title: The p53 target gene desmocollin 3 acts as a novel tumor suppressor through inhibiting EGFR/ERK pathway in human lung cancer.
abstract: 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 reverse transcription-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 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 extracellular signal-regulated kinase1/2. Taken together, our data suggested that DSC3 acts as a novel tumor suppressor gene through inhibition of epidermal growth factor receptor/extracellular signal-regulated kinase signaling in lung cancer cells.
authors.affiliation: Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmühlenweg 1,  07743 Jena, Germany.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Cui
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Linlin
authors.initials: L
authors.lastname: Yang
authors.forename: Thomas
authors.initials: T
authors.lastname: Knösel
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
authors.forename: Manuela
authors.initials: M
authors.lastname: Pacyna-Gengelbach
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D051187:Desmocollins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C490356:DSC3 protein, human; D051187:Desmocollins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases