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

Abstract

BackgroundGastric 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 β4.MethodsIntegrin β4-expression vector or siRNA were used to analyze the functional effects of integrin β4 on chemoresistance of gastric cancer cells to gefitinib. EGFR and integrin β4 expression, proliferation and apoptosis of gastric cancer cells were assayed by indirect immunofluorescence, western blot, MTT and flow cytometry respectively. EGFR and integrin β4 expression were also assayed on patient samples.ResultsIt was found that the integrin β4 expression was increased in gefitinib-resistant gastric cell line. The upregulated integrin β4 expression was identified to promote gefitinib resistance and proliferation, and inhibit apoptosis, while downregulation of integrin β4 was to inhibit gefitinib resistance and proliferation, and induce apoptosis. Moreover, the overexpression of integrin β4 in SGC7901 cells resulted in the down-regulation of p-EGFR protein levels while down-regulation of integrin β4, 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 β4 in gastric cancer patients.ConclusionConsidering the above results, it is concluded that the interaction of EGFR and integrin β4 may change the sensitivity of gefitinib treatment.

Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

“…This effect was verified by Western blot analysis ( Figure 7 b). Integrin β 4 (ITGB4) is unable to bind to COL1 but has been described to mediate cell-cell-contacts as a hemidesmosome and to induce an active crosstalk with growth factor receptors, e.g., EGFR [ 48 , 49 ]. Concerning the upregulated pEGFR levels in MDA-MB-231kd cells shown in Figure 1 , we therefore explicitly checked for pEGFR in both cell lines by Western blot ( Figure 7 c).…”

Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer

“…Gefitinib-mediated cell toxicity was substantially reduced when hepatocarcinoma cells were exposed to laminin-332 but not to other ECM proteins such as collagen or fibronectin [27]. More recently, high β4 integrin expression was associated with a gefitinib-resistant phenotype in gastric cancer cells [26]. The resistant phenotype could be reverted by RNA-mediated β4 silencing, whereas sensitive cells became more resistant to gefitinib after β4 overexpression.…”

“…A clinical study in 38 patients has indicated some correlation between β4 expression and gefitinib resistance. However, given the small sample size, it is far too early to draw any conclusion about the potential repercussions of this observation [26]. Another clinical study showed that β4 integrin polymorphism expression was associated with resistance to therapy.…”

Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development

“…For instance, ECM-mediated integrin β1 promotes liver metastasis of gastrointestinal cancer through focal adhesion kinase (FAK)-yes-associated protein 1 (YAP1)/tafazzin (TAZ) signaling, which is enhanced by vasodilator-stimulated phosphoprotein (VASP) [116]. In addition, ECM1-mediated integrin β4 promotes EMT and glucose metabolism via SOX2/HIF-1α signaling in gastric cancer [117] and modulates epidermal growth factor receptor (EGFR) signaling to induce gefitinib chemoresistance [118]. In pancreatic cancer, solute carrier family 39 member 4 (ZIP4) induces ZEB1 expression via STAT3 signaling and subsequently activate integrin α3β1 to regulate the JNK signaling pathway, leading to inhibit chemosensitivity by decrease gemcitabine transporter ENT1 [119].…”

“…Taken together, the data support the critical roles of cancer cell adhesion molecules in tumor growth, metastasis, and chemoresistance ( Table 2). L-selectin Metastasis [113] Liver cancer E-selectin Tumor growth, Angiogenesis [111] Integrins Gastric cancer integrin β4 SOX2/HIF-1α signaling, EGFR EMT, Glucose metabolism, gefitinib chemoresistance [117,118] integrin β1 CXCL1, FAK/Akt signaling, MMP2/9 Adhesion, Metastasis [121] Pancreatic cancer integrin α3β1 ZIP4, ZEB1, STAT3 signaling, JNK signaling pathway Chemoresistance [119] Integrin family galectin-3, IL-8, NF-κB signaling Promote tumor growth, Metastasis [125] Colorectal cancer integrin α2β1 CDH17, FAK and Ras pathways Proliferation, Metastasis [120] integrin β1 TLR4, PI3K/Akt pathway Adhesion, Metastasis [123] Liver cancer integrin β3 IL-8, PI3K/Akt pathway Invasion [122] integrin αvβ3 galectin-1, FAK/PI3K/Akt signaling EMT, Sorafenib resistance [124] 3.4. Programmed Death-Ligand 1…”