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Gene silencing of β‐catenin in melanoma cells retards their growth but promotes the formation of pulmonary metastasis in mice
Author(s) -
Takahashi Yuki,
Nishikawa Makiya,
Suehara Tetsuya,
Takiguchi Naomi,
Takakura Yoshinobu
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23812
Subject(s) - transfection , gene silencing , catenin , biology , cancer research , wnt signaling pathway , microbiology and biotechnology , cell culture , cell adhesion , small hairpin rna , cell growth , metastasis , cell , signal transduction , gene , cancer , gene knockdown , genetics
Abstract Altered expression of β‐catenin, a key component of the Wnt signaling pathway, is involved in a variety of cancers because increased levels of β‐catenin protein are frequently associated with enhanced cellular proliferation. Although our previous study demonstrated that gene silencing of β‐catenin in melanoma B16‐BL6 cells by plasmid DNA (pDNA) expressing short‐hairpin RNA targeting the gene (pshβ‐catenin) markedly suppressed their growth in vivo , gene silencing of β‐catenin could promote tumor metastasis by the rearranging cell adhesion complex. In this study, we investigated how silencing of β‐catenin affects metastatic aspects of melanoma cells. Transfection of B16‐BL6 cells with pshβ‐catenin significantly reduced the amount of cadherin protein, a cell adhesion molecule binding to β‐catenin, with little change in its mRNA level. Cadherin‐derived fragments were detected in culture media of B16‐BL6 cells transfected with pshβ‐catenin, suggesting that cadherin is shed from the cell surface when the expression of β‐catenin is reduced. The mobility of B16‐BL6 cells transfected with pshβ‐catenin was greater than that of cells transfected with any of the control pDNAs. B16‐BL6 cells stably transfected with pshβ‐catenin (B16/pshβ‐catenin) formed less or an equal number of tumor nodules in the lung than cells stably transfected with other plasmids when injected into mice via the tail vein. However, when subcutaneously inoculated, B16/pshβ‐catenin cells formed more nodules in the lung than the other stably transfected cells. These results raise concerns about the gene silencing of β‐catenin for inhibiting tumor growth, because it promotes tumor metastasis by reducing the amount of cadherin in tumor cells. © 2008 Wiley‐Liss, Inc.