A cross-talk between integrin β4 and epidermal growth factor receptor induces gefitinib chemoresistance to gastric cancer

Background: Gastric cancer presents a major health burden worldwide. Therefore, many molecular targeting agents have been evaluated for treatment of gastric cancer. Gefitinib has shown anticancer activity against gastric cancer which work through inhibiting epidermal growth factor receptor (EGFR). However, the effect of gefitinib is limited due to its resistance. Therefore, understanding the mechanisms of gefitinib resistance is desperately needed to formulate novel strategies against gastric cancer. Here, we analyzed resistance mechanism from the crosstalk between EGFR and integrin beta 4. Methods: Integrin beta 4-expression vector or siRNA were used to analyze the functional effects of integrin beta 4 on chemoresistance of gastric cancer cells to gefitinib. EGFR and integrin beta 4 expression, proliferation and apoptosis of gastric cancer cells were assayed by indirect immunofluorescence, western blot, MTT and flow cytometry respectively. EGFR and integrin beta 4 expression were also assayed on patient samples. Results: It was found that the integrin beta 4 expression was increased in gefitinib-resistant gastric cell line. The upregulated integrin beta 4 expression was identified to promote gefitinib resistance and proliferation, and inhibit apoptosis, while downregulation of integrin beta 4 was to inhibit gefitinib resistance and proliferation, and induce apoptosis. Moreover, the overexpression of integrin beta 4 in SGC7901 cells resulted in the down-regulation of p-EGFR protein levels while down-regulation of integrin beta 4, significantly resulted in overexpression of p-EGFR. The results of western blot from patients also showed there was obvious negative correlation between p-EGFR and integrin beta 4 in gastric cancer patients. Conclusion: Considering the above results, it is concluded that the interaction of EGFR and integrin beta 4 may change the sensitivity of gefitinib treatment.