The p53 target gene desmocollin 3 acts as a novel tumor suppressor through inhibiting EGFR/ERK pathway in human lung cancer
Menée sur des lignées cellulaires de cancer du poumon, cette étude met en évidence un mécanisme par lequel, en inhibant la voie de signalisation EGFR/ERK, le gène de la desmocolline 3 joue un rôle de suppresseur de tumeurs
Desmosomes are intercellular junctions that confer strong cell-cell adhesion. Altered expression of desmocollin 3 (DSC3), a member of the desmosomal cadherin family, was found in various cancers, however its functional involvement in carcinogenesis has not yet been elucidated. Expression/localization of DSC3 was analyzed by real-time RT-PCR, western blotting, immunofluorescence, and immunohistochemistry. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR, and bisulfite sequencing. It turned out that downregulation of DSC3 in lung cancer cells was associated with DNA hypermethylation. In primary lung tumors, DSC3 was a potential diagnostic marker for lung squamous cell carcinoma, and DSC3 DNA hypermethylation was correlated with poor clinical outcome. To investigate the effect of the tumor suppressor gene p53 on DSC3, transient transfection with a wild type p53-expression vector was performed. Overexpression of p53 resulted in an increased expression of DSC3 in a DSC3-unmethylated lung cancer cell line H2170, but not in H1299, a DSC3-methylated cell line. However, combination of p53 transfection with demethylation agent 5-aza-2’-deoxycytidine (DAC) treatment led to increased expression of DSC3 in H1299 cells. Furthermore, functional studies after stable transfection of a DSC3 expression vector showed that ectopic expression of DSC3 inhibited cell proliferation, anchorage-independent growth, migration, as well as invasion, and most interestingly led to reduced phosphorylation levels of ERK1/2. Taken together, our data suggested that DSC3 acts as a novel tumor suppressor gene through inhibition of EGFR/ERK signaling in lung cancer cells. The epigenetic mechanism and p53 regulation in DSC3 expression implies clinical application.
http://carcin.oxfordjournals.org/content/early/2012/08/30/carcin.bgs273.abstract