title: Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells.
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.
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing 40016, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liao
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kaisa L
authors.initials: KL
authors.lastname: Hanley
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Helen He
authors.initials: HH
authors.lastname: Zhu
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kirsten N
authors.initials: KN
authors.lastname: Malo
authors.affiliation: Department of Medicine, NAFLD Research Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hernandez
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing 40016, China.
authors.forename: Xufu
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Nazilla
authors.initials: N
authors.lastname: Alderson
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chu
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Shuangwei
authors.initials: S
authors.lastname: Li
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Medicine, NAFLD Research Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Loomba
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Shuang-Jian
authors.initials: SJ
authors.lastname: Qiu
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: gfeng@ucsd.edu.
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D048031:JNK Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PTEN; Shp2; liver tumorigenesis; non-alcoholic steatohepatitis; tumor suppressor; tumor-initiating cells