1. Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells
- Author
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Xiaolin Luo, Carolyn Hernandez, Shuangwei Li, Kaisa L. Hanley, Rohit Loomba, Nazilla Alderson, Helen He Zhu, Jia Fan, Gen-Sheng Feng, Nissi Varki, Rui Liao, Xufu Wei, Catherine Chu, Shuang-Jian Qiu, and Kirsten N. Malo
- Subjects
0301 basic medicine ,PTEN ,Carcinogenesis ,Medical Physiology ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Proto-Oncogene Mas ,Oral and gastrointestinal ,Hepatitis ,law.invention ,Mice ,Non-alcoholic Fatty Liver Disease ,law ,2.1 Biological and endogenous factors ,Aetiology ,Cancer ,Mice, Knockout ,Liver Disease ,Liver Neoplasms ,Gene Expression Regulation, Neoplastic ,Haematopoiesis ,Liver ,Neoplastic Stem Cells ,liver tumorigenesis ,Stem Cell Research - Nonembryonic - Non-Human ,non-alcoholic steatohepatitis ,medicine.symptom ,Liver cancer ,Signal Transduction ,Liver Cancer ,Carcinoma, Hepatocellular ,Liver tumor ,tumor suppressor ,Knockout ,Chronic Liver Disease and Cirrhosis ,Inflammation ,Biology ,tumor-initiating cells ,Non-Receptor Type 11 ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Rare Diseases ,medicine ,Animals ,Humans ,Neoplastic ,Animal ,Carcinoma ,JNK Mitogen-Activated Protein Kinases ,PTEN Phosphohydrolase ,Hepatocellular ,Stem Cell Research ,medicine.disease ,PTPN11 ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Disease Models ,Immunology ,Cancer research ,biology.protein ,Suppressor ,Shp2 ,Protein Tyrosine Phosphatase ,Biochemistry and Cell Biology ,Steatohepatitis ,Digestive Diseases - Abstract
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.
- Published
- 2016