Activation of signal transduction pathways during hepatic oncogenesis

作者：Chung Waihong; Kim Miran; de la Monte Suzanne; Longato Lisa; Carlson Rolf; Slagle Betty L; Dong Xiaoqun; Wands Jack R^*

来源：Cancer Letters, 2016, 370(1): 1-9.

DOI：10.1016/j.canlet.2015.09.016

• Hepatocellular carcinoma
• Transgenic mice
• Growth factor signaling pathways

Background and aims: Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) is essential to identify therapeutic targets. A hepatitis B virus (HBV) related double transgenic murine model was developed.
Methods: Liver specific expression of HBV X protein (HBx) and insulin receptor substrate 1 (IRS1) was achieved and transgenic mice were followed from birth to age 21 months. Liver and tumor tissue were assessed for histologic changes as well as activation of signal transduction pathways by qRT-PCR and multiplex ELM protein assays.
Results: Overexpression of HBx and IRS1 stimulates liver cell proliferation in the double transgenic mice. Only the male mice developed HCC starting at age 15-18 months. The IN/IGF1/IRS1/MAPK/ERK and IN/IGF1/IRS1/PI3K/AKT/GSK3 beta cascades were activated early (6-9 months) in the liver followed by WNT/beta-catenin and Notch signaling. Aspartate beta-hydroxylase (ASPH) was found to link these upstream growth factor signaling pathways to downstream Notch activation in tumor tissues.
Conclusions: Sustained overexpression of HBx and IRS1 led to constitutive activation of a tripartite growth factor signal transduction cascade in the liver and was necessary and sufficient to promote HCC development and progression.

• 出版日期2016