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Background & Aims: Epithelial-Mesenchymal Transition (EMT) plays a pivotal role in tumor invasion and dissemination.Although it is well documented that EMT occurred predominantly at the tumor edge where it is induced by cytokines, the extracellular matrix environment, or hypoxia, the mechanism(s) underlying the tumor microenvironment-induced Epithelial-Mesenchymal Transition remains unclear.Grainyhead-like-2 (GRHL2) is a new transcription factor involved in embryo development and epithelial, morphogenesis.Dysfunction of GRHL2 has been noted in several tumor types, including breast cancer, colon cancer.In addition, it has been reported that GRHL2 regulated the epithelial apical junctional complex by targeting the tight junction gene claudin 4(Cldn4).These findings imply that GRHL2 might play a key role in Epithelial-Mesenchymal Transition.Methods & Results: We systemically analyzed the expression of GRHL2 in colon and liver cancer vs.normal control by querying oncornine database and real time PCR analysis, the resulted showed that GRHL2 was respectively down-regulated in 40% and 76% of colon cancer and liver cancer.Further investing the expression of GRHL2 in colon cancer by irnmunohistochemistry analysis indicated that GRHL2 was loss of expression at the tumor edge and surround fibroblast cells.We further found that promoter of GRHL2 was embedded in a large CpG island and methylated in tumor cells with a low level of GRHL2.Demethylation by 5-aza-dc treatment significantly enhanced GRHL2 expression in SW480 and SW620 cells, revealed that GRHL2 is epigenetically silenced by DNA methylation.Overexprssion of GRHL2 in SW480 and SW620 promotes Epithelial-Mesenchymal Transition (MET).Real time PCR, Western blot and Immunoprecipitation (ChIP) assay indicated that over-expression of GRHL2 enhances E-cadherin and Rab25 expression by binding to the promoter of these two genes.In addition, we also found that overexpression of GRHL2 suppresses CD24 expression.Conclusions: These data indicated that loss of expression GRHL2 in colon and liver cancer cells at the tumor edge facilitates Epithelial-Mesenchymal Transition through targeting Rab25 and E-cadherin, and over-expression of GRHL2 in tumor cells promotes MET, and therefore provide new lights on inhibiting tumor metastasis by target GRHL2.