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Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss

Shelli M Morris1, Ji Yeon Baek, Amanda Koszarek

  • 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.

Hepatology (Baltimore, Md.)
|September 8, 2011
PubMed
Abstract

Insights

Transforming growth factor-beta (TGF-β) signaling paradoxically promotes liver tumor formation when p53 is inactivated. Loss of TGF-β receptor type II (Tgfbr2) with p53 loss decreased hepatocellular carcinoma (HCC) incidence in mice.

Area of Science:

  • Hepatocellular carcinoma (HCC) research
  • Molecular oncology
  • Cancer genetics

Background:

  • Hepatocellular carcinoma (HCC) arises from genetic alterations in hepatocytes.
  • TP53 inactivation and TGF-β signaling inhibition are common in liver cancer.
  • The interplay between p53 and TGF-β in HCC development requires further investigation.

Purpose of the Study:

  • To investigate whether TGF-β receptor type II (Tgfbr2) inactivation cooperates with Trp53 loss in driving HCC formation.
  • To elucidate the role of TGF-β signaling in liver tumor development under conditions of p53 deficiency.

Main Methods:

  • Generation of genetically engineered mouse models with liver-specific deletion of Trp53 and/or Tgfbr2 using Albumin-cre and floxed alleles.
  • Analysis of tumor incidence, latency, and histopathology in generated mouse cohorts.
  • Assessment of molecular markers including alpha-fetoprotein, TGF-β1, phosphorylated Smad3, ERK1/2, Pai1, and Ctgf expression.

Main Results:

  • Trp53 deletion alone (Trp53(KO)) induced liver tumors in 41% of mice by 10 months.
  • Tgfbr2 deletion alone (Tgfbr2(KO)) did not induce liver tumors.
  • Combined deletion (Trp53(KO);Tgfbr2(KO)) reduced tumor incidence to 17% and delayed onset.
  • Both genotypes developed HCC and cholangiocarcinomas, suggesting a common stem cell origin.
  • Trp53(KO) tumors showed increased alpha-fetoprotein, TGF-β1, p-Smad3, p-ERK1/2, Pai1, and Ctgf compared to Trp53(KO);Tgfbr2(KO) tumors.

Conclusions:

  • TGF-β signaling paradoxically promotes liver tumor formation in the context of p53 inactivation.
  • Loss of p53 may influence liver tumor development via a common liver stem cell population, independent of TGF-β signaling.
  • TGF-β signaling contributes to the progression of p53-deficient liver tumors through specific molecular pathways.

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