WNT10B functional dualism: β-catenin/Tcf-dependent growth promotion or independent suppression with deregulated expression in cancer

Hirohide Yoshikawa, Kenichi Matsubara, Xiaoling Zhou, Shu Okamura, Takahiko Kubo, Yaeko Murase, Yuko Shikauchi, Manel Esteller, James G. Hennan, Wei Wang Xin, Curtis C. Harris

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

We found aberrant DNA methylation of the WNT10B promoter region in 46% of primary hepatocellular carcinoma (HCC) and 15% of colon cancer samples. Three of 10 HCC and one of two colon cancer cell lines demonstrated low or no expression, and 5-aza-2′deoxycytidine reactivated WNT10B expression with the induction of demethylation, indicating that WNT10B is silenced by DNA methylation in some cancers, whereas WNT10B expression is up-regulated in seven of the 10 HCC cell lines and a colon cancer cell line. These results indicate that WNT10B can be deregulated by either overexpression or silencing in cancer. We found that WNT10B up-regulated β-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the β-catenin/Tcf activation, because mutant β-catenin-transduced cells did not suppress growth, and dominant-negative hTcf-4 failed to alleviate the growth suppression by WNT10B. Although WNT10B expression alone inhibits cell growth, it acts synergistically with the fibroblast growth factor (FGF) to stimulate cell growth. WNT10B is bifunctional, one function of which is involved in β-catenin/Tcf activation, and the other function is related to the down-regulation of cell growth through a different mechanism. We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator.

Original languageEnglish
Pages (from-to)4292-4303
Number of pages12
JournalMolecular biology of the cell
Volume18
Issue number11
DOIs
Publication statusPublished - Nov 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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