Role for Daple in non-canonical Wnt signaling during gastric cancer invasion and metastasis.

Abstract

In gastric cancer, the non-canonical Wnt signaling pathway is activated by Wnt5a, which has a critical role in disease outcome. Previous studies have shown that Wnt5a mediates the expression of the extracellular matrix protein laminin γ2 through Rac and JNK activation to promote gastric cancer progression. However, the mechanism of this regulatory pathway has not been completely addressed. The scaffold protein Dvl is a major component of the Wnt signaling pathway. Here, we show that Dvl-associating protein with a high frequency of leucine residues (Daple) mediates Wnt5a-induced laminin γ2 expression. Immunohistochemical analysis showed marked expression of Daple in advanced clinical stages of gastric cancer, where it highly correlated with Wnt5a/b and laminin γ2 expression, the depth of wall invasion, and the frequency of lymph node metastasis. In cultured cancer cells, Daple depletion led to the suppression of Wnt5a-induced Rac and JNK activation, laminin γ2 expression, and cell migration and invasion. Accordingly, Daple depletion also suppressed liver metastasis in a mouse xenograft model of gastric cancer. These results suggest that the non-canonical Wnt signaling pathway contributes to gastric cancer progression at least in part via Daple, which provides a new therapeutic opportunity for the treatment of the disease.

• Authors: Hosne Ara, Maki Takagishi, Atsushi Enomoto, Masato Asai, Kaori Ushida, Naoya Asai, Yoshie Shimoyama, Kozo Kaibuchi, Yasuhiro Kodera, Masahide Takahashi
• Journal: Cancer science (Cancer Sci) Vol. 107 Issue 2 Pg. 133-9 (Feb 2016) ISSN: 1349-7006 [Electronic] England
• PMID: 26577606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• CCDC88C protein, human
• Intracellular Signaling Peptides and Proteins
• Microfilament Proteins

Topics

• Animals
• Blotting, Western
• Cell Movement
• Gene Knockdown Techniques
• Heterografts
• Humans
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mice
• Mice, Nude
• Microfilament Proteins (metabolism)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms (pathology)
• Wnt Signaling Pathway (physiology)