title: MicroRNA-191 acts as a tumor promoter by modulating the TET1-p53 pathway in intrahepatic cholangiocarcinoma.
abstract: Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003).
  
  
  
  Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).
authors.affiliation: Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Zun-Qiang
authors.initials: ZQ
authors.lastname: Zhou
authors.affiliation: Department of Radiation Oncology, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Zhang-Ru
authors.initials: ZR
authors.lastname: Yang
authors.affiliation: Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Da-Nian
authors.initials: DN
authors.lastname: Tong
authors.affiliation: Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Guan
authors.affiliation: Department of Surgery, Shanghai Jiao Tong University, Affiliated First People's Hospital, Shanghai, China.
authors.forename: Bao-Jie
authors.initials: BJ
authors.lastname: Shi
authors.affiliation: School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai, China.|Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Nie
authors.affiliation: School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xian-Ting
authors.initials: XT
authors.lastname: Ding
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Guang-Wen
authors.initials: GW
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Zheng-Yun
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D001707:Biopsy, Needle; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: C546177:MIRN191 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human