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

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. (Cancer Res 2006; 66(21): 10439-48)

[1]  A. Bosserhoff,et al.  Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer , 2006, Oncogene.

[2]  L. Trümper,et al.  Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Nusse,et al.  Purified Wnt5a Protein Activates or Inhibits β-Catenin–TCF Signaling Depending on Receptor Context , 2006, PLoS biology.

[4]  T. Asahara,et al.  Glycogen Synthase Kinase 3 and h-prune Regulate Cell Migration by Modulating Focal Adhesions , 2006, Molecular and Cellular Biology.

[5]  T. Andersson,et al.  Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. , 2005, Cancer research.

[6]  Hideki Yamamoto,et al.  SUMO-1 Modification of PIASy, an E3 Ligase, Is Necessary for PIASy-Dependent Activation of Tcf-4 , 2005, Molecular and Cellular Biology.

[7]  Hirofumi Nakayama,et al.  Molecular-pathological prognostic factors of gastric cancer: a review , 2005, Gastric Cancer.

[8]  G. Brabant,et al.  Wnt-5a has tumor suppressor activity in thyroid carcinoma , 2005, Oncogene.

[9]  Hideki Yamamoto,et al.  Wnt-3a and Dvl Induce Neurite Retraction by Activating Rho-Associated Kinase , 2004, Molecular and Cellular Biology.

[10]  Xi He,et al.  LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way , 2004, Development.

[11]  Mitsuru Sasako,et al.  Focus on gastric cancer. , 2004, Cancer cell.

[12]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[13]  A. Bradley,et al.  Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. , 2003, Cancer cell.

[14]  Hosoon Choi,et al.  Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation , 2003, The Journal of cell biology.

[15]  Ken Jacobson,et al.  JNK phosphorylates paxillin and regulates cell migration , 2003, Nature.

[16]  Yoshiaki Kawano,et al.  Secreted antagonists of the Wnt signalling pathway , 2003, Journal of Cell Science.

[17]  Yoshiharu Matsuura,et al.  Sumoylation is involved in β‐catenin‐dependent activation of Tcf‐4 , 2003 .

[18]  J. Parsons,et al.  Focal adhesion kinase: the first ten years , 2003, Journal of Cell Science.

[19]  Naoto Ueno,et al.  The TAK1-NLK Mitogen-Activated Protein Kinase Cascade Functions in the Wnt-5a/Ca2+ Pathway To Antagonize Wnt/β-Catenin Signaling , 2003, Molecular and Cellular Biology.

[20]  A. Hall,et al.  Rho GTPases in cell biology , 2002, Nature.

[21]  H. Yokozaki,et al.  Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR‐beta in intestinal, diffuse–adherent, and diffuse–scattered type gastric carcinomas , 2002, The Journal of pathology.

[22]  Hans Clevers,et al.  T‐cell factors: turn‐ons and turn‐offs , 2002, The EMBO journal.

[23]  M. Bittner,et al.  Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. , 2002, Cancer cell.

[24]  Xi He,et al.  Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism , 2002, Cell.

[25]  E. Nishida,et al.  JNK functions in the non‐canonical Wnt pathway to regulate convergent extension movements in vertebrates , 2002, EMBO reports.

[26]  C. Turner.  Paxillin and focal adhesion signalling , 2000, Nature Cell Biology.

[27]  H. Yokozaki,et al.  Molecular characteristics of eight gastric cancer cell lines established in Japan , 2000, Pathology international.

[28]  R. Moon,et al.  The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. , 2000, Trends in genetics : TIG.

[29]  A. Kikuchi,et al.  Roles of Axin in the Wnt signalling pathway. , 1999, Cellular signalling.

[30]  M. Kitagawa,et al.  An F‐box protein, FWD1, mediates ubiquitin‐dependent proteolysis of β‐catenin , 1999, The EMBO journal.

[31]  D. Olson,et al.  Antisense wnt-5a mimics wnt-1-mediated C57MG mammary epithelial cell transformation. , 1998, Experimental cell research.

[32]  Akira Kikuchi,et al.  Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK‐3β and β‐catenin and promotes GSK‐3β‐dependent phosphorylation of β‐catenin , 1998 .

[33]  G. Tortora,et al.  Expression of Wnt5a is downregulated by extracellular matrix and mutated c-Ha-ras in the human mammary epithelial cell line MCF-10A. , 1997, Biochemical and biophysical research communications.

[34]  R. Iozzo,et al.  Aberrant expression of the growth factor Wnt-5A in human malignancy. , 1995, Cancer research.

[35]  A. Harris,et al.  Regulation of Wnt5a mRNA Expression in Human Mammary Epithelial Cells by Cell Shape, Confluence, and Hepatocyte Growth Factor (*) , 1995, The Journal of Biological Chemistry.

[36]  A. McMahon,et al.  Differential transformation of mammary epithelial cells by Wnt genes , 1994, Molecular and cellular biology.

[37]  P. Laurén,et al.  THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. , 1965, Acta pathologica et microbiologica Scandinavica.

[38]  K. Nakayama,et al.  Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. , 2005, Molecular and cellular biology.

[39]  Randall T Moon,et al.  Wnt and calcium signaling: beta-catenin-independent pathways. , 2005, Cell calcium.

[40]  J. Ajani,et al.  Molecular basis of gastric cancer development and progression , 2004, Gastric Cancer.

[41]  R. Nusse,et al.  Mechanisms of Wnt signaling in development. , 1998, Annual review of cell and developmental biology.

[42]  I S Anishchenko,et al.  [Stomach cancer]. , 1981, Fel'dsher i akusherka.