title: Loss of Smad4 correlates with loss of the invasion suppressor E-cadherin in advanced colorectal carcinomas.
abstract: Smad4 is a tumour suppressor gene predominantly involved in gastrointestinal carcinogenesis. Loss of Smad4 is considered to be a genetically late step and occurs in up to 30% of metastatic colorectal carcinomas. Smad4, originally characterized as an intracellular transmitter of transforming growth factor-beta (TGF-beta) signals, is a transcriptional co-modulator capable of integrating cellular responses to multiple signalling cascades. Thus, there are many Smad4 target genes and they are presumably strongly context-dependent. It was recently shown that re-expression of Smad4 in Smad4-deficient SW480 human colon carcinoma cells restored epithelioid morphology and induced P-cadherin and E-cadherin transcription. The cadherins are key players in cell-cell adhesion connecting adjacent cells via the cadherin-catenin adhesion complex. Frequent loss of E-cadherin expression in human cancers has been a long-standing observation, but the underlying mechanisms are not yet fully understood. To assess the role of Smad4 in E-cadherin regulation in colorectal carcinogenesis further, the present study has analysed Smad4 and E-cadherin RNA and protein expression in colorectal carcinoma cell lines and in 51 late-stage colorectal carcinomas. In primary tumours, loss of Smad4 expression correlated highly significantly with loss of E-cadherin expression, thus providing further evidence for involvement of the tumour suppressor Smad4 in the control of expression of the tumour and invasion suppressor E-cadherin.
authors.affiliation: Department of Internal Medicine, IMBL, University of Bochum, Bochum, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Reinacher-Schick
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Baldus
authors.forename: Bashra
authors.initials: B
authors.lastname: Romdhana
authors.forename: Stephanie
authors.initials: S
authors.lastname: Landsberg
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Mönig
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Hölscher
authors.forename: Hans P
authors.initials: HP
authors.lastname: Dienes
authors.forename: Wolff
authors.initials: W
authors.lastname: Schmiegel
authors.forename: Irmgard
authors.initials: I
authors.lastname: Schwarte-Waldhoff
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D051176:beta Catenin