Expression of Wnt-5a Is Correlated with Aggressiveness of Gastric Cancer by Stimulating Cell Migration and Invasion

Abstract

Wnt-5a is a representative ligand that activates a B-cateninindependent pathway in the Wnt signaling. Although abnormal activation of B-catenin-dependent pathway is often observed in human cancer, the relationship between Bcatenin-independent pathway and tumorigenesis is not clear. We sought to clarify how Wnt-5a is involved in aggressiveness of gastric cancer. Abnormal expression of Wnt-5a was observed in 71 of 237 gastric cancer cases by means of immunohistochemistry. The positivity of Wnt-5a expression was correlated with advanced stages and poor prognosis of gastric cancer. Wnt-5a had the abilities to stimulate cell migration and invasion in gastric cancer cells. Wnt-5a activated focal adhesion kinase and small GTP-binding protein Rac, both of which are known to play a role in cell migration. Cell migration, membrane ruffling, and turnover of paxillin were suppressed in Wnt-5a knockdown cells. Furthermore, anti-Wnt-5a antibody suppressed gastric cancer cell migration. These results suggest that Wnt-5a stimulates cell migration by regulating focal adhesion complexes and that Wnt-5a is not only a prognostic factor but also a good therapeutic target for gastric cancer.

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

“…Among the current 98 cases, PCa abnormally expressing both Wnt5a and b-catenin was observed in only 5 cases. This is similar to the situation in cases of gastric cancer (Kurayoshi et al, 2006). At present the reason why the expression of Wnt5a and b-catenin is mutually exclusive is not known.…”

“…As shown in other cells (Kurayoshi et al, 2006(Kurayoshi et al, , 2007, Wnt5a activated Rac, which stimulates cell migration, in DU145 cells. However, the Wnt5a-Rac pathway was not involved in the expression of MMP-1.…”

“…Preceding immunohistochemical studies showed that approximately 30% of 237 gastric cancer cases exhibit high expression levels of Wnt5a (Kurayoshi et al, 2006). Using the same antibody, we examined the expression of Wnt5a in PCa.…”

“…Although evidence has been accumulated that Wnt5a is expressed in various cancers (Weeraratna et al, 2002;Veeman et al, 2003;Huang et al, 2005;Kurayoshi et al, 2006;Pukrop et al, 2006;Kikuchi and Yamamoto, 2008;Yamamoto et al, 2009), how Wnt5a is upregulated in cancer cells has not been determined. It has been shown that Wnt5a is upregulated at the transcriptional level in PCa by hypomethylation in the 5 0 -untranslated region and that three CpG sites were consistently methylated in normal tissues but not in primary PCa (Wang et al, 2007).…”

“…Wnt5a is a representative of the Wnt proteins that activate the b-catenin-independent pathway, which includes multiple pathways, and Wnt5a activates distinct routes (Veeman et al, 2003;Kurayoshi et al, 2007;Kikuchi and Yamamoto, 2008). It has been shown that Wnt5a stimulates migration in some cancer cells and that its expression is correlated with the aggressiveness of melanoma, breast cancer, lung cancer and gastric cancer (Weeraratna et al, 2002;Veeman et al, 2003;Huang et al, 2005;Kurayoshi et al, 2006;Pukrop et al, 2006;Kikuchi and Yamamoto, 2008;Yamamoto et al, 2009), suggesting that Wnt5a has oncogenic properties. Other reports indicate that Wnt5a acts as a tumor suppressor based on the finding that Wnt5a has an ability to inhibit proliferation, migration and invasiveness in thyroid tumor and colorectal cancer cell lines (Dejmek et al, 2005;Kremenevskaja et al, 2005).…”