Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice

• DOI: 10.1038/s41388-018-0188-1
• Publication Date: 2018-03-14T11:06:54Z
• Authors: Jingxiao Wang; Mingjie Dong; Zhong Xu; Xinhua Song; Shanshan Zhang; Yu Qiao; Li Che; John Gordan; Kaiwen Hu; Yan Liu; Diego F. Calvisi; Xin Chen
• Keywords: Intrahepatic Cholangiocarcinoma; Hepatocellular adenoma; JAG1

Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious associated with poor clinical outcome. Studies have shown that subset human ICCs may originate from mature hepatocytes. However, mechanisms driving trans-differentiation hepatocytes into cholangiocytes remain poorly defined. We adopted lineage tracing techniques an established murine hepatocyte-derived model by hydrodynamic injection activated forms AKT (myr-AKT) Yap (YapS127A) proto-oncogenes. Wild-type, Notch1flox/flox, Notch2flox/flox mice were used to investigate role canonical Notch signaling receptors in AKT/Yap-driven formation. Human HCC cell lines transfected siRNA against Notch2 determine whether regulates biliary marker expression liver tumor cells. found AKT/Yap-induced formation hepatocyte derived this process strictly dependent on pathway vivo. Deletion tumors switched phenotype adenoma-like lesions, while inactivation Notch1 did not result significant histomorphological changes. Finally, vitro studies revealed silencing down-regulates Sox9 EpCAM markers. major determinant mice.