UCP2 regulates cholangiocarcinoma cell plasticity via mitochondria-to-AMPK signals

Uncoupling protein 2 (UCP2) is upregulated in several human cancers which contributes to tumorigenesis. However, whether UCP2 expression is amplified in cholangiocarcinoma and whether UCP2 promotes cholangiocarcinoma progression are not known. Our results found that in human cholangiocarcinoma tissues, UCP2 was highly expressed in tumors and its levels were negatively associated with prognosis. Importantly, lymph node invasion of cholangiocarcinoma was associated with higher UCP2 expression. In cholangiocarcinoma cells, cell proliferation and migration were suppressed when UCP2 expression was inhibited via gene knockdown. In UCP2 knockdown cells, glycolysis was inhibited, the mesenchymal markers were downregulated whereas AMPK was activated. The increased mitochondrial ROS and AMP/ATP ratio might be responsible for this activation. When the UCP2 inhibitor genipin was applied, tumor cell migration and 3D growth were suppressed via enhancing the mesenchymal-epithelial transition of cholangiocarcinoma cells. Furthermore, cholangiocarcinoma cells became sensitive to cisplatin and gemcitabine treatments when genipin was applied. In conclusion, our results demonstrate that the amplified expression of UCP2 contributes to the progression of cholangiocarcinoma through a glycolysis-mediated mechanism.