Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Xiaolin Luo, Rui Liao, Kaisa L. Hanley, Helen He Zhu, Kirsten N. Malo, Carolyn Hernandez, Xufu Wei, Nissi M. Varki, Nazilla Alderson, Catherine Chu, Shuangwei Li, Jia Fan, Rohit Loomba, Shuang-Jian Qiu, Gen-Sheng Feng
The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

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Teaser

Shp2 antagonizes Pten in leukemogenesis. Luo et al. now find that Shp2 and Pten synergistically suppress carcinogenesis in the liver. Ablating Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of tumor-initiating cells. These findings suggest a mechanism underlying disease as well as a therapeutic strategy.


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