MiR-206 suppresses the deterioration of intrahepatic cholangiocarcinoma and promotes sensitivity to chemotherapy by inhibiting interactions with stromal CAFs

作者：Renjie Yang, Dong Wang, Shen Han, Yichao Gu, Zhi Li, Lei Hong Deng, Aihong Yin, Yun Gao, Xiangcheng Li, Yue Yu, Xuehao Wang · 发表于：International Journal of Biological Sciences · 年份：2021 · DOI：10.7150/ijbs.62602 · 被引用次数：21 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、MicroRNA in disease regulation、Circular RNAs in diseases

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant subtype of cholangiocarcinoma (CCA) with poor prognosis. In iCCA, the interplay between the stroma and tumor cells results in resistance to adjuvant chemotherapy. Increasing evidence indicates that miR-206 participates in tumor progression, but its role in iCCA is still unclear. The aim of this study was to identify dysregulated miR-206 expression in iCCA and to further explore the underlying mechanism. Methods: MiR-206 expression was proven to be downregulated in iCCA tissues by qPCR, and its correlation with clinical characteristics and prognosis was investigated. iCCA-derived cancer-associated fibroblast cells (CAFs) and normal fibroblast cells (NFs) were isolated and identified. MiR-206 was knocked in or down in CAFs and CCA cells, respectively, to explore the role of miR-206, and coculture of these treated CCAs and CAFs was conducted to explore the effects of miR-206 on their mutual promoting effects. Exosomes carrying miR-206 and an orthotopic mouse model were used to determine the inhibitory effects of miR-206 on iCCA deterioration in vivo. Results: We confirmed that miR-206 is a suppressor of iCCA. Overexpressing miR-206 in CCA cells inhibited cell proliferation, migration and invasion. When cocultured with CCA cells, NFs downregulated miR-206 expression, and NFs were susceptible to transforming into CAFs. Moreover, CAFs promoted CCA cell malignant behaviors and gemcitabine resistance. Overexpres...