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DGC-specific RHOA mutations maintained cancer cell survival and promoted cell migration via ROCK inactivation

Takashi Nishizawa1, Kiyotaka Nakano1, Aya Harada1

  • 1Department for Research, Forerunner Pharma Research Co., Ltd., Tokyo, Japan.

Oncotarget
|May 26, 2018
PubMed

Insights

Mutations in RHOA (Ras homolog family member A) drive diffuse gastric cancer by inhibiting the ROCK pathway, promoting cell survival and migration. This pathway inactivation is a key step in cancer development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • RHOA missense mutations are driver events in diffuse gastric cancer (DGC).
  • The precise mechanisms by which RHOA mutations contribute to DGC pathogenesis remain incompletely understood.
  • Understanding these mechanisms is crucial for identifying therapeutic targets.

Purpose of the Study:

  • To investigate how specific RHOA mutations impact cancer cell survival and motility.
  • To elucidate the role of the ROCK pathway in RHOA-mutated DGC.
  • To compare the effects of RHOA mutations with CLDN18-ARHGAP (CLG) fusions.

Main Methods:

  • Analysis of RHOA missense mutations (G17, Y42, L57) in cancer cell lines.
  • Assessment of MLC2 phosphorylation and actin stress fiber formation.
  • Cell survival and migration assays.
  • Functional studies of CLDN18-ARHGAP (CLG) fusions and site-directed mutagenesis.

Main Results:

  • Specific RHOA mutations (G17, Y42, L57) promote cancer cell survival.
  • These mutations act in a dominant-negative manner, suppressing the ROCK pathway by inhibiting MLC2 phosphorylation and actin stress fiber formation.
  • RHOA mutations enhance cancer cell migration through ROCK pathway inactivation.
  • CLDN18-ARHGAP (CLG) fusions, mutually exclusive to RHOA mutations, also promote cell survival and migration, maintaining RHOA in an inactive state via the GAP domain.

Conclusions:

  • ROCK pathway inactivation is a critical mechanism in diffuse gastric cancer development.
  • RHOA mutations and CLG fusions converge on ROCK pathway inactivation.
  • Targeting ROCK activation presents a potential therapeutic strategy for DGC.
Keywords:
ARHGAPRHOAROCKdiffuse gastric cancermutation

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