Anderson, M.R.; Campbell, M.; Jankowski, J.A.Z.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA31
Academic Journal
Background: The development of oesophageal adenocarcinoma is characterised by progression along the Barrett's metaplasiodysplasia-carcinoma sequence. The HGF receptor, Met, shows increased expression along this sequence and patients with carcinomas that overexpress Met exhibit poorer short term survival. The perturbation of cadherin/catenin complexes has been shown in oesophageal adenocarcinoma with downregulation of E-cadherin a commonfinding. We sought to investigate a/ink between Met activation and cadherin/catenin biology. Aims: To investigate the effect of Met activation on E-cadherin expression and on Beta-catenin nuclear signaling in oesophageal cells. Methods: Two cell lines that express Met (OE33, SEG1) and a celt line that does not (TE7) were incubated with HGF at doses ranging from 1 n g/ml to 500 ng/ml. At set time points from 30 min to 24 h, mRNA and protein were harvested. Real time PCR was used to assess levels of E-cadherin mRNA. Western blot was used to assess levels of E-cadherin protein. Levels of nuclear TCF/Beta-catenin signaling were assessed following transient transfection with a TCF/luciferase reporter construct. An ELISA was used to measure levels of HGF in the culture media at different time points to detect any endogenous synthesis of HGF by the cell lines themselves. Results: OE33 and SEG1 showed a 37% and 69% reduction in E-cadherin mRNA following 30 min stimulation with HGF at 100 ng/ml (p < 0.01). This minimum dose was reduced by altering the amount of calf serum supplemented in the culture media. Reduced E-cadherin protein expression was seen. OE33 showed a two-fold increase in the relative levels of luciferase activity following HGF stimulation (p < 0.01 ). TE7 (which lacks the Met receptor) showed no response. Conclusions: Met activation induces downregulation of E-cadherin and increases nuclear TCF/Beta-catenin signaling. Thus Met activation may impair cell adhesion and play a role in regulating gene transcription.


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