RRC ID 67189
Author Wang J, Dong M, Xu Z, Song X, Zhang S, Qiao Y, Che L, Gordan J, Hu K, Liu Y, Calvisi DF, Chen X.
Title Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice.
Journal Oncogene
Abstract 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 and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes. Wild-type, Notch1 flox/flox , and Notch2 flox/flox mice were used to investigate the role of canonical Notch signaling and Notch receptors in AKT/Yap-driven ICC formation. Human ICC and HCC cell lines were transfected with siRNA against Notch2 to determine whether Notch2 regulates biliary marker expression in liver tumor cells. We found that AKT/Yap-induced ICC formation is hepatocyte derived and this process is strictly dependent on the canonical Notch signaling pathway in vivo. Deletion of Notch2 in AKT/Yap-induced tumors switched the phenotype from ICC to hepatocellular adenoma-like lesions, while inactivation of Notch1 in hepatocytes did not result in significant histomorphological changes. Finally, in vitro studies revealed that Notch2 silencing in ICC and HCC cell lines down-regulates the expression of Sox9 and EpCAM biliary markers. Notch2 is the major determinant of hepatocyte-derived ICC formation in mice.
Volume 37(24)
Pages 3229-3242
Published 2018-6-1
DOI 10.1038/s41388-018-0188-1
PII 10.1038/s41388-018-0188-1
PMID 29545603
PMC PMC6002343
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism Animals Bile Duct Neoplasms / metabolism Bile Duct Neoplasms / pathology* Bile Ducts, Intrahepatic / pathology Carcinoma, Hepatocellular / metabolism Carcinoma, Hepatocellular / pathology* Cell Cycle Proteins Cell Line, Tumor Cholangiocarcinoma / metabolism Cholangiocarcinoma / pathology* Female Hepatocytes / metabolism Hepatocytes / pathology Liver Neoplasms / metabolism Liver Neoplasms / pathology* Male Mice, Transgenic Phosphoproteins / genetics Phosphoproteins / metabolism Proto-Oncogene Proteins c-akt / metabolism Receptor, Notch1 / genetics Receptor, Notch1 / metabolism Receptor, Notch2 / genetics Receptor, Notch2 / metabolism* Signal Transduction / physiology YAP-Signaling Proteins
IF 7.971
Human and Animal Cells RBE(RCB1292)