TITLE

IMPAIRMENT OF TGFβ SIGNALLING IN BARRETT'S ASSOCIATED OESOPHAGEAL ADENOCARCINOMA: ROLE OF SMAD4

AUTHOR(S)
Onwuegbusi, B.A.; Fitzgerald, R.C.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA44
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Introduction: The accumulation of somatic mutations during the Barrett's metaplasia-dysplasia-adenocarcinoma sequence leads to uncontrolled epithelial cell proliferation. Since transforming growth factor β (TGFβ) is a potent anti-proliferative agent, and signalling mutations Frequently occur in gastrointestinal malignancies, we hypothesise that alterations in this pathway may be important in oesophageal adenocarcinoma development. Methods: Western blot, RT-PCR and immunohistochemistry were used to analyse the expression of TGFβ receptors I and II, and Smad2, 3 and 4 in oesophageal samples from normal squamous mucosa (n=20), Barrett's oesophagus (BE) without dysplasia (n=20), BE with Iow-grade dysplasio (n=10), BE with high-grade dysplasia (n=10) and BE adenocarcinoma (n=20). TGFβ responsiveness, TGFβ receptor and Smad expression of a panel oF oesophageal cell lines were also determined, and mutational analysis was performed by PCR and sequencing. Results: There was a significant decrease in the mRNA expression of Smad2 (p<0.001), Smad3 (p<0.001) and Smad4 (p<0.002) in BE samples, and in high-grade dysplasia samples (Smad2 p<0.001; Smad3 p<0.01; Smad4 p<0.001) when compared to squamous epithelium. Smad4 mRNA was also significantly decreased in adenocarcinoma samples compared to squamous epithelium (p<0.05). A shift in protein mobility was seen for Smad4 in 25% of adenocarcinoma samples analysed by Western blot. OE21 cells (squamous carcinoma), OE33 and SEG-1 (BE adenocarcinoma) were responsive to TGFβ. BIC-1 and TE7 (BE adenocarcinoma) were unresponsive to TGFβ, as were KYSE-30 (squamous carcinoma). BIC-1 did not express Smad4 mRNA and protein, due to a base pair substitution in exon 9 of the Smad4 gene. TGFβ receptor and Smad mRNA and protein were expressed in these cells, and no mutations could be identified in exon 3, 5, or 7 of the TβRII gene. Conclusion: The TGFβ signalling pathway is impaired in Barrett's...
ACCESSION #
9747560

 

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