Molecular Pathogenesis and Regulation of the -Family: Involvement of and in Intra-Hepatic Cholangiocarcinoma.

The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the -family members (, and ) are key tumor-suppressive microRNAs that control many oncogenic genes/pathways in several cancers. In this study, we searched for therapeutic targets for ICC using the -family as a starting point. Our functional studies of cell proliferation, migration and invasion confirmed that the -family act as tumor-suppressors in ICC cells. Moreover, in silico analysis revealed that "focal adhesion", "ECM-receptor", "endocytosis", "PI3K-Akt signaling" and "Hippo signaling" were involved in oncogenic pathways in ICC cells. Our analysis focused on the genes for integrin-α6 () and integrin-β1 (), which are involved in multiple pathways. Overexpression of and enhanced malignant transformation of ICC cells. Both and were directly regulated by the -family in ICC cells. Interestingly, expression of / was positively controlled by the transcription factor SP1, and was negatively controlled by the -family. Downregulation of the -family enhanced -mediated / expression in ICC cells. MicroRNA-based exploration is an attractive strategy for identifying therapeutic targets for ICC.