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Vol. 18, Issue 11, 4292-4303, November 2007

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WNT10B Functional Dualism: -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. Herman, Xin Wei Wang, and Curtis C. Harris

*Department of Epigenetic Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; DNA Chip Research Inc., Kanagawa 230-0045, Japan; Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20896; and The Johns Hopkins University School of Medicine, The Oncology Center, Baltimore, MD 21231

Submitted October 4, 2006; Revised August 6, 2007; Accepted August 21, 2007
Monitoring Editor: John Cleveland

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 -catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the -catenin/Tcf activation, because mutant -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 -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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Curtis C. Harris (curtis_harris{at}nih.gov)

Abbreviations used: 5Aza-dC, 5-aza-2'deoxycytidine; COX-2, cyclooxygenase-2; FGF, fibroblast growth factor; HCC, hepatocellular carcinoma; MMTV, mouse mammary tumor virus; MSP, methylation-specific polymerase chain reaction; TSA, trichostatin A.