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

• Published in: Cell reports (Cambridge) 2016-12, Vol.17 (11), p.2979-2993
• Main Authors: Luo, Xiaolin, Liao, Rui, Hanley, Kaisa L., Zhu, Helen He, Malo, Kirsten N., Hernandez, Carolyn, Wei, Xufu, Varki, Nissi M., Alderson, Nazilla, Chu, Catherine, Li, Shuangwei, Fan, Jia, Loomba, Rohit, Qiu, Shuang-Jian, Feng, Gen-Sheng
• Format: Article
• Language: English
• Subjects: Animals; Carcinogenesis - genetics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; JNK Mitogen-Activated Protein Kinases - genetics; Liver - metabolism; Liver - pathology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; liver tumorigenesis; Mice, Knockout; Neoplastic Stem Cells - metabolism; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; non-alcoholic steatohepatitis; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; PTEN; PTEN Phosphohydrolase - genetics; Shp2; Signal Transduction; tumor suppressor; tumor-initiating cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.11.048

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. [Display omitted] •Shp2/Ptpn11 cooperates with Pten to maintain liver homeostasis and functions•Dual deletion of Shp2 and Pten induces NASH-driven hepatocarcinogenesis•Combined Shp2/Pten deficiencies promote genesis of liver tumor-initiating cells•Inhibiting c-Jun suppressed liver cancer without improving NASH 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.