| RRC ID |
67189
|
| 著者 |
Wang J, Dong M, Xu Z, Song X, Zhang S, Qiao Y, Che L, Gordan J, Hu K, Liu Y, Calvisi DF, Chen X.
|
| タイトル |
Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice.
|
| ジャーナル |
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.
|
| 巻・号 |
37(24)
|
| ページ |
3229-3242
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
RBE(RCB1292) |
