Loss of Smad4 correlates with loss of the invasion suppressor E-cadherin in advanced colorectal carcinomas.
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.
Reinacher-Schick
Anke
A
Department of Internal Medicine, IMBL, University of Bochum, Bochum, Germany.
Baldus
Stephan E
SE
Romdhana
Bashra
B
Landsberg
Stephanie
S
Zapatka
Marc
M
Mönig
Stefan P
SP
Hölscher
Arnulf H
AH
Dienes
Hans P
HP
Schmiegel
Wolff
W
Schwarte-Waldhoff
Irmgard
I
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
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