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Occludin expression inhibits tumorigenicity and metastasis
Author(s) -
Osanai Makoto,
Nishikiori Nami,
Murata Masaki,
Chiba Hideki,
Kojima Takashi,
Sawada Norimasa
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a223-b
Subject(s) - occludin , cancer research , biology , microbiology and biotechnology , cancer cell , histone deacetylase , tight junction , cancer , histone , gene , biochemistry , genetics
Occludin is the first identified integral protein for tight junction (TJ), and its long C‐terminal domain is considered to have functions in receiving or transmitting cell survival signals. Loss of TJ‐associated molecules such as occludin has been correlated with tumor progression in carcinogenesis: however, the precise molecular mechanisms explaining its loss of expression and whether occludin expression has any effects on cancer phenotypes remain to be examined. Here we demonstrate that forced expression of occludin in cancer cells exhibits enhanced sensitivity to the differently acting apoptogenic factors, and thus inhibits the tumorigenicity of transformed cells. In addition, studies using deletion mutants of occludin constructs show that 44 amino acids at the C‐terminal end play a critical role in modifying the cellular phenotypes. Interestingly, occludin decreases the cellular invasiveness and motility, thereby abrogating metastatic potencies of cancer cells. We also reveal that occludin expression is silenced by CpG island methylation on its promoter region. Either the synergy with demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor alpha induce endogenous occludin, which is sufficient for apoptotic sensitization. Our findings identify occludin as a potent inhibitor of tumorigenic, invasive, and metastatic properties of cancer cell, and suggest that occludin is a likely candidate for a tumor suppressor gene in certain types of cancer.