Notch–Sox9 Axis Mediates Hepatocyte Dedifferentiation in KrasG12V-Induced Zebrafish Hepatocellular Carcinoma

Abstract

Liver cancer is one of the most prevalent cancers in humans. Hepatocytes normally undergo dedifferentiation after the onset of hepatocellular carcinoma, which in turn facilitates the progression of cancer. Although the process of hepatocellular carcinoma dedifferentiation is of significant research and clinical value, the cellular and molecular mechanisms underlying it are still not fully characterized. We constructed a zebrafish liver cancer model based on overexpression of the oncogene krasG12V to investigate the hepatocyte dedifferentiation in hepatocellular carcinoma. We found that, after hepatocarcinogenesis, hepatocytes dedifferentiated and the Notch signaling pathway was upregulated in this progress. Furthermore, we found that inhibition of the Notch signaling pathway or deficiency of sox9b both prevented hepatocyte dedifferentiation following hepatocellular carcinoma induction, reducing cancer metastasis and improving survival. In conclusion, we found that hepatocytes undergo dedifferentiation after hepatocarcinogenesis, a process that requires Notch signaling and likewise the activation of Sox9.