MicroRNA‐191 acts as a tumor promoter by modulating the TET1–p53 pathway in intrahepatic cholangiocarcinoma

Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miRNA-191, play an important role in tumorigenesis, but expression and biological functions of miRNA-191 in ICC remain to be established. This study aimed to investigate the functions and underlying mechanisms of miRNA-191 in ICC. ICC miRNA profiles were generated in 5 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 reverse transcription PCR (qRT-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 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 let the methylated CpG-rich regions at the p53 gene transcription start site (TSS) stay methylated, leading to the reduced p53 expression level, which compromises the p53 anti-cancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival: HR, 3.742; 95%CI, 2.080-6.733; p<0.001; disease-free survival: HR, 2.331; 95%CI, 1.346-4.037; p=0.003). Conclusion: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. This article is protected by copyright. All rights reserved.