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PMID: 17761539 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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

Molecular biology of the cell ·Vol. 18 ·No. 11 ·2007-11-00 ·Pages 4292-303

Yoshikawa H, Matsubara K, Zhou X, Okamura S, Kubo T, Murase Y, Shikauchi Y, Esteller M, Herman JG, Wei Wang X, Harris CC

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 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 function of which is involved in beta-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.

MeSH Terms
Animals Cell Line, Tumor Cell Proliferation Female Gene Expression Regulation, Neoplastic Mice Mice, Nude Neoplasm Metastasis/pathology Neoplasms/metabolism,pathology Protein Binding Proto-Oncogene Proteins/genetics,metabolism RNA, Small Interfering/genetics TCF Transcription Factors/classification,metabolism Wnt Proteins/genetics,metabolism Xenograft Model Antitumor Assays beta Catenin/metabolism
Chemicals
Proto-Oncogene Proteins RNA, Small Interfering TCF Transcription Factors WNT10B protein, human Wnt Proteins beta Catenin
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Yoshikawa Hirohide
Department of Epigenetic Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Matsubara Kenichi
Zhou Xiaoling
Okamura Shu
Kubo Takahiko
Murase Yaeko
Shikauchi Yuko
Esteller Manel
Herman James G
Wei Wang Xin
Harris Curtis C
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e06-10-0889
Published
2007-11-00
Epub
2007-00-29
Pages
4292-303
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2043567
Subset
IM
Grants
NCI NIH HHS · P50 CA058184 · United States
NCI NIH HHS · P50 CA58184 · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1091/mbc.e06-10-0889 PMC Full Text View journal details
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