title: Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis.
abstract: The human gene Ptpn11, which encodes the tyrosine phosphatase Shp2, may act as a proto-oncogene because dominantly activating mutations have been detected in several types of leukemia. Herein we report a tumor-suppressor function of Shp2. Hepatocyte-specific deletion of Shp2 promotes inflammatory signaling through the Stat3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and development of tumors in aged mice. Furthermore, Shp2 ablation dramatically enhanced diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) development, which was abolished by concurrent deletion of Shp2 and Stat3 in hepatocytes. Decreased Shp2 expression was detected in a subfraction of human HCC specimens. Thus, in contrast to the leukemogenic effect of dominant-active mutants, Ptpn11/Shp2 has a tumor-suppressor function in liver.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA 92093-0864, USA.
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Bard-Chapeau
authors.forename: Shuangwei
authors.initials: S
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Zhang
authors.forename: Helen H
authors.initials: HH
authors.lastname: Zhu
authors.forename: Frederic
authors.initials: F
authors.lastname: Princen
authors.forename: Diane D
authors.initials: DD
authors.lastname: Fang
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
mesh_terms: D018248:Adenoma, Liver Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004052:Diethylnitrosamine; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000008:administration & dosage; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000032:analysis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D025521:Tumor Suppressor Proteins; D004052:Diethylnitrosamine; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse