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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma

Wei-Tien Tai1, Pei-Yi Chu2, Chung-Wai Shiau3

  • 1Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 25, 2014
PubMed
Abstract

Insights

Regorafenib inhibits hepatocellular carcinoma (HCC) by directly activating SHP-1 phosphatase, which suppresses STAT3 signaling. STAT3 may serve as a prognostic marker and therapeutic target in HCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide.
  • Identifying effective therapeutic strategies and molecular targets for HCC is crucial.
  • STAT3 signaling is frequently dysregulated in HCC and associated with poor prognosis.

Purpose of the Study:

  • To elucidate the molecular mechanism of regorafenib in hepatocellular carcinoma (HCC).
  • To identify druggable targets for HCC treatment.
  • To investigate the role of STAT3 signaling in HCC progression and its modulation by regorafenib.

Main Methods:

  • In vitro studies using HCC cell lines (PLC5, HepG2, Hep3B, SK-Hep1, HA59T) to assess regorafenib effects.
  • Analysis of phosphatase activity in HCC cells and purified SHP-1 protein.
  • In vivo efficacy testing of regorafenib in PLC5-bearing mice.
  • Investigation of STAT3 signaling in 142 HCC patient tumor samples.

Main Results:

  • Regorafenib demonstrated dose-dependent inhibition of STAT3 signaling, surpassing sorafenib's potency.
  • Regorafenib directly enhanced SHP-1 phosphatase activity.
  • Mutations in SHP-1's N-SH2 domain partially abrogated regorafenib's effects on STAT3 and apoptosis.
  • Elevated STAT3 expression correlated with advanced HCC stages and poor differentiation.

Conclusions:

  • Regorafenib exerts anti-tumor effects by directly activating SHP-1, relieving its autoinhibition, and subsequently inhibiting p-STAT3 signaling.
  • STAT3 is a potential prognostic biomarker for HCC development.
  • STAT3 represents a druggable target for HCC-specific therapies utilizing regorafenib.

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