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Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression

Michiru Nishita1, Koki Kamizaki2, Kyoka Hoshi1

  • 1Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan.

The Journal of Biological Chemistry
|September 13, 2023
PubMed

Insights

Rho in filopodia (Rif) protein interacts with Ror1, activating Wnt5a signaling. This promotes polarized filopodia formation, crucial for lung adenocarcinoma cell growth, survival, and invasion.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Rho in filopodia (Rif) induces dorsal cell surface filopodia, but its precise function is largely unknown.
  • Wnt5a receptor Ror1 also induces dorsal filopodia and is implicated in cell signaling.

Purpose of the Study:

  • To elucidate the function of Rif in lung adenocarcinoma.
  • To investigate the interaction between Rif and Wnt5a-Ror1 signaling in cancer cell behavior.

Main Methods:

  • Immunohistochemical analysis of Ror1 and Rif coexpression in lung adenocarcinoma.
  • In vitro cell culture on Matrigel to observe cell polarity and filopodia formation.
  • Suppression of Ror1 or Rif expression to assess effects on cell proliferation, survival, invasion, and tumor growth in vivo.

Main Results:

  • Rif interacts with Ror1, a Wnt5a receptor, and both are coexpressed in lung adenocarcinoma.
  • Rif and Ror1 accumulate at the front surfaces of polarized lung adenocarcinoma cells with massive filopodia on Matrigel.
  • Suppression of Rif or Ror1 inhibited proliferation, survival, and invasion, reduced filopodia, and impaired polarity in vitro, while preventing tumor growth in vivo.
  • Rif activates Wnt5a-Ror1 signaling, leading to Dvl2 phosphorylation, further enhanced by Matrigel culture.

Conclusions:

  • Rif plays a novel role in mediating Wnt5a-Ror1-Dvl2 signaling.
  • This signaling pathway is essential for polarized filopodia formation on 3D matrices in lung adenocarcinoma.
  • Rif and Ror1 are critical for lung adenocarcinoma progression, highlighting them as potential therapeutic targets.
Keywords:
Rho GTPaseWnt signalingcell invasioncell polaritycell proliferationfilopodialung cancer

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