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1
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El-Korany WA, Zahran WE, Alm El-Din MA, Al-Shenawy HA, Soliman AF. Rs12039395 Variant Influences the Expression of hsa-miR-181a-5p and PTEN Toward Colorectal Cancer Risk. Dig Dis Sci 2024; 69:3318-3332. [PMID: 38940971 DOI: 10.1007/s10620-024-08517-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 05/31/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes could alter miRNA expression levels or processing and, thus, may contribute to colorectal cancer (CRC) development. Therefore, this study aimed to examine whether the MIR181A1 genomic sequence possesses SNPs that can affect the expression of hsa-miR-181a-5p and, subsequently, impact its targets and associate with CRC risk. METHODS The NCBI dbSNP database was searched for possible SNPs associated with MIR181A1. One SNP with a minor allele frequency > 5%, rs12039395 G > T was identified. In silico analyses determined the effect of the SNP on the secondary structure of the miRNA and predicted the hsa-miR-181a-5p target genes. The SNP was genotyped using allelic discrimination assay, the relative hsa-miR-181a-5p expression level was determined using quantitative real-time PCR, and immunohistochemical staining was used to detect target genes in 192 paraffin-embedded specimens collected from 160 CRC patients and 32 healthy subjects. RESULTS The rs6505162 SNP conferred protection against CRC, and the G-allele presence provides may provide accessibility for the transcriptional machinery. Hsa-miR-181a-5p was significantly over-expressed in the CRC group compared to controls and in samples carrying the G-allele compared to those with T-allele. PTEN, identified as the only hsa-miR-181a-5p target implicated in CRC, was significantly diminished in the CRC group compared to controls and showed an inverse relationship with hsa-miR-181a-5p expression level as well as negatively associated with the G-allele presence in CRC. CONCLUSION This study highlights that rs12039395 G > T may protect against CRC by influencing the expression of hsa-mir-181a-5p and its target gene, PTEN.
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Affiliation(s)
- Wael A El-Korany
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Walid E Zahran
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohamed A Alm El-Din
- Clinical Oncology Department, Faculty of Medicine, Tanta University, Gharbia, Egypt
| | - Hanan A Al-Shenawy
- Pathology Department, Faculty of Medicine, Tanta University, Gharbia, Egypt
| | - Ahmed F Soliman
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
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2
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Mobinikhaledi M, Faridzadeh A, Farkhondeh T, Pourhanifeh MH, Samarghandian S. The Roles of Autophagy-related miRNAs in Gynecologic Tumors: A Review of Current Knowledge for Possible Targeted Therapy. Curr Mol Med 2024; 24:1269-1281. [PMID: 39300715 DOI: 10.2174/0115665240263059231002093454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/12/2023] [Accepted: 08/24/2023] [Indexed: 09/22/2024]
Abstract
Gynecological cancers are the leading cause of malignancy-related death and disability in the world. These cancers are diagnosed at end stages, and unfortunately, the standard therapeutic strategies available for the treatment of affected women [including chemotherapy, radiotherapy and surgery] are not safe and effective enough. Moreover, the unwanted side-effects lowering the patients' life quality is another problem for these therapies. Therefore, researchers should search for better alternative/complementary treatments. The involvement of autophagy in the pathogenesis of various cancers has been demonstrated. Recently, a novel crosstalk between microRNAs, small non-coding RNAs with important regulatory functions, and autophagy machinery has been highlighted. In this review, we indicate the importance of this interaction for targeted therapy in the treatment of cancers including gynecological cancers, with a focus on underlying mechanisms.
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Affiliation(s)
- Mahya Mobinikhaledi
- Department of Pediatrics, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Arezoo Faridzadeh
- Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Tahereh Farkhondeh
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran
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3
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Elhelaly M, Shaker OG, Ayeldeen G, Elsergany AR, Mostafa N. Breast cancer risk is associated with the HULC rs7763881, MTMR3 rs12537 polymorphisms, and serum levels of HULC and MTMR3 in Egyptian patients. Mol Biol Rep 2023; 50:10073-10081. [PMID: 37910386 PMCID: PMC10676311 DOI: 10.1007/s11033-023-08897-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 10/04/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Highly upregulated in liver cancer (HULC) is one of the LncRNAs that was documented to enhance cancer progression, and its downregulation is associated with cell cycle arrest and apoptosis. Myotubularin-related protein 3 (MTMR3) is required for autophagy, and many studies consider MTMR3 to be a negative regulator of autophagy processes. However, nothing is understood about how they regulate breast cancer. MATERIAL AND METHODS This case-control study included 245 patients (Group A: 85 early BC Group B: 40 metastatic BC cases, Group C: 40 fibroadenoma cases; and Group D: 80 age matched healthy control subjects. TaqMan Real-time PCR was used to analyse rs7158663 and rs12537. MTMR3 and HULC gene expression levels were measured using RT-PCR. RESULT Breast cancer patients exhibited elevated serum MTMR3 and HULC compared to fibroadenomas and control cases. The MTMR3 rs12537 "T/T" genotype was highly expressed in cases of breast cancer (early and metastatic) compared to controls (risk genotype). On the other hand, the HULC rs7158663 genotypes were not statistically associated with breast cancer. However, when compared to the control, the C/C genotype of the HULC gene is higher in the case.MTMR3 gene expression was higher in the T/T genotype compared to both the C/C and C/T genotypes, while HULC gene expression was lower in the A/C genotype compared to both the A/A and C/C genotypes. Positive correlation between MTMR3 and HULC. MTMR3 and ALT, as well as HULC and alkaline phosphatase, both showed a statistically significant positive correlation. CONCLUSION Our findings reveal that MTMR3 and HULC serum expression and their SNPs (HULC rs7763881, MTMR3 rs12537) are associated with a higher risk for the development of breast cancer in the Egyptian population.
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Affiliation(s)
- Mona Elhelaly
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Olfat G Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ghada Ayeldeen
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Alyaa R Elsergany
- Internal Medicine Department, Medical Oncology Unit, Oncology Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nora Mostafa
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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4
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Hajibabaie F, Abedpoor N, Assareh N, Tabatabaiefar MA, Shariati L, Zarrabi A. The Importance of SNPs at miRNA Binding Sites as Biomarkers of Gastric and Colorectal Cancers: A Systematic Review. J Pers Med 2022; 12:jpm12030456. [PMID: 35330456 PMCID: PMC8954022 DOI: 10.3390/jpm12030456] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
Dysregulated mRNA–miRNA profiles might have the prospective to be used for early diagnosis of gastrointestinal cancers, estimating survival, and predicting response to treatment. Here, a novel biomarker based on miRNAs binding to mRNAs in single nucleotide polymorphism (SNP) sites related to gastrointestinal cancers is introduced that could act as an early diagnosis. The electronic databases used for the recruiting published articles included EMBASE, SCOPUS, Web of Science, and PubMed, based on MESH keywords and PRISMA methodology. Based on the considered criteria, different experimental articles were reviewed, during which 15 studies with the desired criteria were collected. Accordingly, novel biomarkers in prediction, early prognosis, and diagnosis of gastrointestinal cancers were highlighted. Moreover, it was found that 20 SNP sites and 16 miRNAs were involved in gastrointestinal cancers, with altered expression patterns associated with clinicopathological and demographic data. The results of this systematic study revealed that SNPs could affect the binding of miRNAs in the SNP sites that might play a principal role in the progression, invasion, and susceptibility of gastrointestinal cancers. In addition, it was found that the profiles of SNPs and miRNAs could serve as a convenient approach for the prognosis and diagnosis of gastric and colorectal cancers.
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Affiliation(s)
- Fatemeh Hajibabaie
- Department of Physiology, Medicinal Plants Research Center, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan 81595-158, Iran; (F.H.); (N.A.)
| | - Navid Abedpoor
- Department of Sports Physiology, Faculty of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan 81595-158, Iran;
| | - Nazanin Assareh
- Department of Physiology, Medicinal Plants Research Center, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan 81595-158, Iran; (F.H.); (N.A.)
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran;
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
| | - Laleh Shariati
- Department of Biomaterials, Nanotechnology and Tissue Engineering, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
- Biosensor Research Center, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
- Correspondence: (L.S.); (A.Z.)
| | - Ali Zarrabi
- Biomedical Engineering Department, Faculty of Engineering and Natural Sciences, Istinye University, Sariye, Istanbul 34396, Turkey
- Correspondence: (L.S.); (A.Z.)
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5
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Xu J, Li G, Chen M, Li W, Wu Y, Zhang X, Cui Y, Zhang B. rs12537 Is a Novel Susceptibility SNP Associated With Estrogen Receptor Positive Breast Cancer in Chinese Han Population. Front Med (Lausanne) 2021; 8:708644. [PMID: 34395483 PMCID: PMC8355624 DOI: 10.3389/fmed.2021.708644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 06/21/2021] [Indexed: 01/15/2023] Open
Abstract
Genetic testing is widely used in breast cancer and has identified a lot of susceptibility genes and single nucleotide polymorphisms (SNPs). However, for many SNPs, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are not in place. A recent genome-wide long non-coding RNA (lncRNA) association study in Chinese Han has verified a genetic association between rs12537 and breast cancer. This study is aimed at investigating the association between rs12537 and the phenotype. We collected the clinical information of 5,634 breast cancer patients and 6,308 healthy controls in the early study. And χ2 test was used for the comparison between different groups in genotype. The frequency of genotypic distribution among SNP rs12537 has no statistically significant correlation with family history (p = 0.8945), menopausal status (p = 0.3245) or HER-2 (p = 0.2987), but it is statistically and significantly correlated with ER (p = 0.004006) and PR (p = 0.01379). Most importantly, compared to the healthy control, rs12537 variant is significantly correlated with ER positive patients and the p-value has reached the level of the whole genome (p = 1.66E-08 <5.00E-08). Furthermore, we found rs12537 associated gene MTMR3 was lower expressed in breast cancer tissues but highly methylated. In conclusion, our findings indicate that rs12537 is a novel susceptibility gene in ER positive breast cancer in Chinese Han population and it may influence the methylation of MTMR3.
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Affiliation(s)
- Jingkai Xu
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.,Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guozheng Li
- School of Life Sciences, Anhui Medical University, Hefei, China.,Department of Oncology, No. 2 Hospital, Anhui Medical University, Hefei, China
| | - Mengyun Chen
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wenjing Li
- School of Life Sciences, Anhui Medical University, Hefei, China.,Department of Oncology, No. 2 Hospital, Anhui Medical University, Hefei, China
| | - Yaxing Wu
- School of Life Sciences, Anhui Medical University, Hefei, China.,Department of Oncology, No. 2 Hospital, Anhui Medical University, Hefei, China
| | - Xuejun Zhang
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yong Cui
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Bo Zhang
- School of Life Sciences, Anhui Medical University, Hefei, China.,Department of Oncology, No. 2 Hospital, Anhui Medical University, Hefei, China
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Pourhanifeh MH, Vosough M, Mahjoubin-Tehran M, Hashemipour M, Nejati M, Abbasi-Kolli M, Sahebkar A, Mirzaei H. Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers. Pharmacol Res 2020; 161:105133. [DOI: 10.1016/j.phrs.2020.105133] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/23/2020] [Accepted: 08/07/2020] [Indexed: 02/08/2023]
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Association of MTMR3 rs12537 at miR-181a binding site with rheumatoid arthritis and systemic lupus erythematosus risk in Egyptian patients. Sci Rep 2019; 9:12299. [PMID: 31444373 PMCID: PMC6707250 DOI: 10.1038/s41598-019-48770-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 08/12/2019] [Indexed: 12/15/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in microRNA-target sites influence an individual's risk and prognosis for autoimmune diseases. Myotubularin-related protein 3 (MTMR3), an autophagy-related gene, is a direct target of miR-181a. We investigated whether MTMR3 SNP rs12537 in the miR-181a-binding site is associated with the susceptibility and progression of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Overall, 94 patients with RA, 80 patients with SLE, and 104 healthy volunteers were recruited. Genotyping and expression analysis of circulating MTMR3 and miR-181a were performed by qPCR. The autophagic marker MAP1LC3B was measured by ELISA. The rs12537 minor homozygote (TT) genotype was a candidate risk factor of both RA and SLE. rs12537TT was associated with lower serum MTMR3 expression and higher LC3B levels than other genotypes in patients with both diseases. Serum miR-181a expression was higher in rs12537TT carriers than in other genotypes among SLE patients. Serum miR-181a and MTMR3 levels were inversely correlated in SLE but not in RA patients. rs12537TT and serum miR-181a were positively associated with disease severity in both diseases. Our results identify a novel role of rs12537 in the susceptibility and progression of RA and SLE, possibly through impacting the interaction between miR-181a and MTMR3 leading to increased autophagy.
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8
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Chang Q, He ZL, Peng YC, Duan SG, Dai YX, Zhao XH. A meta-analysis of MDR1 polymorphisms rs1128503 and rs1045642 and susceptibility to hepatocellular carcinoma. J Int Med Res 2019; 47:2800-2809. [PMID: 31234681 PMCID: PMC6683882 DOI: 10.1177/0300060519855869] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective A relationship between polymorphisms rs1128503 and rs1045642 in the multidrug resistance 1 gene ( MDR1) and susceptibility to hepatocellular carcinoma (HCC) has been reported but is inconclusive. This study was performed to explore the significance of MDR1 polymorphisms rs1128503 and rs1045642 in screening and diagnosis of HCC. Methods Studies of association analyses between MDR1 gene polymorphisms rs1128503 and rs1045642 and HCC were selected from three foreign language databases (PubMed, Cochrane, and Embase) and three Chinese databases (Wanfang, China National Knowledge Infrastructure, and China Knowledge Network) and subjected to meta-analysis. Results We found no significant relationship between the rs1128503 polymorphism and susceptibility to HCC in 4 cohorts and no significant relationship between the rs1045642 polymorphism and susceptibility to HCC in 3 cohorts. Conclusions There was no relationship between polymorphisms rs1128503 or rs1045642 of the MDR1 gene and susceptibility to HCC.
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Affiliation(s)
- Qing Chang
- Department of General Surgery, 9th People's Hospital of Chongqing, Chongqing, China
| | - Zhong-Lin He
- Department of General Surgery, 9th People's Hospital of Chongqing, Chongqing, China
| | - Yu-Chong Peng
- Department of General Surgery, 9th People's Hospital of Chongqing, Chongqing, China
| | - Shi-Gang Duan
- Department of General Surgery, 9th People's Hospital of Chongqing, Chongqing, China
| | - Yu-Xin Dai
- Department of General Surgery, 9th People's Hospital of Chongqing, Chongqing, China
| | - Xiao-Hui Zhao
- Department of General Surgery, 9th People's Hospital of Chongqing, Chongqing, China
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Regulatory effects of lncRNAs and miRNAs on autophagy in malignant tumorigenesis. Biosci Rep 2018; 38:BSR20180516. [PMID: 30266744 PMCID: PMC6200703 DOI: 10.1042/bsr20180516] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/19/2018] [Accepted: 08/06/2018] [Indexed: 12/16/2022] Open
Abstract
Autophagy is an important process in endogenous substrate degradation by lysosomes within cells, with a degree of evolutionary conservation. Like apoptosis and cell senescence, cell autophagy is a very important biological phenomenon involving the development and growth of biological processes. Abnormal autophagy may lead to tumorigenesis. In recent years, increasing studies have demonstrated that long non-coding RNAs (lncRNAs) and miRNAs can regulate cell autophagy by modulating targetting gene expression. In this review, we will provide an overview of lncRNAs and miRNAs in autophagy modulation and new insights into the underlying mechanisms, as well as their potential utilization in disease diagnosis, prognosis, and therapy.
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Hu X, Miao J, Zhang M, Wang X, Wang Z, Han J, Tong D, Huang C. miRNA-103a-3p Promotes Human Gastric Cancer Cell Proliferation by Targeting and Suppressing ATF7 in vitro. Mol Cells 2018; 41:390-400. [PMID: 29754469 PMCID: PMC5974616 DOI: 10.14348/molcells.2018.2078] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 02/28/2018] [Accepted: 03/15/2018] [Indexed: 12/11/2022] Open
Abstract
Studies have revealed that miR-103a-3p contributes to tumor growth in several human cancers, and high miR-103a-3p expression is associated with poor prognosis in advanced gastric cancer (GC) patients. Moreover, bioinformatics analysis has shown that miR-103a-3p is upregulated in The Cancer Genome Atlas (TCGA) stomach cancer cohort. These results suggest that miR-103a-3p may function as an oncogene in GC. The present study aimed to investigate the role of miR-103a-3p in human GC. miR-103a-3p expression levels were increased in 33 clinical GC specimens compared with adjacent nontumor stomach tissues. Gain- and loss-of-function studies were performed to identify the correlation between miR-103a-3p and tumorigenesis in human GC. Inhibiting miR-103a-3p suppressed GC cell proliferation and blocked the S-G2/M transition in MKN-45/SGC-7901 cells, whereas miR-103a-3p overexpression improved GC cell proliferation and promoted the S-G2/M transition in vitro. Bioinformatics and dual-luciferase reporter assays confirmed that ATF7 is a direct target of miR-103a-3p. Analysis of the TCGA stomach cancer cohort further revealed that miR-103a-3p expression was inversely correlated with ATF7 expression. Notably, silencing ATF7 showed similar cellular and molecular effects as miR-103a-3p overexpression, namely, increased GC cell proliferation, improved CDK2 expression and decreased P27 expression. ATF7 overexpression eliminated the effects of miR-103a-3p expression. These findings indicate that miR-103a-3p promotes the proliferation of GC cell by targeting and suppressing ATF7 in vitro.
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Affiliation(s)
- Xiaoyi Hu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
- Department of Oral Maxillofacial Surgery, Stomatological Hospital, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
| | - Jiyu Miao
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
| | - Min Zhang
- College of Life Science, Yanan University, Yan’an, Shaanxi,
China
| | - Xiaofei Wang
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
| | - Zhenzhen Wang
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
| | - Jia Han
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
| | - Dongdong Tong
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
| | - Chen Huang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi,
China
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Yang W, Ma J, Zhou W, Cao B, Zhou X, Yang Z, Zhang H, Zhao Q, Fan D, Hong L. Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer. Expert Opin Ther Targets 2017; 21:1063-1075. [PMID: 28994330 DOI: 10.1080/14728222.2017.1389900] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.
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Affiliation(s)
- Wanli Yang
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Jiaojiao Ma
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Wei Zhou
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Bo Cao
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Xin Zhou
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Zhiping Yang
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Hongwei Zhang
- c Department of Digestive Surgery, Xijing Hospital , Fourth Military Medical University , Xi'an , China
| | - Qingchuan Zhao
- c Department of Digestive Surgery, Xijing Hospital , Fourth Military Medical University , Xi'an , China
| | | | - Liu Hong
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
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Hu X, Zhang M, Miao J, Wang X, Huang C. miRNA-4317 suppresses human gastric cancer cell proliferation by targeting ZNF322. Cell Biol Int 2017; 42:923-930. [PMID: 28880489 DOI: 10.1002/cbin.10870] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 09/03/2017] [Indexed: 11/10/2022]
Abstract
Studies have shown that miR-4317 is dysregulated in tumor, but the biologic role of miR-4317 in tumor development and progression remains unknown. The present study aimed to investigate the role of miR-4317 in human gastric cancer. Quantitative real-time PCR was used to quantify miR-4317 expression levels in clinical gastric cancer specimens and cell lines. MTT, colony formation and cell cycle assays were performed to identify the contributions of miR-4317 to cell proliferation in gastric cancer cell lines. The results showed that miR-4317 was significantly decreased in 17 clinical gastric cancer specimens compared with adjacent non-tumor stomach tissues. Forced expression of miR-4317 suppressed gastric cancer cell proliferation and blocked S-G2/M transition. Bioinformatics and dual-luciferase reporter assays confirmed that ZNF322 is a direct target of miR-4317. Silencing ZNF322 recapitulated the cellular and molecular effects seen upon miR-4317 overexpression. These findings indicate that miR-4317 represses the proliferation of gastric cancer cell, at least in part, by targeting and suppressing ZNF322 and that it may serve as a therapeutic target for gastric cancer treatment.
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Affiliation(s)
- Xiaoyi Hu
- Department of Oral Maxillofacial Surgery, Stomatological Hospital, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Min Zhang
- College of Life Science, Yanan University, Yan'an, Shaanxi, China
| | - Jiyu Miao
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaofei Wang
- Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Chen Huang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, 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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14
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Lin Y, Zhao J, Wang H, Cao J, Nie Y. miR-181a modulates proliferation, migration and autophagy in AGS gastric cancer cells and downregulates MTMR3. Mol Med Rep 2017; 15:2451-2456. [PMID: 28447759 PMCID: PMC5428200 DOI: 10.3892/mmr.2017.6289] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 01/02/2017] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRs) have emerged as crucial regulators of tumorigenesis by regulating post-transcriptional gene expression. miR-181a was previously demonstrated to be overexpressed in human gastric cancer tissues and cell lines, whereas MTMR3 was underexpressed. The MTMR3 gene was identified as a direct target of miR-181a. However, its functional role in gastric cancer remains to be established. In the present study, miR-181a was demonstrated to inhibit MTMR3 expression in AGS cells. Ectopic expression of miR-181a mimics or introduction of MTMR3 small interfering RNA resulted in an increase in cell proliferation, colony formation, migration, invasion, as well as suppression of apoptosis. Further investigation in the present study indicated that overexpression of miR-181a, or depletion of MTMR3, attenuated starvation-induced autophagy in AGS cells. In addition, inhibition of endogenous miR-181a led to stimulation of autophagic activity. Collectively, these data suggest that miR-181a is a novel regulator of gastric cancer progression and autophagy, and miR-181a modulation may be a potential strategy for the development of miRNA-based therapeutics for gastric cancer.
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Affiliation(s)
- Yong Lin
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Jing Zhao
- School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Hong Wang
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Jie Cao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
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15
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Tian Y, Xiao X, Gong X, Peng F, Xu Y, Jiang Y, Gong G. HBx promotes cell proliferation by disturbing the cross-talk between miR-181a and PTEN. Sci Rep 2017; 7:40089. [PMID: 28053323 PMCID: PMC5215388 DOI: 10.1038/srep40089] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 12/01/2016] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the mechanism is still needed to be elucidated. In this study, we explored the relationship between HBx and microRNA and their roles in hepato-carcinogenesis. Firstly, by global microarray-based microRNA profiling and qRT-PCR, we found miR-181a was strongly up-regulated in HepG2.2.15 cells (HBV positive) and pHBV1.3-expressing HepG2 cells, and HBx played a major role in it. Secondly, reduced PTEN protein expression in the presence of HBx was aslo mediated by miR-181a, and in the Luciferase reporter system, miR-181a inhibited the PTEN translation by binding the PTEN 3'-untranslated-region (UTR), and PTEN protein was decreased when epigenetic expression of miR-181a and rescued by knocking down miR-181a. Finally, HBx interrupted the balance between apoptosis and proliferation, which contributed to the development of hepatocellular carcinoma, was also related to the interaction of miR-181a and PTEN. Taken together, we presented here a novel cross-talk between miR-181a and PTEN which was raised by HBx, and this shined a new line in HBV-related hepato-carcinogenesis.
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Affiliation(s)
- Yi Tian
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Xinqiang Xiao
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Xing Gong
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Feng Peng
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yun Xu
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yongfang Jiang
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Guozhong Gong
- Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha 410011, China
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16
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The Emerging Role of miRNAs and Their Clinical Implication in Biliary Tract Cancer. Gastroenterol Res Pract 2016; 2016:9797410. [PMID: 28115929 PMCID: PMC5223017 DOI: 10.1155/2016/9797410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 10/07/2016] [Accepted: 12/04/2016] [Indexed: 01/17/2023] Open
Abstract
Biliary tract cancers are aggressive malignancies that include gallbladder cancer and tumors of intra- and extrahepatic ducts and have a poor prognosis. Surgical resection remains the main curative therapy. Nevertheless, numerous patients experience recurrence even after radical surgery. This scenario drives the research to identify biliary tract cancer biomarkers despite the limited progress that has been made. Recently, a large number of studies have demonstrated that deregulated expression of microRNAs is closely associated with cancer development and progression. In this review, we highlight the role and importance of microRNAs in biliary tract cancers with an emphasis on utilizing circulating microRNAs as potential biomarkers. Additionally, we report several single-nucleotide polymorphisms in microRNA genes that are associated with the susceptibility of biliary tract tumors.
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17
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Hang D, Zhou W, Jia M, Wang L, Zhou J, Yin Y, Ma H, Hu Z, Li N, Shen H. Genetic variants within microRNA-binding site of RAD51B are associated with risk of cervical cancer in Chinese women. Cancer Med 2016; 5:2596-601. [PMID: 27334422 PMCID: PMC5055154 DOI: 10.1002/cam4.797] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 04/30/2016] [Accepted: 05/19/2016] [Indexed: 12/19/2022] Open
Abstract
RAD51B plays a central role in homologous recombinational repair (HRR) of DNA double-strand breaks (DSBs), which is important to prevent genomic instability, a hallmark of cancer. Recent studies suggested that common genetic variants of RAD51B may contribute to cancer susceptibility. In this study, we aimed to investigate whether potentially functional variants within miRNA-binding sites of RAD51B are associated with risk of cervical cancer. A total of 1486 cervical cancer patients and 1536 cancer-free controls were enrolled, and two genetic variants, rs963917 (A > G) and rs963918 (T > C), were genotyped in all participants. Using multivariate logistic regression analyses, we found that G allele of rs963917 conferred lower risk of cervical cancer compared to A allele (adjusted OR = 0.89, 95% CI = 0.80-0.99, P = 0.039). Similarly, rs963918 allele C was associated with a decreased risk for cervical cancer compared with allele T (adjusted OR = 0.84, 95% CI = 0.74-0.94, P = 0.004). Haplotype analyses showed that haplotype GC was also correlated with lower risk (OR = 0.83, 95% CI = 0.73-0.95, P = 0.005) compared with the most common haplotype AT. In summary, our study suggested that miRNA-binding site genetic variants of RAD51B may modify the susceptibility to cervical cancer, which is important to identify individuals with differential risk for this malignancy and to improve the effectiveness of preventive intervention.
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Affiliation(s)
- Dong Hang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wen Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Meiqun Jia
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lihua Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jing Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yin Yin
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongxia Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Ni Li
- National Office for Cancer Prevention and Control, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.
| | - Hongbin Shen
- Department of Epidemiology and Biostatistics, School of Public Health, 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.
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18
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Zhao J, Nie Y, Wang H, Lin Y. MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin. Gene 2015; 576:828-33. [PMID: 26589846 DOI: 10.1016/j.gene.2015.11.013] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 10/22/2015] [Accepted: 11/12/2015] [Indexed: 12/16/2022]
Abstract
A number of chemotherapy drugs can induce autophagy. This inducible autophagy is a pro-survival mechanism and contributes to the development of acquired drug resistance. Emerging evidence indicates that miRNA regulates autophagy via targeting autophagy related genes and is involved in drug resistance. We previously demonstrated that miR-181a plays an important role in gastric cancer. The present study aimed to explore the effect of miR-181a on autophagy regulation and cisplatin resistance. We revealed that miR-181a is a novel negative regulator of autophagy in cisplatin-resistant cells SGC7901/CDDP. Then we indicated that ATG5 was a potential target of miR-181a. Furthermore, overexpression of miR-181a significantly enhanced the sensitivity of SGC7901/CDDP cells to cisplatin in vitro and reduced the volumes of gastric tumor xenografts in nude mice. Our finding provides evidence that miR-181a functions as a primary autophagy-related modulator and reverses cisplatin-resistance in GC cells.
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Affiliation(s)
- Jing Zhao
- School of Public Health, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou Medical University, No. 1 Panfu Road, Guangzhou 510180, PR China
| | - Hong Wang
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou Medical University, No. 1 Panfu Road, Guangzhou 510180, PR China
| | - Yong Lin
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou Medical University, No. 1 Panfu Road, Guangzhou 510180, PR China.
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19
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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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20
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Gupta A, Sharma A, Yadav A, Rastogi N, Agrawal S, Kumar A, Kumar V, Misra S, Mittal B. Evaluation of miR-27a, miR-181a, and miR-570 genetic variants with gallbladder cancer susceptibility and treatment outcome in a North Indian population. Mol Diagn Ther 2015; 19:317-327. [PMID: 26288960 DOI: 10.1007/s40291-015-0159-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION miR-27a, miR-181a, and miR-570 genetic variants have been found to play an important role in many cancers, but their contribution in gallbladder carcinoma (GBC) has not been explored. Therefore, we investigated the role of these micro RNA (miRNA) genetic variants in terms of GBC susceptibility, therapeutic response, toxicities associated with chemo-radiotherapy and survival outcome. METHODS This study included 606 GBC patients and 200 healthy controls. From among the larger study cohort, 219 patients receiving adjuvant or palliative chemo-radiotherapy as per disease status were followed up for toxicity profile. Treatment response was recorded in 159 patients who received palliative chemo-radiotherapy. Genotypes were determined using allelic discrimination assay. Statistical analysis was carried out with SPSS version 16. Generalized multifactor dimensionality reduction (GMDR) analysis was performed for gene-gene interactions. Survival analysis was performed using Kaplan-Meier and Cox regression tests. RESULTS In univariate logistic regression analysis, no association with any of the studied polymorphisms was found in overall GBC susceptibility. Furthermore, univariate and multivariate analyses revealed no significant association with response to chemo-radiotherapy. In GMDR analysis, miR-27ars895819, miR-570rs4143815, and miR-181ars12537 combination was found as the best gene-gene interaction model for susceptibility and treatment response. Furthermore, miR-27ars895819miR-181ars12537 was associated with neutropenia toxicity in patients undergoing chemo-radiotherapy. However, miRNA variants had no influence over the survival outcomes of GBC patients (locally advanced, metastatic). CONCLUSION In conclusion, the miRNA variants cumulatively influence GBC susceptibility and treatment outcomes.
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Affiliation(s)
- Annapurna Gupta
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, 226014, India
| | - Aarti Sharma
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, 226014, India
| | - Anu Yadav
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, 226014, India
| | - Neeraj Rastogi
- Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | - Sushma Agrawal
- Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | - Vijay Kumar
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Sanjeev Misra
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Balraj Mittal
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, 226014, India.
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21
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Sun Y, Li M. Genetic polymorphism of miR-146a is associated with gastric cancer risk: a meta-analysis. Eur J Cancer Care (Engl) 2015. [PMID: 26202478 DOI: 10.1111/ecc.12355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Several studies have investigated the associations between miR-146a rs2910164 and gastric cancer (GC) risk, but results have been inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. PubMed and China National Knowledge Infrastructure searches were carried out for relevant studies published before July 2014. Meta-analysis was performed with the stata, version 11.0. A total of seven case-control studies, including 3283 cases and 4535 controls, were selected. A significant association was found between rs2910164 and GC risk under all genetic models (CC vs. GG, OR = 0.76, 95% CI = 0.66-0.87; CC vs. GC+GG, OR = 0.84, 95% CI = 0.71-0.99; CC+GC vs. GG, OR = 0.82, 95% CI = 0.73-0.91) for the total data. In the subgroup analysis by ethnicity, statistically significant association was found in Asian. This meta-analysis suggested that the miR-146a rs2910164 was a risk factor for developing GC.
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Affiliation(s)
- Y Sun
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - M Li
- Department of Orthopedic Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
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22
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Human genetic variation and its effect on miRNA biogenesis, activity and function. Biochem Soc Trans 2015; 42:1184-9. [PMID: 25110023 DOI: 10.1042/bst20140055] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
miRNAs are small non-coding regulators of gene expression that are estimated to regulate over 60% of all human genes. Each miRNA can target multiple mRNA targets and as such, miRNAs are responsible for some of the 'fine tuning' of gene expression and are implicated in regulation of all cellular processes. miRNAs bind to target genes by sequence complementarity, resulting in target degradation or translational blocking and usually a reduction in target gene expression. Like mRNA, miRNAs are transcribed from genomic DNA and are processed in several steps that are heavily reliant on correct secondary and tertiary structure. Secondary structure is determined by RNA sequence, which is in turn determined by the sequence of the genome. The human genome, however, like most eukaryotes is variable. Large numbers of SNPs (single nucleotide polymorphisms), small insertions and deletions (indels) and CNVs (copy number variants) have been described in our genome. Should this genetic variation occur in regions critical for the correct secondary structure or target binding, it may interfere with normal gene regulation and cause disease. In this review, we outline the consequences of genetic variation involving different aspects of miRNA biosynthesis, processing and regulation, with selected examples of incidences when this has potential to affect human disease.
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23
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He S, Zeng S, Zhou ZW, He ZX, Zhou SF. Hsa-microRNA-181a is a regulator of a number of cancer genes and a biomarker for endometrial carcinoma in patients: a bioinformatic and clinical study and the therapeutic implication. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:1103-75. [PMID: 25733820 PMCID: PMC4342183 DOI: 10.2147/dddt.s73551] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The aberrant expression of human microRNA-181a-1 (hsa-miR-181a) has been implicated in the pathogenesis of various cancers, serving as an oncogene or a tumor suppressor. However, the role of hsa-miR-181a in the pathogenesis of endometrial carcinoma (EC) and its clinical significance are unclear. This study aimed to search for the molecular targets of hsa-miR-181a using bioinformatic tools and then determine the expression levels of hsa-miR-181a in normal, hyperplasia, and EC samples from humans. To predict the targets of hsa-miR-181a, ten different algorithms were used, including miRanda-mirSVR, DIANA microT v5.0, miRDB, RNA22 v2, TargetMiner, TargetScan 6.2, PicTar, MicroCosm Targets v5, and miRWALK. Two algorithms, TarBase 6.0 and miRTarBase, were used to identify the validated targets of hsa-miR-181a-5p (a mature product of hsa-miR-181a), and the web-based Database for Annotation, Visualization and Integrated Discovery (DAVID) 6.7 was used to provide biological functional interpretation of the validated targets of hsa-miR-181a-5p. A total of 78 formalin-fixed, paraffin-embedded tissue specimens from 65 patients and 13 healthy subjects were collected and examined, including normal endometrium (n=13), endometrial hyperplasia (n=18), and EC (37 type I and 10 type II EC cases). Our bioinformatic studies have showed that hsa-miR-181a might regulate a large number of target genes that are important in the regulation of critical cell processes, such as cell fate, cell survival, metabolism, and cell death. To date, 313 targets of hsa-miR-181a have been validated, and 22 of these targets are cancer genes. The precision of predictions by all the algorithms for hsa-miR-181a-1’s targets was low. Many of these genes are involved in tumorigenesis of various cancers, including EC, based on the DAVID and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In comparison with normal endometrial tissue, the expression level of hsa-miR-181a was significantly increased in type I and type II EC (P<0.05), and type II EC exhibited a significant higher expression level of hsa-miR-181a than that in type I EC (P<0.05). In addition, there was a significant increase in the expression level of hsa-miR-181a in type II EC compared with endometrial hyperplasia (P<0.05). Taken together, these results suggest that hsa-miR-181a may serve as an oncogene in endometrial tumorigenesis and that hsa-miR-181a might be used as a new biomarker in the prediction of prognosis of EC in clinical practice. More functional and mechanistic studies are needed to validate the role of hsa-miR-181a in the development, progression, and metastasis of EC.
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Affiliation(s)
- Shuming He
- Department of Obstetrics and Gynecology, Xiaolan People's Hospital affiliated to Southern Medical University, Zhongshan, Guangdong, People's Republic of China
| | - Shumei Zeng
- Department of Obstetrics and Gynecology, Xiaolan People's Hospital affiliated to Southern Medical University, Zhongshan, Guangdong, People's Republic of China
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People's Republic of China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People's Republic of China
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People's Republic of China
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24
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Chang S, Gao L, Yang Y, Tong D, Guo B, Liu L, Li Z, Song T, Huang C. miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells. Oncotarget 2015; 6:7675-7685. [PMID: 25762621 PMCID: PMC4480708 DOI: 10.18632/oncotarget.3048] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/06/2015] [Indexed: 12/19/2022] Open
Abstract
VitaminD3 signaling is involved in inhibiting the development and progression of gastric cancer (GC), while the active vitamin D metabolite 1-alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3)-mediated gene regulatory mechanisms in GC remain unclear. We found that miR-145 is induced by 1,25(OH)2D3 in a dose- and vitamin D receptor (VDR)-dependent manner in GC cells. Inhibition of miR-145 reverses the antiproliferative effect of 1,25(OH)2D3. Furthermore, miR-145 expression was lower in tumors compared with matched normal samples and correlated with increased the E2F3 transcription factor protein staining. Overexpression of miR-145 inhibited colony formation, cell viability and induced cell arrest in S-phase in GC cells by targeting E2F3 and CDK6. miR-145 inhibition consistently abrogates the 1,25(OH)2D3-mediated suppression of E2F3 , CDK6 , CDK2 and CCNA2 genes. Altogether, our results indicate that miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 in GC cells and might hold promise for prognosis and therapeutic strategies for GC treatment.
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Affiliation(s)
- Su'e Chang
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Ling Gao
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
- Department of Oral Maxillofacial Surgery, Stomatology Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P. R. China
| | - Yang Yang
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Dongdong Tong
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Bo Guo
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Liying Liu
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Zongfang Li
- Department of General Surgery, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Tusheng Song
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Chen Huang
- Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
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Song X, Zhong H, Zhou J, Hu X, Zhou Y, Ye Y, Lu X, Wang J, Ying B, Wang L. Association between polymorphisms of microRNA-binding sites in integrin genes and gastric cancer in Chinese Han population. Tumour Biol 2014; 36:2785-92. [PMID: 25472585 DOI: 10.1007/s13277-014-2903-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 11/26/2014] [Indexed: 02/06/2023] Open
Abstract
Highly elevated expression of integrin has been observed in a variety of malignant tumors. Single nucleotide polymorphisms (SNPs) in the microRNA-binding sites in the 3' UTR region of target genes may result in the level change of target gene expression and subsequently susceptible to diseases, including cancer. In this study, we aimed to investigate the association between polymorphisms of microRNA-binding sites of integrin genes and gastric cancer (GC) in Chinese Han population. Five SNPs of the microRNA-binding sites in the 3' UTR region of integrin genes (rs1062484 C/T in ITGA3, rs17664 A/G in ITGA6, rs3809865 A/T in ITGB3, rs743554 C/T in ITGB4, and rs2675 A/C in ITGB5) were studied using high resolution melting (HRM) analysis in 1000 GC patients and 1000 unrelated controls. The polymorphism of SNP rs2675 was associated with susceptibility of GC [odds ratio (OR) = 0.52, 95% confidence interval (CI) = 0.28-0.97, P = 0.028]. In addition, genotype AA of rs2675 and genotype GG of rs17664 were associated with a lower chance of GC at stage 1b [OR = 0.39 (0.18-0.85), P = 0.009; and OR = 0.37 (0.17-0.78), P = 0.004, respectively]; also, the frequency of allele G of rs17664 was associated with a lower chance of stage 1b tumor [OR = 0.50 (0.26-0.95), P = 0.021]. Furthermore, the frequency of genotype AA and allele A of rs3809865 were associated with a higher risk of stage 4 GC [OR = 1.85 (1.11-3.09), P = 0.012; and OR = 1.52 (0.99-2.33), P = 0.043, respectively]. For rs17664, GG genotype and allele G appeared to be associated with a higher risk with GC with lymphatic metastasis 3b [OR = 1.76 (1.00-3.11), P = 0.036; and OR = 1.64 (0.98-2.75), P = 0.048, respectively]. Our data suggest that polymorphisms of the microRNA-binding sites in the 3' UTR region of integrin are associated with GC susceptibility (rs2675), tumor stage (rs2675, rs17664, and rs3809865), and lymphatic metastasis (rs17664) in Chinese Han population.
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Affiliation(s)
- Xingbo Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People's Republic of China, 610041
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Bansal C, Sharma KL, Misra S, Srivastava AN, Mittal B, Singh US. Common genetic variants in pre-microRNAs and risk of breast cancer in the North Indian population. Ecancermedicalscience 2014; 8:473. [PMID: 25374621 PMCID: PMC4208924 DOI: 10.3332/ecancer.2014.473] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE MicroRNAs (miRNAs) are short regulatory RNAs that can modulate gene expression and function as negative regulators. Common genetic variants like single nucleotide polymorphisms (SNPs) in miRNA genes may alter their expression or maturation resulting in varied functional consequences in carcinogenesis. Therefore, we evaluated the genetic variants in pre-miRNAs: hsa-miR-146a G/C (rs2910164), hsa-miR-196a2 C/T (rs11614913), and hsa-miR-499 T>C (rs3746444) for their role in breast cancer susceptibility. STUDY DESIGN The study comprised 121 breast cancer patients, 115 with benign breast disease, and 164 controls. The genotypic frequency of miRNA polymorphisms was determined by PCR-RFLP assay. Logistic regression was used for statistical analysis using SPSS Software version 15.0. In silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). RESULTS The heterozygous variant of miR-146a G/C (rs2910164) is associated with the reduced risk of breast cancer at the genotype level as well as at the allele level (p < 0.05, OR = 0.5) as compared to controls. On the contrary, no significant difference was observed in the distribution of miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) polymorphisms in any groups both at genotype and allele levels. On the other hand, in multivariate analysis, we found that the miR-196a2 (rs11614913) C>T was associated with an increased risk of breast cancer risk in postmenopausal females (p = 0.02, OR = 3.2). We also attempted to find out the risk of malignant breast disease in relation to each of the above SNPs on dividing our data on the basis of benign and malignant status, but no significant difference was observed. In silico analysis using F-SNP showed change in transcriptional regulation by miR-146a G/C (rs2910164), miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) variations; the functional score was 0.100, 0.065 and 0.277, respectively. CONCLUSION The results of the present study demonstrate that miR-146a G/C (rs2910164) polymorphism is associated with reduced genetic susceptibility to breast cancer. However, multivariate analysis showed as miR-196a2 (rs11614913) C>T to be associated with increased risk of breast cancer risk in postmenopausal females. Further multicentric studies involving a large number of cases need to be carried out to strengthen the present results.
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Affiliation(s)
- C Bansal
- Pathology Department, King George Medical University, Lucknow 226003, India ; Pathology Department, Era's Medical College and Hospital, Lucknow 226003, India
| | - K L Sharma
- Genetics Department, Sanjay Ghandi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India
| | - Sanjeev Misra
- Department of Surgical Oncology, King George Medical University, Lucknow 226003, India
| | - A N Srivastava
- Pathology Department, Era's Medical College and Hospital, Lucknow 226003, India
| | - Balraj Mittal
- Genetics Department, Sanjay Ghandi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India
| | - U S Singh
- Pathology Department, King George Medical University, Lucknow 226003, India
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Wang Z, Wei M, Ren Y, Liu H, Wang M, Shi K, Jiang H. miR149 rs71428439 polymorphism and risk of clear cell renal cell carcinoma: a case-control study. Tumour Biol 2014; 35:12127-30. [PMID: 25213695 DOI: 10.1007/s13277-014-2517-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 08/15/2014] [Indexed: 12/13/2022] Open
Abstract
Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell cancer and accounts for 70 % of renal cell cancer. CCRCC remains an enigmatic tumor type, as the molecular genetic mechanisms are still unclear. MicroRNA (miR) 149 functions as a tumor suppressor and plays an important role in the carcinogenesis of renal cells. In this study, we enrolled 1,000 CCRCC patients and 1,000 cancer-free controls to evaluate the association of miR149 rs71428439 with the risk of CCRCC by a case-control study to determine the effects on CCRCC risk. miR149 rs71428439 was significantly associated with increased CCRCC risk (odds ratio (OR) for trend = 1.53, P for trend = 4.04 × 10(-11)), with ORs (95 % confidence intervals (CIs)) of 1.42 (1.17-1.72) associated with AG genotype and 2.27 (1.76-2.94) associated with GG genotype, compared with subjects with AA genotype. The expression levels of miR149 in cancer tissues were significantly lower than those in adjacent normal tissues (P = 0.005), and per G allele has significantly lower miR149 levels in both tumor tissues and adjacent normal tissues. Our data suggest that the GG genotypes of miR149 rs71428439 predispose their carriers to CCRCC, and miR149 rs71428439 may be a new biomarker for predicting the risk of CCRCC.
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Affiliation(s)
- Zhigang Wang
- School of Medicine Dialysis Center of First Affiliated Hospital of Medicine School, Xi'an Jiaotong University, No. 277 West Yanta Street, Xi'an, Shaanxi, 710061, China
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28
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MicroRNA and signaling pathways in gastric cancer. Cancer Gene Ther 2014; 21:305-16. [PMID: 25060632 DOI: 10.1038/cgt.2014.37] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs) function as either oncogenes or tumor suppressors by inhibiting the expression of target genes, some of which are either directly or indirectly involved with canonical signaling pathways. The relationship between miRNAs and signaling pathways in gastric cancer is extremely complicated. In this paper, we determined the pathogenic mechanism of gastric cancer related to miRNA expression based on recent high-quality studies and then clarified the regulation network of miRNA expression and the correlated functions of these miRNAs during the progression of gastric cancer. We try to illustrate the correlation between the expression of miRNAs and outcomes of patients with gastric cancer. Understanding this will allow us to take a big step forward in the treatment of gastric cancer.
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Cipollini M, Landi S, Gemignani F. MicroRNA binding site polymorphisms as biomarkers in cancer management and research. Pharmgenomics Pers Med 2014; 7:173-91. [PMID: 25114582 PMCID: PMC4126202 DOI: 10.2147/pgpm.s61693] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie several human diseases. Single nucleotide polymorphisms of transcripts may modulate the posttranscriptional regulation of gene expression by miRNAs and explain interindividual variability in cancer risk and in chemotherapy response. On the basis of recent association studies published in the literature, the present review mainly summarizes the potential role of miRNAs as molecular biomarkers for disease susceptibility, diagnosis, prognosis, and drug-response prediction in tumors. Many clues suggest a role for polymorphisms within the 3' untranslated regions of KRAS rs61764370, SET8 rs16917496, and MDM4 rs4245739 as SNPs in miRNA binding sites highly promising in the biology of human cancer. However, more studies are needed to better characterize the composite spectrum of genetic determinants for future use of markers in risk prediction and clinical management of diseases, heading toward personalized medicine.
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Affiliation(s)
| | - Stefano Landi
- Department of Biology, University of Pisa, Pisa, Italy
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McDermott AM, Miller N, Wall D, Martyn LM, Ball G, Sweeney KJ, Kerin MJ. Identification and validation of oncologic miRNA biomarkers for luminal A-like breast cancer. PLoS One 2014; 9:e87032. [PMID: 24498016 PMCID: PMC3909065 DOI: 10.1371/journal.pone.0087032] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 12/04/2013] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION Breast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting. METHODS Blood samples were prospectively collected from patients with Luminal A-like breast cancer (n = 54) and controls (n = 56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n = 10 Luminal A-like; n = 10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n = 44 Luminal A; n = 46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated. RESULTS Microarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis (miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652). The biomarker potential of 4 miRNAs (miR-29a, miR-181a, miR-223 and miR-652) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p = 0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs (miR-29a, miR-181a and miR-652) could reliably differentiate between cancers and controls with an AUC of 0.80. CONCLUSION This study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype-specific breast tumor detection.
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Affiliation(s)
- Ailbhe M. McDermott
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | - Nicola Miller
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | - Deirdre Wall
- School of Mathematics, Statistics and Applied Mathematics, National University of Ireland, Galway, Ireland
| | - Lorcan M. Martyn
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | - Graham Ball
- School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Karl J. Sweeney
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | - Michael J. Kerin
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
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Abstract
A multifactorial and multistep model of gastric cancer (GC) is currently accepted, according to which different environmental and genetic factors are involved at different stages in the cancer process. The aim of this article is to review the most relevant information published on the relative contribution of genetic and environmental factors. Large meta-analyses confirmed the association between IL8, IL10, TNF-b, TP53 and PSCA, while genetic variation at different genes such as XPG, PLCE1, HFE, ERCC5, EZH2, DOC2, CYP19A1, ALDH2, and CDH1 have been reported to be associated with GC risk. Several microRNAs have also been associated with GC and their prognosis. Cohort studies have shown the association between GC and fruit, flavonoid, total antioxidant capacity, and green tea intake. Obesity was associated with cardia GC, heme iron intake from meat with GC risk. Several large meta-analyses have confirmed the positive association of GC with salt intake and pickled foods and the negative association with aspirin use.
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Affiliation(s)
- Carlos A González
- Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology- Idibell, Barcelona, Spain
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Bulik-Sullivan B, Selitsky S, Sethupathy P. Prioritization of genetic variants in the microRNA regulome as functional candidates in genome-wide association studies. Hum Mutat 2013; 34:1049-56. [PMID: 23595788 PMCID: PMC3807557 DOI: 10.1002/humu.22337] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 04/03/2013] [Indexed: 02/06/2023]
Abstract
Comprehensive analyses of results from genome-wide association studies (GWAS) have demonstrated that complex disease/trait-associated loci are enriched in gene regulatory regions of the genome. The search for causal regulatory variation has focused primarily on transcriptional elements, such as promoters and enhancers. microRNAs (miRNAs) are now widely appreciated as critical posttranscriptional regulators of gene expression and are thought to impart stability to biological systems. Naturally occurring genetic variation in the miRNA regulome is likely an important contributor to phenotypic variation in the human population. However, the extent to which polymorphic miRNA-mediated gene regulation underlies GWAS signals remains unclear. In this study, we have developed the most comprehensive bioinformatic analysis pipeline to date for cataloging and prioritizing variants in the miRNA regulome as functional candidates in GWAS. We highlight specific findings, including a variant in the promoter of the miRNA let-7 that may contribute to human height variation. We also provide a discussion of how our approach can be expanded in the future. Overall, we believe that the results of this study will be valuable for researchers interested in determining whether GWAS signals implicate the miRNA regulome in their disease/trait of interest.
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Affiliation(s)
- Brendan Bulik-Sullivan
- Department of Genetics, University of North Carolina at Chapel HillChapel Hill, North Carolina
| | - Sara Selitsky
- Department of Genetics, University of North Carolina at Chapel HillChapel Hill, North Carolina
| | - Praveen Sethupathy
- Department of Genetics, University of North Carolina at Chapel HillChapel Hill, North Carolina
- Carolina Center for Genome Sciences, University of North Carolina at Chapel HillChapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillChapel Hill, North Carolina
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Jiang Y, Chen J, Wu J, Hu Z, Qin Z, Liu X, Guan X, Wang Y, Han J, Jiang T, Jin G, Zhang M, Ma H, Wang S, Shen H. Evaluation of genetic variants in microRNA biosynthesis genes and risk of breast cancer in Chinese women. Int J Cancer 2013; 133:2216-24. [PMID: 23629745 DOI: 10.1002/ijc.28237] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 04/15/2013] [Indexed: 01/05/2023]
Abstract
MicroRNAs (miRNA) are a class of small, noncoding RNA molecules involved in a diversity of cellular functions. Single nucleotide polymorphisms (SNPs) in miRNA biosynthesis genes may affect the biogenesis of miRNAs and consequently affect the miRNAs regulation. In this study, we systematically selected 24 functional SNPs located in eight key biosynthesis genes of miRNA (DROSHA, DGCR8, RAN, DICER, AGO2, GEMIN3, GEMIN4 and HIWI) and investigated the association between these SNPs and the risk of breast cancer in a Chinese population. All 24 SNPs were firstly genotyped in stage 1 (878 cases and 900 controls) and three promising SNPs (DROSHA rs2291109, RAN rs7301722 and DGCR8 rs417309) were selected for further validation in stage 2 (914 cases and 967 controls). We found that only one SNP (rs417309) located in the 3'-UTR of DGCR8 was consistently associated with an increased breast cancer risk in two stages with a combined odds ratio (OR) of 1.50 [95% confidence interval (CI) = 1.16-1.93]. Based on the bioinformatics prediction, rs417309 is located at the binding sites of miR-106b and miR-579 in the 3'-UTR of DGCR8. To evaluate whether rs417309 variant affects the binding capacity of miRNAs, we cotransfected luciferase reporter plasmids of DGCR8 3'-UTR and miR-106b/miR-579 in three cell lines. Luciferase activity assay showed a higher expression level with rs417309 A allele compared with G allele in MCF-7 cell lines (p = 3.31 × 10(-7) , 9.29 × 10(-7) for miR-106b and miR-579, respectively). Our findings suggested that DGCR8 rs417309 G > A might affect breast cancer risk through the interruption of miRNA binding.
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Affiliation(s)
- Yue Jiang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
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Hendriks WJAJ, Pulido R. Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities. Biochim Biophys Acta Mol Basis Dis 2013; 1832:1673-96. [PMID: 23707412 DOI: 10.1016/j.bbadis.2013.05.022] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 05/14/2013] [Accepted: 05/16/2013] [Indexed: 12/18/2022]
Abstract
Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism to steer normal development and physiological functioning of multicellular organisms. Phosphotyrosine dephosphorylation is exerted by members of the super-family of protein tyrosine phosphatase (PTP) enzymes and many play such essential roles that a wide variety of hereditary disorders and disease susceptibilities in man are caused by PTP alleles. More than two decades of PTP research has resulted in a collection of PTP genetic variants with corresponding consequences at the molecular, cellular and physiological level. Here we present a comprehensive overview of these PTP gene variants that have been linked to disease states in man. Although the findings have direct bearing for disease diagnostics and for research on disease etiology, more work is necessary to translate this into therapies that alleviate the burden of these hereditary disorders and disease susceptibilities in man.
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Affiliation(s)
- Wiljan J A J Hendriks
- Department of Cell Biology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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Association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer: evidence from a meta-analysis. Tumour Biol 2013; 34:2147-52. [PMID: 23636796 DOI: 10.1007/s13277-013-0747-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 03/11/2013] [Indexed: 01/25/2023] Open
Abstract
UNLABELLED Previous studies published to evaluate the association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer provided inconclusive outcomes. To derive a more precise estimation on this association, a meta-analysis of published case-control studies was performed. Eligible studies up to November 13, 2012 were identified from PubMed, Wanfang Medicine database, and Web of Science. Nine studies with a total of 2,086 cases and 2,701 controls were finally included into this meta-analysis. Overall, there was an obvious association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer (for AA versus GG: odds ratio (OR) = 1.38; 95 % confidence interval (CI) 1.00-1.91, P = 0.05; for AA versus GA/GG OR = 1.28; 95 %CI 1.07-1.53, P = 0.006). After excluding studies with low quality, there was no between-study heterogeneity, and there was still an obvious association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer (for AA versus GG: OR = 1.25; 95 %CI 1.02-1.52, P = 0.03; for AA versus GA/GG OR = 1.27; 95 %CI 1.05-1.53, P = 0.01). Subgroup analyses by ethnicity showed that the association above was still obvious in Asians, but the association was still unclear in Caucasians owing to the limited sample. In summary, this meta-analysis suggests that the FAS-1377 G/A polymorphism is associated with susceptibility to gastric cancer, especially in Asians. More studies from Caucasians are needed to provide further evidence for the possible association in Caucasians.
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Xiong Q, Xu L, Li Q, Li HM, Lou T, Wang AJ, Liu P, Lv NH. Expression profile of circulating microRNAs in patients with irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2013; 21:392-396. [DOI: 10.11569/wcjd.v21.i5.392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the differential expression of circulating microRNAs (miRNAs) between diarrhea-predominant irritable bowel syndrome (D-IBS)/constipation-predominant irritable bowel syndrome (C-IBS) and normal controls to profile abnormally expressed circulating miRNAs in IBS patients.
METHODS: Patients were diagnosed with D-IBS or C-IBS based on the Rome III criteria. MiRNA microarray was performed to detect mixed serum samples of either three patients with D-IBS, three patients with C-IBS, or three normal controls. After miRNA profiling, clustering analysis was conducted.
RESULTS: Compared to normal controls, there were two miRNAs down-regulated and two miRNAs up-regulated in the D-IBS group, and four miRNAs down-regulated and 59 miRNAs up-regulated in the C-IBS group. There was only one miRNA that was expressed differentially in D-IBS patients and 60 miRNAs in C-IBS patients. MiR-23b* was down-regulated and HCMV-miR-US5-2 and hsv2-miR-H11 up-regulated in both types of IBS. Compared to D-IBS patients, one miRNA was down-regulated and 26 miRNAs up-regulated in C-IBS patients.
CONCLUSION: Abnormal expression profile of circulating miRNAs in IBS patients may provide new biomarkers for diagnosis of this disease.
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