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Updated: Jul 11, 2025

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Published on: January 7, 2019

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Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis

Sophie Klemm1, Katja Evert1, Kirsten Utpatel1

  • 1Institute of Pathology, University of Regensburg, Regensburg, Germany.

BMC Cancer
|November 10, 2023
PubMed
Abstract

Insights

Neuroblastoma RAS viral oncogene homolog (NRAS) mutations can initiate liver cancer in mice. Overexpressed Dual Specificity Phosphatases 4 and 6 (DUSP4/6) and CD133 may represent therapeutic targets for hepatocellular carcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mitogen-activated protein kinase (MAPK) pathway dysregulation is frequent in hepatocellular carcinoma (HCC).
  • Neuroblastoma RAS viral oncogene homolog (NRAS) mutations are found in a subset of HCC but were not previously considered sufficient drivers of liver cancer.
  • This study investigates NRAS-driven liver carcinogenesis and identifies potential therapeutic targets.

Purpose of the Study:

  • To characterize the process of NRAS-dependent hepatocarcinogenesis.
  • To identify molecular vulnerabilities and potential therapeutic targets in NRAS-driven HCC.

Main Methods:

  • NRAS V12 plasmid was introduced into mouse livers via hydrodynamic tail vein injection (HTVI).
  • Tumor and preneoplastic tissues were analyzed using NanoString® gene expression, Western Blot, and Immunohistochemistry (IHC).
  • In vitro studies using HCC cell lines confirmed gene expression changes.

Main Results:

  • NRAS V12 expression induced preneoplastic and neoplastic lesions resembling HCC in mouse livers.
  • Upregulation of the RAS/RAF/MEK/ERK signaling pathway was observed.
  • Overexpression of cancer stem cell marker CD133 and Dual Specificity Phosphatases 4 and 6 (DUSP4/6) was detected in lesions.
  • In vitro, NRAS V12 increased DUSP4/6 expression, which paradoxically decreased phosphorylated ERK (pERK) and, when silenced, increased HCC cell proliferation.

Conclusions:

  • The G12V NRAS mutant is sufficient to drive hepatocarcinogenesis in mice, challenging previous assumptions.
  • MAPK pathway activation correlated with increased DUSP4, DUSP6, and CD133 expression.
  • DUSP4 and DUSP6 may act as negative regulators of MAPK signaling, presenting potential therapeutic targets for HCC.
Keywords:
CD133CholangiocarcinomaDUSP4Hepatocellular carcinomaMAPK pathwayNRAS

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