Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis

Cancer Cell. 2011 May 17;19(5):629-39. doi: 10.1016/j.ccr.2011.03.023.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma, Liver Cell / enzymology*
  • Adenoma, Liver Cell / genetics
  • Adenoma, Liver Cell / pathology
  • Animals
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / enzymology*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control
  • Cytokines / blood
  • Cytokines / genetics
  • Diethylnitrosamine
  • Gene Expression Regulation
  • Hepatitis / enzymology
  • Hepatitis / genetics
  • Hepatitis / pathology
  • Humans
  • Hyperplasia
  • Inflammation Mediators / blood
  • Interleukin-6 / administration & dosage
  • Lipopolysaccharides / administration & dosage
  • Liver / drug effects
  • Liver / enzymology*
  • Liver / pathology
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control
  • Liver Regeneration
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / analysis*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • STAT3 Transcription Factor / deficiency
  • STAT3 Transcription Factor / genetics
  • Signal Transduction
  • Time Factors
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cytokines
  • Inflammation Mediators
  • Interleukin-6
  • Lipopolysaccharides
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tumor Suppressor Proteins
  • Diethylnitrosamine
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse