Novel tumor suppressor role of miRNA-876 in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a rare, highly invasive malignancy, and its incidence is increasing globally. MicroRNAs (miRNAs) mediate a wide array of cellular and biological processes and are dysregulated in various tumors. The functional and biological roles of miRNAs in CCA have not been fully elucidated. In this study, we show that miR-876 expression levels and copy number are significantly attenuated in the TCGA cohort of CCA tissue samples. TCGA expression data was consistent with the observed substantial decrease in miR-876 expression in patient samples and CCA cell lines. In-silico algorithm databases revealed BCL-XL as a potential target of miR-876. We observed miR-876 expression to be downregulated, whereas, BCL-XL upregulated in CCA cell lines. BCL-XL was identified as a direct functional target of miR-876 in CCA. miR-876-mediated reduction of BCL-XL regulated cell survival, induced apoptosis and caspase 3/7 expression in CCA. BCL-XL overexpression reversed the miR-876 mediated effect on CCA cell growth and apoptosis. Stable overexpression of miR-876 produced potent tumor suppressor activity and in vivo tumor cell growth reduction. Overexpression of miR-876 in a patient-derived xenograft (PDX) cell line significantly suppressed BCL-XL expression and spheroid formation with a concomitant induction of caspase 3/7 activity and apoptosis. This study demonstrates a novel tumor suppressor role for miR-876 in CCA, identifies BCL-XL as an actionable target, and suggests a potential therapeutic role for miR-876 in CCA.