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RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway

Xiaoming Dong1, Wanqin Liao1, Li Zhang1

  • 1School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.

Cancer Letters
|June 11, 2017
PubMed

Insights

R-spondin 2 (RSPO2) inhibits colorectal cancer (CRC) metastasis by regulating noncanonical Wnt signaling. This finding offers a potential therapeutic strategy for aggressive CRC tumors.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Signaling

Background:

  • R-spondins are key regulators of Wnt/β-catenin signaling.
  • The role of R-spondins in noncanonical Wnt signaling is not well understood.
  • Colorectal cancer (CRC) metastasis is a major clinical challenge.

Purpose of the Study:

  • To investigate the role of R-spondin 2 (RSPO2) in colorectal cancer (CRC) metastasis.
  • To elucidate the underlying molecular mechanisms of RSPO2's function in CRC.
  • To explore RSPO2 as a potential therapeutic target for aggressive CRC.

Main Methods:

  • Analysis of RSPO2 expression in CRC patient samples.
  • In vitro assays to assess CRC cell migration and invasion.
  • Investigation of RSPO2 interactions with Fzd7 and Wnt5a.
  • Studies on ZNRF3-mediated ubiquitination and downstream signaling pathways (PKC/ERK).

Main Results:

  • RSPO2 suppresses CRC cell migration, invasion, and metastasis.
  • Reduced RSPO2 expression correlates with tumor metastasis and poor patient survival.
  • RSPO2's metastasis-suppressive activity is mediated by Fzd7-dependent noncanonical Wnt signaling, not Wnt/β-catenin.
  • RSPO2 promotes Fzd7 degradation via ZNRF3, inhibiting PKC/ERK signaling.
  • RSPO2 antagonizes Wnt5a-induced CRC cell migration by blocking Wnt5a-Fzd7 interaction.

Conclusions:

  • RSPO2 acts as a metastasis suppressor in CRC through a novel noncanonical Wnt signaling mechanism.
  • The RSPO2/Wnt5a axis regulates cellular migration and invasion.
  • Secreted RSPO2 protein represents a promising therapeutic candidate for Wnt5a/Fzd7-driven aggressive CRC.
Keywords:
Colorectal cancerFzd7MetastasisRSPO2Wnt5a

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