Abstract
The purpose of this study was to investigate the clinicopathologic significance and potential role of miR-200b and miR-200c in the development and progression of gastric cancer. We examined miR-200b and miR-200c expression in 36 paired normal and stomach tumor specimens, as well as gastric cancer cell lines, by quantitative real-time PCR. In addition, miR-200b and miR-200c were detected by ISH using gastric cancer tissue microarrays, and the association between miR-200b and miR-200c levels and clinicopathologic factors and prognosis were analyzed. A luciferase assay was conducted for target evaluation. The functional effects of miR-200b and miR-200c on gastric cancer cells were validated by a cell proliferation assay and cell invasion and migration assays. miR-200b and miR-200c were downregulated in the gastric cancer specimens and cell lines tested. miR-200b and miR-200c levels were significantly correlated with the clinical stage, T stage, lymph node metastasis, and survival of patients. Ectopic expression of miR-200b and miR-200c impaired cell growth and invasion. In addition, when overexpressed, miR-200b and miR-200c commonly directly targeted DNMT3A, DNMT3B, and SP1 (a transactivator of the DNMT1 gene), which resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at the protein level. This effect, in turn, led to a decrease in global DNA methylation and reexpression of p16, RASS1A1, and E-cadherin via promoter DNA hypomethylation. Our findings suggest that miR-200b and miR-200c, as valuable markers of gastric cancer prognosis, may be a promising approach to human gastric cancer treatment.
Highlights
An increasing number of studies have showed that microRNAs can function as oncogenes or tumor suppressors and are often dysregulated in tumors [1, 2]
Our findings suggest that miR-200b and miR-200c, as valuable markers of gastric cancer prognosis, may be a promising approach to human gastric cancer treatment
We found that miR-200b/c were strongly downregulated in gastric cancer, and their expression levels were associated with lymph node metastasis and clinical stage, as well as overall survival and relapse-free survival of gastric cancer patients
Summary
An increasing number of studies have showed that microRNAs (miRNA) can function as oncogenes or tumor suppressors and are often dysregulated in tumors [1, 2]. In this regard, oncogenic miRNAs are frequently upregulated, whereas tumor suppressive miRNAs are frequently downregulated in tumors. The oncogenic miR-183/182/96 cluster of miRNAs is upregulated in a variety of tumors [3,4,5], Authors' Affiliations: 1Department of Breast Oncology,Sun Yat-Sen University Cancer Center; 2State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center; 3Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong; and 4Cancer Research Institute, University of South China, Hengyang, Hunan, China.
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