title: Methylation-mediated repression of potential tumor suppressor miR-203a and miR-203b contributes to esophageal squamous cell carcinoma development.
abstract: MiRNAs regulate gene expression and play pivotal roles in biological processes. MiRNAs can be inactivated by epigenetic mechanisms, such as DNA hypermethylation of CpG sites within CpG islands. Here, we investigated the role and methylation status of miR-203a and miR-203b in esophageal cancer cell lines and primary esophageal squamous cell carcinoma (ESCC) tumors and further elucidate the role of both miRNAs in the prognosis of ESCC. The present study revealed a strong downregulation of miR-203a and miR-203b in esophageal cancer cell lines and primary ESCC samples. Treatment of esophageal cancer cells with demethylating agent 5-Aza-dC led to increased miR-203a and miR-203b expression, confirming the epigenetic regulation of both miRNAs. The inhibition of proliferation and invasiveness in esophageal cancer cells after treated with 5-Aza-dC or transfected with miR-203a or miR-203b mimics, suggesting the tumor suppressor role of both miRNAs in esophageal cancer. Furthermore, the critical CpG sites of miR-203a and miR-203b were found to be located in proximal promoter region, and the proximal promoter hypermethylation of both miRNAs was found to influence transcriptional activity. Downregulation and hypermethylation of miR-203a and miR-203b were associated with TNM stage, pathological differentiation, and lymph node metastasis. ESCC patients in stages III and IV, with reduced expression of miR-203a or hypermethylation of miR-203a or miR-203b, demonstrated poor patient survival. In summary, our results suggest that miR-203a and miR-203b may function as tumor-suppressive miRNAs that are inactivated through proximal promoter hypermethylation and miR-203a expression and methylation may be useful prognostic marker in ESCC patients.
authors.affiliation: Department of Internal Medicine-Oncology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liang
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
authors.forename: Supeng
authors.initials: S
authors.lastname: Shen
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Kuang
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China. guowei7303@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D014408:Biomarkers, Tumor; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D001374:Azacitidine
keywords: Esophageal squamous cell carcinoma; Expression; Methylation; miR-203a; miR-203b