Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic

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Published on: October 27, 2020

Takashi Yamaguchi1, Koichi Matsuzaki, Ryosuke Inokuchi

  • 1Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan.

Hepatology Research : the Official Journal of the Japan Society of Hepatology
|March 6, 2013
PubMed
Abstract

Insights

Hepatitis C virus (HCV) clearance can reverse liver fibrosis and reduce hepatocellular carcinoma (HCC) risk by altering phospho-Smad signaling. However, established fibrotic changes may persist if cancer-driving signals are already active before viral eradication.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Oncology

Background:

  • Hepatitis C virus (HCV) infection is a major cause of liver fibrosis and hepatocellular carcinoma (HCC).
  • Transforming growth factor-beta (TGF-β) signaling, mediated by Smad proteins, plays a critical role in hepatic fibrogenesis and carcinogenesis.
  • Phosphorylation patterns of Smad2 and Smad3 (pSmad2/3) are crucial in regulating these processes.

Purpose of the Study:

  • To investigate the role of phospho-Smad signaling in HCV-induced liver fibro-carcinogenesis.
  • To elucidate how HCV clearance impacts phospho-Smad signaling and subsequent liver disease progression.

Main Methods:

  • Analyzed phospho-Smad2/3 (pSmad2/3) positivity in 100 patients with HCV-related chronic liver disease.
  • Examined paired liver biopsies from 32 patients before and after sustained virological response (SVR) to HCV.
  • Stratified patients into non-HCC and HCC groups based on HCC development post-SVR.

Main Results:

  • Advanced liver disease showed a shift from tumor-suppressive pSmad3C to pro-carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling.
  • HCV clearance (SVR) in the non-HCC group restored pSmad3C signaling, leading to fibrotic regression and reduced inflammation.
  • In the HCC group, persistent fibrosis despite SVR correlated with sustained pro-carcinogenic/fibrogenic pSmad signaling and low pSmad3C signaling.

Conclusions:

  • HCV clearance promotes anti-fibrotic and anti-carcinogenic effects by modulating Smad signaling pathways.
  • The transition from inflammation-dependent to inflammation-independent fibro-carcinogenic signaling can lead to HCC progression even after viral clearance in advanced fibrosis.
Keywords:
Smadhepatocarcinogenesisliver fibrosistransforming growth factor-β

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