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MBC in Press, published online ahead of print August 29, 2007
Mol. Biol. Cell 10.1091/mbc.E06-10-0889

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Submitted on October 4, 2006
Revised on August 6, 2007
Accepted on August 21, 2007

WNT10B Functional Dualism: {beta}-Catenin/Tcf-dependent Growth Promotion or Independent Suppression with Deregulated Expression in Cancer

Hirohide Yoshikawa,* Kenichi Matsubara,{dagger} Xiaoling Zhou,{ddagger} Shu Okamura,{ddagger} Takahiko Kubo,* Yaeko Murase,* Yuko Shikauchi,* Manel Esteller,{sect} James G. Herman,{sect} Xin Wei Wang,{ddagger} and Curtis C. Harris{ddagger}

*Department of Epigenetic Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan; {dagger}DNA Chip Research Inc., 1-1-43 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; {ddagger}Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20896; {sect}The Johns Hopkins University School of Medicine, The Oncology Center, Baltimore, MD 21231

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 out of ten HCC and one out 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, while WNT10B expression is up-regulated in seven of the ten 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 {beta}-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the {beta}-catenin/Tcf activation, because mutant {beta}-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 of which is involved in {beta}-catenin/Tcf activation, and the other 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.

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






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