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RhoA G17E/Vav1 Signaling Induces Cancer Invasion via Matrix Metalloproteinase-9 in Gastric Cancer

Satoshi Nakamura1, Masato Kitazawa1, Yusuke Miyagawa1

  • 1Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.

Technology in Cancer Research & Treatment
|January 9, 2023
PubMed
Abstract

Insights

Mutant RhoA (G17E) interacts with Vav1, promoting gastric cancer cell invasion and peritoneal dissemination. This RhoA G17E/Vav1 signaling pathway presents a potential therapeutic target for diffuse gastric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • RAS homolog family member A (RhoA) and Vav1 regulate the actin cytoskeleton, influencing cell shape, attachment, and motility.
  • While their interaction is implicated in lymphoma, their role in epithelial malignancies like gastric cancer remains unclear.
  • This study investigates the role of mutant RhoA in gastric cancer signaling.

Purpose of the Study:

  • To investigate the role of mutant RhoA, specifically RhoA G17E, in gastric cancer.
  • To explore the interaction between RhoA G17E and Vav1 in malignant signaling.
  • To evaluate RhoA G17E/Vav1 as a potential therapeutic target for diffuse gastric cancer.

Main Methods:

  • Gastric cancer cell line MKN74 was stably transduced with wild-type and mutant RhoA (R5W, G17E, Y42C).
  • In vitro assays assessed morphology, proliferation, migration, and invasion.
  • Peritoneal xenograft models were used to evaluate in vivo effects.

Main Results:

  • RhoA mutations G17E and Y42C induced morphological changes in MKN74 cells.
  • RhoA G17E significantly increased Vav1 expression and promoted cell migration and invasion.
  • Vav1 knockdown suppressed RhoA G17E-enhanced invasion, indicating a crucial role for Vav1.
  • RhoA G17E and Vav1 were found to specifically bind and function via matrix metalloproteinase-9.
  • In vivo, RhoA G17E promoted peritoneal dissemination, while Vav1 knockdown inhibited it.

Conclusions:

  • RhoA G17E interacts with Vav1, driving gastric cancer cell invasion through matrix metalloproteinase-9.
  • The RhoA G17E/Vav1 signaling pathway is a promising therapeutic target for diffuse gastric cancer.
Keywords:
RhoAVav1diffuse gastric cancermalignant phenotypematrix metalloproteinase −9

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