuse), lymph node metastasis (N0), distant metastasis (M0), and TNM stage (I/II).Conclusions: Our results suggested that the miR-146b rs1536309 polymorphism may be a potential biomarker for the prognosis of gastric cancer.Impact: This is the first evidence showing that patients carrying the miR-146b-5p rs1536309 CC/CT genotypes exhibited better survival than those carrying the TT genotype, suggesting the protective effect of the C allele in the prognosis of gastric cancer. Cancer Epidemiol Biomarkers Prev; 27(7); 822-8. ©2018 AACR.
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Affiliation(s)
- Weizhi Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mulong Du
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.,Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zheng Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lei Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,The Affiliated Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Qing Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhipeng Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bowen Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Linjun Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fengyuan Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Diancai Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Yang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weida Gong
- Department of General Surgery, Yixing Tumor Hospital, Yixing, China
| | - Fulin Qiang
- Core Laboratory, Nantong Tumor Hospital, Nantong, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China. .,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zekuan Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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18
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Effects of miR-200a and FH535 combined with taxol on proliferation and invasion of gastric cancer. Pathol Res Pract 2018; 214:442-449. [DOI: 10.1016/j.prp.2017.12.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 11/18/2017] [Accepted: 12/04/2017] [Indexed: 01/03/2023]
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19
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Lario S, Brunet-Vega A, Quílez ME, Ramírez-Lázaro MJ, Lozano JJ, García-Martínez L, Pericay C, Miquel M, Junquera F, Campo R, Calvet X. Expression profile of circulating microRNAs in the Correa pathway of progression to gastric cancer. United European Gastroenterol J 2018; 6:691-701. [PMID: 30083331 DOI: 10.1177/2050640618759433] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 01/17/2018] [Indexed: 12/23/2022] Open
Abstract
Background Helicobacter pylori infection causes long-term chronic active gastritis, a risk factor for the intestinal and diffuse forms of gastric cancer. Most gastric cancers develop in a stepwise progression from chronic active gastritis to precursor lesions of gastric cancer. The early detection of gastric cancer improves survival. Studies with recent evidence have proposed circulating-microRNAs as biomarkers of cancer. Objective The purpose of this study was to explore the circulating-microRNA profile from H. pylori infection to gastric adenocarcinoma. Methods One hundred and twenty-three patients were enrolled and assigned to the discovery or the validation sets. In the discovery phase, circulating-microRNAs were measured by dye-based quantitative polymerase chain reaction and a selection of circulating-microRNAs was validated by probe-based quantitative polymerase chain reaction. A quality control protocol was used. Results One hundred and sixty-seven circulating-microRNAs were detected. Precursor lesions of gastric cancer and gastric cancer patients showed the downregulation of eight and five circulating-microRNAs, respectively. We further validated the deregulation of miR-196a-5p in precursor lesions of gastric cancer and the deregulation of miR-134-5p, miR-144-3p and miR-451a in gastric cancer. However, circulating-microRNAs exhibited moderate diagnostic performance due to the overlap of circulating-microRNA expression between non-cancer and cancer patients. miR-144-3p/miR-451a expression levels were correlated. Interestingly, these microRNAs are in 17q11.2, a site of rearrangements associated with gastric cancer. Conclusion Circulating-microRNAs are deregulated in precancerous and gastric cancer patients but efforts are needed to improve their diagnostic accuracy.
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Affiliation(s)
- Sergio Lario
- Fundació Parc Taulí, Spain.,Digestive Diseases Service, Hospital de Sabadell, Sabadell, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain
| | - Anna Brunet-Vega
- Fundació Parc Taulí, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain.,Oncology Service, Hospital de Sabadell, Sabadell, Spain
| | - María E Quílez
- Fundació Parc Taulí, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain.,Oncology Service, Hospital de Sabadell, Sabadell, Spain
| | - María J Ramírez-Lázaro
- Digestive Diseases Service, Hospital de Sabadell, Sabadell, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain
| | - Juan J Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Bioinformatics Platform, CIBEREHD, Madrid, Spain
| | - Lorena García-Martínez
- Fundació Parc Taulí, Spain.,Digestive Diseases Service, Hospital de Sabadell, Sabadell, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain
| | - Carles Pericay
- Institut Universitari Parc Taulí-UAB, Sabadell, Spain.,Oncology Service, Hospital de Sabadell, Sabadell, Spain
| | - Mireia Miquel
- Digestive Diseases Service, Hospital de Sabadell, Sabadell, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain
| | - Félix Junquera
- Digestive Diseases Service, Hospital de Sabadell, Sabadell, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain
| | - Rafael Campo
- Digestive Diseases Service, Hospital de Sabadell, Sabadell, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain
| | - Xavier Calvet
- Digestive Diseases Service, Hospital de Sabadell, Sabadell, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Institut Universitari Parc Taulí-UAB, Sabadell, Spain.,Departament de Medicina, UAB, Sabadell, Spain
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20
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Gao Y, Yi J, Zhang K, Bai F, Feng B, Wang R, Chu X, Chen L, Song H. Downregulation of MiR-31 stimulates expression of LATS2 via the hippo pathway and promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:161. [PMID: 29145896 PMCID: PMC5689139 DOI: 10.1186/s13046-017-0622-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 10/13/2017] [Indexed: 01/07/2023]
Abstract
Background Dysregulation of miRNAs is associated with cancer development by coordinately suppressing abundant target genes. Emerging evidence indicates that miR-31 plays a dual role in tumorigenicity. However, whether miR-31 plays as an oncogene in esophageal squamous cell carcinoma (ESCC) and the potential target molecules are still unclear. MiR-31 role in ESCC was investigated and an association of the target molecules with EMT was identified in the progression of ESCC. Methods Western blot assays and qRT-PCR was performed to detect the protein and mRNA levels. We investigated the role of miR-31 in the regulation of LATS2 expression in ESCC cell lines via functional assays both in vivo and in vitro. The luciferase reporter assays was conducted to confirm LATS2 is a potential target of miR-31. Immunohistochemistry was used to measure LATS2 and TAZ expression in normal and ESCC tissue. Results LATS2 is a component of the Hippo tumor-suppressive signaling pathway. Frequent loss of heterozygosity of LATS2 has been reported in esophageal cancer. We analyzed the reciprocal expression regulation of miR-31 and LATS2 and demonstrated that LATS2 expression was elevated by down-regulation of miR-31 at the post-transcriptional level in ESCC. Moreover, miR-31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3′-UTR, a key molecule in the Hippo pathway. Then, LATS2 consequently promoted the translocation of TAZ, which was examined using immunohistochemistry. Silencing of miR-31 significantly inhibited the cell proliferation, induced apoptosis and decreased the ability of migration/invasion in vitro. LATS2 impedes ESCC cell proliferation and invasion by suppressing miR-31, as well as mice xenograft model in vivo. Meanwhile, the nuclear localization of LATS2 constrained the phosphorylation of TAZ. Then, the expression level of TAZ was notably heightened with a high risk of recurrence compared to that observed in the low-risk patients, as well as, the higher expression associated with a poor survival. Conclusions Our study demonstrated that overexpression of miR-31 undertook an oncogenic role in ESCC by repressing expression of LATS2 via the Hippo Pathway and activating epithelial-mesenchymal transition. LATS2 and TAZ could be potential novel molecular markers for predicting the risk of recurrence and prognosis of ESCC. Electronic supplementary material The online version of this article (10.1186/s13046-017-0622-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yanping Gao
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China
| | - Jun Yi
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China
| | - Kai Zhang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China
| | - Fan Bai
- Department of Medical Oncology, Nanjing Clinical Medical School of the Second Military Medical University, Nanjing General Hospital of Nanjing Military Command, PLA, Nanjing, 210002, China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China.
| | - Haizhu Song
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing, Jiangsu, 210002, China.
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Wang G, Huang YX, Zhang R, Hou LD, Liu H, Chen XY, Zhu JS, Zhang J. Toosendanin suppresses oncogenic phenotypes of human gastric carcinoma SGC-7901 cells partly via miR-200a-mediated downregulation of β-catenin pathway. Int J Oncol 2017; 51:1563-1573. [DOI: 10.3892/ijo.2017.4139] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 07/28/2017] [Indexed: 11/06/2022] Open
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Zhang HC, Tang KF. Clinical value of integrated-signature miRNAs in esophageal cancer. Cancer Med 2017; 6:1893-1903. [PMID: 28707457 PMCID: PMC5548877 DOI: 10.1002/cam4.1129] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 05/13/2017] [Accepted: 05/17/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are crucial regulators of gene expression in tumorigenesis and are of great interest to researchers, but miRNA profiles are often inconsistent between studies. The aim of this study was to confirm candidate miRNA biomarkers for esophageal cancer from integrated‐miRNA expression profiling data and TCGA (The Cancer Genome Atlas) data in tissues. Here, we identify five significant miRNAs by a comprehensive analysis in esophageal cancer, and two of them (hsa‐miR‐100‐5p and hsa‐miR‐133b) show better prognoses with significant difference for both 3‐year and 5‐year survival. Additionally, they participate in esophageal cancer occurrence and development according to KEGG and Panther enrichment analyses. Therefore, these five miRNAs may serve as miRNA biomarkers in esophageal cancer. Analysis of differential expression for target genes of these miRNAs may also provide new therapeutic alternatives in esophageal cancer.
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Affiliation(s)
- Heng-Chao Zhang
- Institute of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China.,Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
| | - Kai-Fu Tang
- Institute of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China.,Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
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Jafari N, Abediankenari S. MicroRNA-34 dysregulation in gastric cancer and gastric cancer stem cell. Tumour Biol 2017; 39:1010428317701652. [PMID: 28468587 DOI: 10.1177/1010428317701652] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is a major cause of cancer mortality worldwide, with a low survival rate for patients with advanced forms of the disease. Over the recent decades, the investigation of the pathophysiological mechanisms of tumourigenesis has opened promising avenues to understand some of the complexities of cancer treatment. However, tumour regeneration and metastasis impose great difficulty for gastric cancer cure. In recent years, cancer stem cells - a small subset of tumour cells in many cancers - have become a major focus of cancer research. Cancer stem cells are capable of self-renewal and are known to be responsible for tumour initiation, metastasis, therapy resistance and cancer recurrence. Recent studies have revealed the key role of microRNAs - small noncoding RNAs regulating gene expression - in these processes. MicroRNAs play crucial roles in the regulation of a wide range of biological processes in a post-transcriptional manner, though their expression is dysregulated in most malignancies, including gastric cancer. In this article, we review the consequences of aberrant expression of microRNA-34 in cancer and cancer stem cells, with a specific focus on the miR-34 dysregulation in gastric cancer and gastric cancer stem cells. We address the critical effects of the aberrant expression of miR-34 and its target genes in maintaining cancer stem cell properties. Information collection and discussion about the advancements in gastric cancer stem cells and microRNAs can be useful for providing novel insights into patient treatment.
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Affiliation(s)
- Narjes Jafari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abediankenari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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24
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Lorenzon L, Cippitelli C, Avantifiori R, Uccini S, French D, Torrisi MR, Ranieri D, Mercantini P, Canu V, Blandino G, Cavallini M. Down-regulated miRs specifically correlate with non-cardial gastric cancers and Lauren's classification system. J Surg Oncol 2017; 116:184-194. [PMID: 28475823 DOI: 10.1002/jso.24648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 03/22/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES Gastric cancers are usually characterized using Lauren's classification into intestinal and diffuse types. We previously documented the down-modulation of miR31, miR148a, miR204, and miR375 in gastric cancers. We aimed this manuscript to investigate these miRs with the end-points of diagnosis, Lauren's classification and prognosis. METHODS A total of 117 resected non-cardial adenocarcinomas were evaluated for miRs' expressions. The performance of miRs' expressions for cancer diagnosis was tested using ROC curves. Logistic regression was conducted with the end-point of Lauren's classification. Kaplan-Meier and Cox analyses were performed for OS, DFS, and DSS. miRs' targets were reviewed using PRISMA method and BCL-2 was further investigated in cell lines. RESULTS ROC curves documented that miRs' down-modulation was significant in differentiating cancer versus normal tissues. Diffuse type cancers were associated with female sex, young age, and miR375 higher expression. We confirmed BCL-2 as a miR204 target. However, survival analyses confirmed the pathologic criteria (advanced stages, LNR, and low LNH) as the significant variables correlated to worse prognosis. CONCLUSIONS The down-modulation of miR31, miR148a, miR204, and miR375 is significantly associated with non-cardial gastric cancers and miR375 is specifically linked to Lauren's classification. Nevertheless, standard pathological features display as the independent variables associated with worse prognosis.
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Affiliation(s)
- Laura Lorenzon
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Claudia Cippitelli
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Riccardo Avantifiori
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Stefania Uccini
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Deborah French
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Maria Rosaria Torrisi
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Danilo Ranieri
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Paolo Mercantini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Valeria Canu
- Italian National Cancer Institute Regina Elena, Translational Oncogenomic Unit, Rome, Italy
| | - Giovanni Blandino
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Marco Cavallini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
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Guo Y, Qi Y, Guo A, Du C, Zhang R, Chu X. miR-564 is downregulated in gastric carcinoma and targets E2F3. Oncol Lett 2017; 13:4155-4160. [PMID: 28588702 DOI: 10.3892/ol.2017.5964] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 02/27/2017] [Indexed: 12/17/2022] Open
Abstract
Numerous aberrantly expressed microRNAs (miRNAs/miRs) have been identified in gastric cancer (GC); however, only a fraction of these have been functionally investigated and novel deregulated miRNAs in GC remain to be explored. Through examining two public miRNA expression profile datasets, the present study identified aberrantly expressed miRNAs in GC. One of these miRNA, miR-564, was identified to be downregulated in GC, which was validated in tissue samples from patients with GC by reverse transcription-quantitative polymerase chain reaction analysis. Targets of miR-564 were then predicted bioinformatically, including transcription factor E2F3 (E2F3), which was identified to be functionally enriched in several cancer signaling pathways. Furthermore, overexpression of miR-564 decreased the activity of a luciferase reporter carrying the 3'-untranslated region of E2F3, in addition to the mRNA and protein level of E2F3, indicating that miR-564 directly targets E2F3. These data suggest that by targeting E2F3, miR-564 may act as a tumor suppressor gene in gastric carcinogenesis.
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Affiliation(s)
- Yong Guo
- Department of Pathology, No. 161 Hospital of the People's Liberation Army, Wuhan, Hubei 430010, P.R. China
| | - Yong Qi
- Outpatient Department, The People's Liberation Army Naval University of Engineering, Wuhan, Hubei 430033, P.R. China
| | - Aitao Guo
- Department of Pathology, The General Hospital of the People's Liberation Army, Beijing 100853, P.R. China
| | - Chengxiong Du
- Department of General Surgery, No. 161 Hospital of the People's Liberation Army, Wuhan, Hubei 430010, P.R. China
| | - Rong Zhang
- Clinical Laboratory, Liuhuaqiao Hospital, Guangzhou, Guangdong 510010, P.R. China
| | - Xiaoyong Chu
- Medical Clinic of Military Economy Academy of the People's Liberation Army, Wuhan, Hubei 430035, P.R. China
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26
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Gao H, Wang H, Yang W. Identification of key genes and construction of microRNA–mRNA regulatory networks in multiple myeloma by integrated multiple GEO datasets using bioinformatics analysis. Int J Hematol 2017; 106:99-107. [DOI: 10.1007/s12185-017-2216-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 03/09/2017] [Accepted: 03/10/2017] [Indexed: 12/18/2022]
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Chen Z, Liu S, Xia Y, Wu K. MiR-31 Regulates Rho-Associated Kinase-Myosin Light Chain (ROCK-MLC) Pathway and Inhibits Gastric Cancer Invasion: Roles of RhoA. Med Sci Monit 2016; 22:4679-4691. [PMID: 27904131 PMCID: PMC5136369 DOI: 10.12659/msm.898399] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background This study evaluated how the expression of miR-31 can be used to detect gastric cancer (GC) to help illuminate the role of miR-31 and RhoA in GC cells. Material/Methods We carried out our experiments using tissue specimens from 70 GC patients. The relative expression of miR-31 and RhoA mRNA in tissues and cells was detected by RT-PCR. The expression level of RhoA protein was detected by immunohistochemistry. GC cell line BGC-823 was transfected with six groups of vectors: blank group, NC (negative control) group, miR-31 mimics group, miR-31 mimics + RhoA group, miR-31 mimics + ROCK group, and miR-31 mimics + MLCK agonist group. AGS cells were also transfected with six groups of vectors: blank group, NC group, miR-31 inhibitor group, miR-31 inhibitor + RhoA siRNA group, miR-31 inhibitor + ROCK siRNA group, and miR-31 inhibitor + MLCK inhibitor group. Transwell assay was performed to detect the invasion and migration of cells. The protein expression in different transfected groups was detected using Western blotting. Results GC tissues exhibited significantly lower levels of miR-31 expression compared to pericarcinous tissues (p<0.01). Moreover, a significantly higher expression of RhoA in GC tissues was observed (p<0.05). MiR-31 inhibited RhoA expression by binding to 3′UTR of mRNA, whereas miR-31 mimics significantly decreased the number of invaded and migrated cells (p<0.05). The activation of RhoA, ROCK, and phosphorylation of MLC remarkably exacerbate the invasion and migration ability of GC cells (p<0.05). Conclusions We found miR-31 could downregulate the ROCK/MLC pathway by inhibiting the expression of RhoA in order to suppress the invasion and migration of GC cells.
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Affiliation(s)
- Zhuo Chen
- Xuzhou Medical College, Xuzhou, Jiangsu, China (mainland)
| | - Shengnan Liu
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China (mainland)
| | - Yuan Xia
- Xuzhou Medical College, Xuzhou, Jiangsu, China (mainland)
| | - Kejian Wu
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China (mainland)
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Chou CK, Chi SY, Huang CH, Chou FF, Huang CC, Liu RT, Kang HY. IRAK1, a Target of miR-146b, Reduces Cell Aggressiveness of Human Papillary Thyroid Carcinoma. J Clin Endocrinol Metab 2016; 101:4357-4366. [PMID: 27533309 DOI: 10.1210/jc.2016-2276] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
CONTEXT MicroRNA (miR)-146b is overexpressed in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal invasion, advanced tumor stage, and poor prognosis. However, the underlying mechanism of miR-146b in relation to its oncogenic behavior in PTC and its putative targets remain unknown. OBJECTIVE The purpose was to investigate IL-1 receptor-associated kinase 1 (IRAK1) as the potential miR-146b target gene and its involvement in PTC. DESIGN We used genome-wide microarray, computational analysis, and 3' UTR reporter gene assays to identify IRAK1 as a miR-146b target gene. In vitro gain/loss-of-function experiments were further performed to determine the effects of IRAK1 on proliferation, colony formation, and wound-healing in PTC cancer cell lines. Expression levels of miR-146b and IRAK1 of 50 cases of PTC and its adjacent normal thyroid specimens were assessed via qRT-PCR. RESULTS Microarray expression profile revealed that the mRNA level of IRAK1 gene was down-regulated by miR-146b. The 3' UTR of IRAK1 mRNA was found to be a molecular target of miR-146b posttranscriptional repression in BCPAP cells by reporter gene assays. MiR-146b promoted the migration and proliferation of PTC cells by down-regulating IRAK1 expression, whereas restoration of IRAK1 expression reversed this effect. In addition, the expression of IRAK1 mRNA was significantly lower in PTC clinical tissue samples than normal adjacent thyroid specimens and showed a strong inverse correlation with the expression of miR-146b in PTC specimens. CONCLUSION Our results demonstrated that IRAK1 is a direct target of miR-146b and has functional roles to inhibit various aggressive PTC cell activities. In conjunction with current therapeutic regimens, targeting the miR-146b-IRAK1 axis may provide a potential approach for PTC management.
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Affiliation(s)
- Chen-Kai Chou
- Division of Endocrinology and Metabolism, Department of Internal Medicine (C.-K.C., C.-H.H., R.-T.L.), Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan, Departments of Surgery (S.-Y.C., F.-F.C.), Pathology (C.-C.H.), and Obstetrics and Gynecology (H.-Y.K.), Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaoshiung City 833, Taiwan
| | - Shun-Yu Chi
- Division of Endocrinology and Metabolism, Department of Internal Medicine (C.-K.C., C.-H.H., R.-T.L.), Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan, Departments of Surgery (S.-Y.C., F.-F.C.), Pathology (C.-C.H.), and Obstetrics and Gynecology (H.-Y.K.), Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaoshiung City 833, Taiwan
| | - Cai-Hua Huang
- Division of Endocrinology and Metabolism, Department of Internal Medicine (C.-K.C., C.-H.H., R.-T.L.), Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan, Departments of Surgery (S.-Y.C., F.-F.C.), Pathology (C.-C.H.), and Obstetrics and Gynecology (H.-Y.K.), Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaoshiung City 833, Taiwan
| | - Fong-Fu Chou
- Division of Endocrinology and Metabolism, Department of Internal Medicine (C.-K.C., C.-H.H., R.-T.L.), Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan, Departments of Surgery (S.-Y.C., F.-F.C.), Pathology (C.-C.H.), and Obstetrics and Gynecology (H.-Y.K.), Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaoshiung City 833, Taiwan
| | - Chao-Cheng Huang
- Division of Endocrinology and Metabolism, Department of Internal Medicine (C.-K.C., C.-H.H., R.-T.L.), Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan, Departments of Surgery (S.-Y.C., F.-F.C.), Pathology (C.-C.H.), and Obstetrics and Gynecology (H.-Y.K.), Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaoshiung City 833, Taiwan
| | - Rue-Tsuan Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine (C.-K.C., C.-H.H., R.-T.L.), Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan, Departments of Surgery (S.-Y.C., F.-F.C.), Pathology (C.-C.H.), and Obstetrics and Gynecology (H.-Y.K.), Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaoshiung City 833, Taiwan
| | - Hong-Yo Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine (C.-K.C., C.-H.H., R.-T.L.), Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan, Departments of Surgery (S.-Y.C., F.-F.C.), Pathology (C.-C.H.), and Obstetrics and Gynecology (H.-Y.K.), Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaoshiung City 833, Taiwan
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Xie M, Dart DA, Owen S, Wen X, Ji J, Jiang W. Insights into roles of the miR-1, -133 and -206 family in gastric cancer (Review). Oncol Rep 2016; 36:1191-8. [PMID: 27349337 DOI: 10.3892/or.2016.4908] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 01/27/2016] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer (GC) remains the third most common cause of cancer deaths worldwide and carries a high rate of metastatic risk contributing to the main cause of treatment failure. An accumulation of data has resulted in a better understanding of the molecular network of GC, however, gaps still exist between the unique bio-resources and clinical application. MicroRNAs are an important part of non-coding RNAs and behave as major regulators of tumour biology, alongside their well-known roles as intrinsic factors of gene expression in cellular processes, via their post-transcriptional regulation of components of signalling pathways in a coordinated manner. Deregulation of the miR-1, -133 and -206 family plays a key role in tumorigenesis, progression, invasion and metastasis. This review aims to provide a summary of recent findings on the miR-1, -133 and -206 family in GC and how this knowledge might be exploited for the development of future miRNA-based therapies for the treatment of GC.
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Affiliation(s)
- Meng Xie
- Department of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Haidian, Beijing 100142, P.R. China
| | - Dafydd Alwyn Dart
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
| | - Sioned Owen
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
| | - Xianzi Wen
- Department of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Haidian, Beijing 100142, P.R. China
| | - Jiafu Ji
- Department of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Haidian, Beijing 100142, P.R. China
| | - Wenguo Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
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Li Y, Deng X, Zeng X, Peng X. The Role of Mir-148a in Cancer. J Cancer 2016; 7:1233-41. [PMID: 27390598 PMCID: PMC4934031 DOI: 10.7150/jca.14616] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 05/07/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are highly conserved noncoding RNAs of about 19-25 nucleotides. Through specifically pairing with complementary sites in 3' untranslated regions (UTRs) of target mRNAs, they mediate post-transcriptional silencing. MicroRNAs have been implicated in many physiological processes including proliferation, differentiation, development, apoptosis, and metabolism. In recent years many studies have revealed that the aberrant expression of miRNA is closely related to oncogenesis and is now an intense field of study. Mir-148a is aberrantly expressed in various cancers and has been identified as an oncogenic or tumor suppressor with crucial roles in the molecular mechanisms of oncogenesis. In this review, we have summarized the role of mir-148a in the oncogenic pathways of gastric, liver, breast and urogenital cancers, and in neurogliocytoma oncogenesis. Studying the functional role of mir-148a is crucial in discovering novel tumor molecular markers and identifying potential therapeutic targets.
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Affiliation(s)
- Yue Li
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
| | - Xiyun Deng
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
| | - Xiaomin Zeng
- 2. Department of Statistics and Epidemiology, Public Health School, Central South University, Changsha 410078, Hunan, China
| | - Xiaoning Peng
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
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ZHANG WEI, LI YAN. miR-148a downregulates the expression of transforming growth factor-β2 and SMAD2 in gastric cancer. Int J Oncol 2016; 48:1877-85. [PMID: 26983401 PMCID: PMC4809655 DOI: 10.3892/ijo.2016.3437] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 02/18/2016] [Indexed: 12/19/2022] Open
Abstract
The effects of miR-148a in regulating the expression of TGFβ2 and SMAD2 in MNNG-initiated gastric cancer rats and the mechanism of action in GC cells were determined. Effects of miR-148a on the proliferation, migration, and invasion of GC cell lines were demonstrated. We used Wistar rats, Balb/c nude mice, and GC cell lines. Rats were treated with MNNG to establish a GC rat model. Levels of miR-148a, TGFα, TGFβ2, SMAD2, SMAD3, and SMAD4 were tested in gastric tissues from different groups. In GC cell lines, we constructed and transfected a primary miR-148a plasmid to determine the expression patterns of TGFβ2, SMAD2, and SMAD4. A luciferase activity assay was used to monitor the effects of miR-148a on the TGFβ2- and SMAD2-3'UTRs. We identified nude mouse models bearing BGC-823-miR-148a or BGC-823-vector cells. Tumor volumes were detected, and TGFβ2, SMAD2 expression levels were determined in tumor tissues. The in vivo study demonstrated an increase in the mRNA and protein levels of TGFβ2, SMAD2, and SMAD4 in the MNNG-treated group compared with the control group. However, there were no differences in the mRNA and protein levels in either TGFα or SMAD3. The in vitro study demonstrated that overexpression of miR-148a reduced TGFβ2 and SMAD2 significantly in GC cells. The results of the luciferase activity assay showed that miR-148a could bind to the 3'UTRs of TGFβ2 and SMAD2 and inhibited their activity. Overexpression of miR-148a inhibited proliferation, migration, and invasion significantly in GC cell lines. In vivo, tumor volume of BGC-823-miR-148a was smaller than that of BGC-823-vector. Overall, miR-148a inhibited the proliferation, migration, invasion, and expression of TGFβ2 and SMAD2 in GC cells. It was concluded that miR-148a might play an important role in gastric cancer, and is a potential candidate for GC treatment.
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Affiliation(s)
- WEI ZHANG
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - YAN LI
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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Mallick R, Patnaik SK, Wani S, Bansal A. A Systematic Review of Esophageal MicroRNA Markers for Diagnosis and Monitoring of Barrett's Esophagus. Dig Dis Sci 2016; 61:1039-50. [PMID: 26572780 DOI: 10.1007/s10620-015-3959-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 10/30/2015] [Indexed: 01/07/2023]
Abstract
BACKGROUND Esophageal epithelial microRNAs may be used to diagnose Barrett's esophagus (BE) and possibly monitor its progression to esophageal adenocarcinoma (EAC). AIMS We reviewed studies that have investigated this to identify microRNAs with high biomarker potential for screening and disease monitoring in BE. METHODS PubMed and EMBASE databases were searched for studies that quantified esophageal epithelial microRNAs. Publications reporting microRNA comparisons of normal, non-dysplastic BE, BE with high-grade dysplasia (HGD), and EAC tissues using both unbiased discovery and independent validation phases were reviewed. RESULTS Eleven studies on microRNA expression differences between normal epithelium and non-dysplastic BE (seven studies), HGD (4) or EAC (7), or between non-dysplastic BE and HGD (3) or EAC (6) were identified, and the findings of their validation phase were analyzed. Increased miR-192, -194, and -215, and reduced miR-203 and -205 expression in BE compared to normal was noticed by all 4-6 of the seven studies that examined these microRNAs. In heterogeneity tests of the reported fold-change values, the I (2) statistics were 7.9-17.1 % (all P < 0.05). Elevated miR-192, -194, and -215, and diminished miR-203 and -205 levels were also noted for comparisons of HGD or EAC against normal. In contrast, a consistent microRNA expression difference was absent for the comparisons of HGD or EAC against BE. CONCLUSIONS MicroRNAs miR-192, -194, -203, -205, and -215 are promising tissue biomarkers for diagnosing BE. Cross-sectional data suggest that microRNAs may have a limited role in separating BE from HGD/EAC epithelia but need further testing in longitudinal follow-up studies.
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Affiliation(s)
- Reema Mallick
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Santosh K Patnaik
- Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Sachin Wani
- Department of Gastroenterology, University of Colorado, Aurora, CO, USA
| | - Ajay Bansal
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA.
- Department of Gastroenterology, University of Kansas School of Medicine, Kansas City, KS, USA.
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Kestens C, Siersema PD, van Baal JWPM. Current understanding of the functional roles of aberrantly expressed microRNAs in esophageal cancer. World J Gastroenterol 2016; 22:1-7. [PMID: 26755856 PMCID: PMC4698477 DOI: 10.3748/wjg.v22.i1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 07/29/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
The incidence of esophageal cancer is rising, mostly because the increasing incidence of esophageal adenocarcinoma in Western countries. Despite improvements in diagnosis and treatment, the overall 5-year survival rates remain low. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of target genes. Recently, disease specific miRNAs have been identified, which act as tumor suppressors or oncogenes. In this review, we will summarize the current knowledge about the function of aberrantly expressed miRNAs in esophageal cancer. We selected 5 miRNAs (miRNA-21, -143, -145, -196a and let-7) based on the available literature, and described their potential role in regulating pathways that are deregulated in esophageal cancer. Finally we will highlight the current achievements of using and targeting miRNAs. Because these miRNAs likely have important regulatory roles in cancer development, they open a therapeutic window for new treatment modalities.
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Yang Q, Zhang RW, Sui PC, He HT, Ding L. Dysregulation of non-coding RNAs in gastric cancer. World J Gastroenterol 2015; 21:10956-10981. [PMID: 26494954 PMCID: PMC4607897 DOI: 10.3748/wjg.v21.i39.10956] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/28/2015] [Accepted: 09/15/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC.
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Wu X, Tan X, Fu SW. May Circulating microRNAs be Gastric Cancer Diagnostic Biomarkers? J Cancer 2015; 6:1206-13. [PMID: 26535061 PMCID: PMC4622850 DOI: 10.7150/jca.12535] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 08/25/2015] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths. More than 80% of the diagnosis was made at the advanced stages of the disease, highlighting the urgent demand for novel biomarkers that can be used for early detection. Recently, a number of studies suggest that circulating microRNAs (miRNAs) could be potential biomarkers for GC diagnosis. Cancer-related circulating miRNAs, as well as tissue miRNAs, provide a hopeful prospect of detecting GC at early stages, and the prospective participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic tests for GC. As miRNAs in blood are stable, their potential value as diagnostic biomarkers in GC has been explored over the past few years. However, due to the inconsistent or sometimes conflicting reports, large-scale prospective studies are needed to validate their potential applicability in GC diagnosis. This review summarizes the current development about potential miRNA biomarkers for GC diagnosis and the obstacles hindering their clinical usage.
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Affiliation(s)
- Xiaoling Wu
- 1. Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, China
- 2. Department of Medicine (Division of Genomic Medicine), The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Xiaohui Tan
- 2. Department of Medicine (Division of Genomic Medicine), The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Sidney W. Fu
- 2. Department of Medicine (Division of Genomic Medicine), The George Washington University School of Medicine and Health Sciences, Washington, DC
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Mitchelson KR, Qin WY. Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease. World J Biol Chem 2015; 6:162-208. [PMID: 26322174 PMCID: PMC4549760 DOI: 10.4331/wjbc.v6.i3.162] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 03/13/2015] [Accepted: 05/28/2015] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/tissue regeneration/tissue inflammation responses, and cancer development.
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He Y, Lin J, Ding Y, Liu G, Luo Y, Huang M, Xu C, Kim TK, Etheridge A, Lin M, Kong D, Wang K. A systematic study on dysregulated microRNAs in cervical cancer development. Int J Cancer 2015; 138:1312-27. [DOI: 10.1002/ijc.29618] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 05/19/2015] [Indexed: 01/15/2023]
Affiliation(s)
- Yuqing He
- Institute of Medical Systems Biology, Guangdong Medical University; Dongguan Guangdong China
| | - Juanjuan Lin
- Department of Epidemiology and Medical Statistics; Guangdong Medical University; Dongguan Guangdong China
| | - Yuanlin Ding
- Department of Epidemiology and Medical Statistics; Guangdong Medical University; Dongguan Guangdong China
| | - Guodong Liu
- Department of Chemistry and Molecular Biology; North Dakota State University; Fargo ND
| | - Yanhong Luo
- Department of Epidemiology and Medical Statistics; Guangdong Medical University; Dongguan Guangdong China
| | - Mingyuan Huang
- Department of Health Inspection; Guangdong Medical University; Dongguan Guangdong China
| | - Chengkai Xu
- Department of Epidemiology and Medical Statistics; Guangdong Medical University; Dongguan Guangdong China
| | | | | | - Mi Lin
- Department of Epidemiology and Medical Statistics; Guangdong Medical University; Dongguan Guangdong China
| | - Danli Kong
- Department of Epidemiology and Medical Statistics; Guangdong Medical University; Dongguan Guangdong China
| | - Kai Wang
- Institute for Systems Biology; Seattle WA
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Amin M, Lam AKY. Current perspectives of mi-RNA in oesophageal adenocarcinoma: Roles in predicting carcinogenesis, progression and values in clinical management. Exp Mol Pathol 2015; 98:411-418. [PMID: 25746664 DOI: 10.1016/j.yexmp.2015.03.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/02/2015] [Indexed: 12/18/2022]
Abstract
Aberrant expressions of micro-ribonucleic acids (miRs) are closely associated with the pathogenesis in many human cancers. In oesophageal adenocarcinomas, altered expressions of different sets of miRs are noted to be associated with the development of adenocarcinoma from Barrett's oesophagus. In different studies, miRs such as miR-192, miR-196 and miR-21 were frequently noted to up-regulated whereas miR-203, miR-205 and miR-let-7 were commonly down-regulated during the development of Barrett's oesophagus to oesophageal adenocarcinoma. In addition, changes in the expression of miRs are associated with the predication of metastasis, prognosis and response to chemo-radiation in the patients with oesophageal adenocarcinoma. Experimental studies in manipulating the miRs in cancer cell lines could provide hints for therapeutics for the cancer. However, the number of studies reported on these aspects of oesophageal adenocarcinoma was limited and the miRs noted needed to be confirmed by additional studies. Overall, the mechanisms of involvements of miRs in pathogenesis and progression of oesophageal adenocarcinoma are complex. Although miRs have the potential to act as prognostic and clinical biomarkers for cancer therapy in oesophageal adenocarcinoma, more works in larger populations and clinical trials are needed to validate these clinical implications.
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Affiliation(s)
- Moein Amin
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland Institute, Griffith University, Gold Coast, Queensland, Australia
| | - Alfred King-yin Lam
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland Institute, Griffith University, Gold Coast, Queensland, Australia; Pathology Queensland, Gold Coast University Hospital, Gold Coast, Queensland, Australia.
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Zaidi AH, Saldin LT, Kelly LA, Bergal L, Londono R, Kosovec JE, Komatsu Y, Kasi PM, Shetty AA, Keane TJ, Thakkar SJ, Huleihel L, Landreneau RJ, Badylak SF, Jobe BA. MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. PLoS One 2015; 10:e0122375. [PMID: 25826212 PMCID: PMC4380408 DOI: 10.1371/journal.pone.0122375] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/15/2015] [Indexed: 02/06/2023] Open
Abstract
Objective To establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC). Background The incidence of esophageal adenocarcinoma (EAC) has dramatically increased and esophageal cancer is now the sixth leading cause of cancer deaths worldwide. Mortality rates remain high among patients with advanced stage disease and esophagectomy is associated with high complication rates. Hence, early identification of potentially metastatic disease would better guide treatment strategies. Methods The modified Levrat’s surgery was performed to induce EAC in Sprague-Dawley rats. Primary EAC and distant metastatic sites were confirmed via histology and immunofluorescence. miRNA profiling was performed on primary tumors with or without metastasis. A unique subset of miRNAs expressed in primary tumors and metastases was identified with Ingenuity Pathway Analysis (IPA) along with upstream and downstream targets. miRNA-linked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5) and metastasis negative (n=28) primary tumors. Results The epithelial origin of distant metastasis was established by IF using villin (VIL1) and mucin 5AC (MUC5AC) antibodies. miRNome analysis identified four down-regulated miRNAs in metastasis positive primary tumors compared to metastasis negative tumors: miR-92a-3p (p=0.0001), miR-141-3p (p=0.0022), miR-451-1a (p=0.0181) and miR133a-3p (p=0.0304). Six target genes identified in the top scoring networks by IPA were validated as significantly, differentially expressed in metastasis positive primary tumors: Ago2, Akt1, Kras, Bcl2L11, CDKN1B and Zeb2. Conclusion In vivo metastasis was confirmed in the modified Levrat’s model. Analysis of the primary tumor identified a distinctive miRNA signature for primary tumors that metastasized.
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Affiliation(s)
- Ali H. Zaidi
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Lindsey T. Saldin
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Lori A. Kelly
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Linda Bergal
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Ricardo Londono
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Juliann E. Kosovec
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Yoshihiro Komatsu
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Pashtoon M. Kasi
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Amit A. Shetty
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Timothy J. Keane
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Shyam J. Thakkar
- Division of Gastroenterology, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Luai Huleihel
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Rodney J. Landreneau
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Stephen F. Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Blair A. Jobe
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
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Wach S, Al-Janabi O, Weigelt K, Fischer K, Greither T, Marcou M, Theil G, Nolte E, Holzhausen HJ, Stöhr R, Huppert V, Hartmann A, Fornara P, Wullich B, Taubert H. The combined serum levels of miR-375 and urokinase plasminogen activator receptor are suggested as diagnostic and prognostic biomarkers in prostate cancer. Int J Cancer 2015; 137:1406-16. [PMID: 25754273 DOI: 10.1002/ijc.29505] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 02/12/2015] [Indexed: 12/17/2022]
Abstract
This study aimed to assess the applicability of miR-375 in combination with the soluble urokinase plasminogen activator receptor (suPAR) protein as a diagnostic and/or prognostic biomarker for prostate cancer (PCa) patients. miR-375 levels by qRT-PCR and suPAR levels by ELISA were evaluated in serum samples from 146 PCa patients, 35 benign prostate hyperplasia (BPH) patients and 18 healthy controls. Antigen levels of suPAR differed between healthy controls and PCa or BPH patients, whereas miR-375 levels differed between PCa and BPH patients or healthy controls (p < 0.001). Additionally, suPAR levels differed between the Gleason sum groups GS = 7 versus GS > 7, with higher levels in the latter group (p = 0.011), and miR-375 levels were higher in the tumor stage group T3-T4 compared with the T1-T2 group (p = 0.039). A high concentration of suPAR was associated with a poor disease-specific survival (DSS; p = 0.039). The combination of suPAR and miR-375 levels identified a patient group possessing high levels for both parameters. This was associated with a poorer 10-year overall survival (OS) and DSS, with a 6.38-fold increased risk of death and a 7.68-fold increased risk of tumor-related death (p = 0.00026 and p = 0.014; univariate Cox's regression analysis). In a multivariate Cox's regression analysis PCa patients with high levels of suPAR and miR-375 showed a 5.72-fold increased risk of death in OS (p = 0.006). In summary, the differences between the PCa/BPH/healthy control cohorts for either suPAR and miR-375 levels in conjunction with the association of combined high suPAR/miR-375 levels with a poor prognosis suggest a diagnostic and prognostic impact for PCa patients.
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Affiliation(s)
- Sven Wach
- Department of Urology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Omar Al-Janabi
- Department of Urology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Katrin Weigelt
- Department of Urology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Kersten Fischer
- Department of Urology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Thomas Greither
- Center for Reproductive Medicine and Andrology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Marios Marcou
- Department of Urology, Martin Luther University Halle-Wittenberg, Halle, Germany.,Center for Reproductive Medicine and Andrology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Gerit Theil
- Department of Urology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Elke Nolte
- Department of Urology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | - Robert Stöhr
- Institute of Pathology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Verena Huppert
- Department of Urology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Paolo Fornara
- Department of Urology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Bernd Wullich
- Department of Urology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Helge Taubert
- Department of Urology, Universitätsklinikum Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
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Miura JT, Xiu J, Thomas J, George B, Carron BR, Tsai S, Johnston FM, Turaga KK, Gamblin TC. Tumor profiling of gastric and esophageal carcinoma reveal different treatment options. Cancer Biol Ther 2015; 16:764-9. [PMID: 25778705 PMCID: PMC4622996 DOI: 10.1080/15384047.2015.1026479] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 02/10/2015] [Accepted: 03/01/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND NCCN states that chemotherapies for advanced esophageal and gastric cancers may be used interchangeably. Biomarkers from gastroesophageal cancer patients were interrogated to identify actionable alterations with therapeutic implications. METHODS 666 gastric and 640 esophageal cancer cases referred to Caris Life Sciences between 2009 thru 2013 were evaluated. Specific testing was performed, which included a combination of sequencing (Sanger, NGS) and protein expression (IHC). RESULTS In the complete cohort (n = 1306), 30 of 45 genes tested harbored mutations; highest rates were seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%), and PIK3CA (5.1%). IHC of TOP2A was high in 76% of cases, TOPO1 in 51% and SPARC in 25%; low IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating potential benefit from epirubicin, irinotecan, nab-paclitaxel, platinum-based agents, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2+ cohort (n = 88), 50% of patients demonstrated possible benefit from a combination of trastuzumab with 5FU/capecitabine based on concurrent low TS, 53% with irinotecan (high TOPO1), 63% with cisplatin (low ERCC1) and 55% with gemcitabine (low RRM1). Subgroup analysis by tumor origin demonstrated significant differences in actionable biomarker profiles with HER2 (13% vs. 4.6%), SPARC (34% vs. 15%), TOP2A (86% vs. 67%), and TOPO1 (55% vs. 46%) in esophageal and gastric adenocarcinoma cases respectively (P < 0.05). CONCLUSION A comprehensive multiplatform biomarker analysis suggested significant biomarker differences between gastric and esophageal cancers. These results can assist in the development of future clinical trials.
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Affiliation(s)
- John T Miura
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
| | | | - James Thomas
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
| | - Ben George
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
| | - Benjamin R Carron
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
| | - Susan Tsai
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
| | - Fabian M Johnston
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
| | - Kiran K Turaga
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
| | - T Clark Gamblin
- Division of Surgical Oncology; Medical College of Wisconsin; Milwaukee, WI USA
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Koumangoye RB, Andl T, Taubenslag KJ, Zilberman ST, Taylor CJ, Loomans HA, Andl CD. SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells. Mol Cancer 2015; 14:24. [PMID: 25644061 PMCID: PMC4374188 DOI: 10.1186/s12943-014-0284-y] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 12/26/2014] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Tumor metastasis is responsible for 90% of cancer-related deaths. Recently, a strong link between microRNA dysregulation and human cancers has been established. However, the molecular mechanisms through which microRNAs regulate metastasis and cancer progression remain unclear. METHODS We analyzed the reciprocal expression regulation of miR-31 and SOX4 in esophageal squamous and adenocarcinoma cell lines by qRT-PCR and Western blotting using overexpression and shRNA knock-down approaches. Furthermore, methylation studies were used to assess epigenetic regulation of expression. Functionally, we determined the cellular consequences using migration and invasion assays, as well as proliferation assays. Immunoprecipitation and ChIP were used to identify complex formation of SOX4 and co-repressor components. RESULTS Here, we report that SOX4 promotes esophageal tumor cell proliferation and invasion by silencing miR-31 via activation and stabilization of a co-repressor complex with EZH2 and HDAC3. We demonstrate that miR-31 is significantly decreased in invasive esophageal cancer cells, while upregulation of miR-31 inhibits growth, migration and invasion of esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) cell lines. miR-31, in turn, targets SOX4 for degradation by directly binding to its 3'-UTR. Additionally, miR-31 regulates EZH2 and HDAC3 indirectly. SOX4, EZH2 and HDAC3 levels inversely correlate with miR-31 expression in ESCC cell lines. Ectopic expression of miR-31 in ESCC and EAC cell lines leads to down regulation of SOX4, EZH2 and HDAC3. Conversely, pharmacologic and genetic inhibition of SOX4 and EZH2 restore miR-31 expression. We show that SOX4, EZH2 and HDAC3 form a co-repressor complex that binds to the miR-31 promoter, repressing miR-31 through an epigenetic mark by H3K27me3 and by histone acetylation. Clinically, when compared to normal adjacent tissues, esophageal tumor samples show upregulation of SOX4, EZH2, and HDAC3, and EZH2 expression is significantly increased in metastatic ESCC tissues. CONCLUSIONS Thus, we identified a novel molecular mechanism by which the SOX4, EZH2 and miR-31 circuit promotes tumor progression and potential therapeutic targets for invasive esophageal carcinomas.
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Affiliation(s)
- Rainelli B Koumangoye
- Department of Surgery, 2213 Garland Ave. 10445 MRB IV, Nashville, TN, 37232-6840, USA.
| | - Thomas Andl
- Division of Dermatology, Department of Medicine, 21st Ave South, A-2310 Medical Center North, Nashville, TN, 37232-6840, USA.
| | - Kenneth J Taubenslag
- Department of Surgery, 2213 Garland Ave. 10445 MRB IV, Nashville, TN, 37232-6840, USA.
| | - Steven T Zilberman
- Department of Surgery, 2213 Garland Ave. 10445 MRB IV, Nashville, TN, 37232-6840, USA.
| | - Chase J Taylor
- Department of Surgery, 2213 Garland Ave. 10445 MRB IV, Nashville, TN, 37232-6840, USA.
| | - Holli A Loomans
- Department of Cancer Biology, 2213 Garland Ave. 10445 MRB IV, Nashville, TN, 37232-6840, USA.
| | - Claudia D Andl
- Department of Surgery, 2213 Garland Ave. 10445 MRB IV, Nashville, TN, 37232-6840, USA. .,Department of Cancer Biology, 2213 Garland Ave. 10445 MRB IV, Nashville, TN, 37232-6840, USA. .,Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232-6840, USA. .,Vanderbilt Digestive Disease Center, Vanderbilt University Medical Center, Nashville, TN, 37232-6840, USA.
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Abstract
The protein encoded by the TP53 gene is one of the most important suppressors of tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation of their target messenger RNAs. In recent years, several miRNAs have been identified as mediators and regulators of p53’s tumor suppressing functions. p53 induces expression and/or maturation of several miRNAs, which leads to the repression of critical effector proteins. Furthermore, certain miRNAs regulate the expression and activity of p53 through direct repression of p53 or its regulators. Experimental findings indicate that miRNAs are important components of the p53 network. In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression. Therefore, p53-regulated miRNAs may represent attractive diagnostic and/or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics may represent a feasible strategy for future cancer treatment. Here we summarize the current published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer.
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Affiliation(s)
- Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Huihui Li
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Longchang Jiang
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Heiko Hermeking
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
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Pinheiro DDR, Ferreira WAS, Barros MBL, Araújo MD, Rodrigues-Antunes S, Borges BDN. Perspectives on new biomarkers in gastric cancer: Diagnostic and prognostic applications. World J Gastroenterol 2014; 20:11574-11585. [PMID: 25206265 PMCID: PMC4155351 DOI: 10.3748/wjg.v20.i33.11574] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 03/14/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is considered one of the most deadly tumors worldwide. Even with the decline in its incidence, the mortality rate of this disease has remained high, mainly due to its late diagnosis and to the lack of precise prognostic markers. The main purpose of this review is to present genetic, epigenetic and proteomic molecular markers that may be used in a diagnostic and prognostic manner and to discuss the pros and cons of each type of marker for improving clinical practice. In this sense, we observed that the use of genetic markers, especially mutations and polymorphisms, should be carefully considered, as they are strongly affected by ethnicity. Proteomic-based markers show promise, but the higher costs of the associated techniques continue to make this approach expensive for routine use. Alternatively, epigenetic markers appear to be very promising, as they can be detected in bodily fluids as well as tissues. However, such markers must be used carefully because epigenetic changes may occur due to environmental factors and aging. Despite the advances in technology and its access, to date, there are few defined biomarkers of prognostic and diagnostic use for gastric tumors. Therefore, the use of a panel of several approaches (genetic, epigenetic and proteomic) should be considered the best alternative for clinical practice.
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Xia J, Guo X, Yan J, Deng K. The role of miR-148a in gastric cancer. J Cancer Res Clin Oncol 2014; 140:1451-6. [PMID: 24659367 DOI: 10.1007/s00432-014-1649-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Accepted: 03/12/2014] [Indexed: 12/14/2022]
Abstract
PURPOSE Gastric cancer is one of the most common malignant diseases worldwide, although much progress has been achieved in recent years, the early diagnosis and treatment for gastric cancer are not yet satisfactory and, thus the prognosis is still poor. MicroRNAs (miRNAs) can regulate a variety of physiological and developmental processes, it has been revealed that many miRNAs contribute the initiation and progression of various cancers. MiR-148a is one of the most important miRNAs in gastric cancer, and the aim of this paper is to provide an overview of various roles of miR-148a in gastric cancer. METHODS AND RESULTS We searched studies in electronic databases. MiR-148a was down-regulated in gastric cancer tissues and cell lines, which was resulted from the hypermethylation in its promoter region. Furthermore, miR-148a could regulate several different target genes and pathways involving tumor proliferation, invasion and metastasis. CONCLUSION MiR-148a may serve as a novel biomarker for the diagnosis and as a new therapeutic target in gastric cancer.
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LI HAILONG, XIE SHOUPIN, LIU XIAOJUN, WU HONGYAN, LIN XINGYAO, GU JING, WANG HUPING, DUAN YONGQIANG. Matrine alters microRNA expression profiles in SGC-7901 human gastric cancer cells. Oncol Rep 2014. [DOI: 10.3892/or_xxxxxxxx] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Sun B, Karin M. The therapeutic value of targeting inflammation in gastrointestinal cancers. Trends Pharmacol Sci 2014; 35:349-57. [PMID: 24881011 DOI: 10.1016/j.tips.2014.04.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/28/2014] [Accepted: 04/30/2014] [Indexed: 12/22/2022]
Abstract
Inflammation has been implicated in the initiation and progression of gastrointestinal (GI) cancers. Inflammation also plays important roles in subverting immune tolerance, escape from immune surveillance, and conferring resistance to chemotherapeutic agents. Targeting key regulators and mediators of inflammation represents an attractive strategy for GI cancer prevention and treatment. However, the targeting of inflammation in GI cancer is not straightforward and sometimes inflammation may contribute to tumor regression. We discuss the origins and effects of inflammation in GI cancer and how to target it successfully.
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Affiliation(s)
- Beicheng Sun
- Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China.
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA.
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Lin CW, Li XR, Zhang Y, Hu G, Guo YH, Zhou JY, Du J, Lv L, Gao K, Zhang Y, Deng H. TAp63 suppress metastasis via miR-133b in colon cancer cells. Br J Cancer 2014; 110:2310-20. [PMID: 24594999 PMCID: PMC4007221 DOI: 10.1038/bjc.2014.118] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/09/2013] [Accepted: 02/10/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND TAp63 is a tumour-suppressor protein that is often underexpressed in various types of cancer. It has been shown to activate gene transcription depending on the transcription domain and to be closely related with metastasis. In this study, we demonstrate that TAp63 suppresses metastasis in colon cancer cells through microRNA-133b. METHODS We evaluated the correlation of TAp63 and miR-133b with HT-29 and SW-620 cells and investigated the roles of TAp63 in the expression of RhoA, E-cadherin and vimentin. We further investigated the roles of TAp63-mediated invasion and migration of colon cancer cells. RESULTS TAp63 expression is downregulated in colon cancer, and microRNA-133b is a transcriptional target of TAp63. Furthermore, microRNA-133b is essential for the inhibitory effects of TAp63 on RhoA, E-cadherin and vimentin. Moreover, TAp63 inhibits cell migration and invasion through microRNA-133b. Correspondingly, the inhibitory effect of TAp63 on RhoA, E-cadherin, vimentin, migration and invasion can be blocked by the microRNA-133b inhibitor. CONCLUSIONS TAp63 and microRNA-133b were able to suppress the metastasis of colon cancer. Both TAp63 and microRNA-133b may be potential biomarkers for diagnosis in colon cancer metastasis and may provide unique therapeutic targets for this common malignancy.
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Affiliation(s)
- C W Lin
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - X R Li
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - Y Zhang
- Department of General Surgery, The XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - G Hu
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - Y H Guo
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - J Y Zhou
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - J Du
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - L Lv
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - K Gao
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - Y Zhang
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - H Deng
- Center for Experimental Medicine, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
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Ao J, Xiao WD. Progresses in research of miR-148a in digestive system cancers. Shijie Huaren Xiaohua Zazhi 2014; 22:4938. [DOI: 10.11569/wcjd.v22.i32.4938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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50
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Identification of a 5-gene signature for clinical and prognostic prediction in gastric cancer patients upon microarray data. Med Oncol 2013; 30:678. [DOI: 10.1007/s12032-013-0678-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 07/22/2013] [Indexed: 01/26/2023]
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