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Abstract
Cisplatin remains to be primary chemotherapeutic drug for gastric cancer patients, especially for advanced stage ones. However, primary or acquired resistance often occurs with the mechanisms being not well understood, which results in relapse of the cancer and poor survival. Herein, we found that HER2 upregulation was associated with cisplatin resistance. We observed that cisplatin-resistant gastric cancer cells underwent a morphological change similar to epithelial-mesenchymal transition (EMT) which is mediated by HER2 overexpression. When specific monoclonal antibody Herceptin, small molecular targeted drug CP724714, or small interfering RNA against HER2 was applied, the EMT-like phenotypic change was dramatically reversed. More importantly, the IC50 and Resistance Index of resistant gastric cancer cells to cisplatin were also decreased by any of these treatments.We demonstrated that expression and amplification of HER2 positively correlated with expression of EMT-related transcription factor Snail in gastric cancer tissues. Furthermore, for the first time, we found that HER2/Snail double positive gastric cancer patients had poorer survival than single positive or double negative counterparts, which provided experimental evidence for the necessity of HER2/Snail double testing in gastric cancer. In conclusion, this study provides some clues of the association of cisplatin resistance with HER2 upregulation-induced EMT in gastric cancer cells.
Highlights
Properties[12,13,14,15]
Based on the above knowledge, we hypothesized that HER2 and EMT may be involved in cisplatin resistance in gastric cancer
The above results demonstrated that cisplatin-resistant gastric cancer cells displayed higher migratory capacity and motility compared with parental cells
Summary
Properties[12,13,14,15]. EMT of Cancer cells associates with resistance to chemotherapy[16,17,18,19]. There has no study investigating the role of EMT in mediating cisplatin resistance in gastric cancer. HER2 ( known as ErbB2), a 185-kDa transmembrane tyrosine kinase (TK) receptor, is a member of the epidermal growth factor receptors (EGFRs) family. Targeted therapeutic drugs, including monoclonal antibody Herceptin and small molecule tyrosine kinase inhibitors targeting HER2, are playing more and more important roles in breast cancer treatment[23,24]. Up to date, there is no study investigating the role of HER2 in mediating cisplatin-resistance in gastric cancer. EMT in the cisplatin-resistant gastric cancer cells could be abrogated by monoclonal antibody Herceptin, small molecular targeted drug CP724714, or small interfering RNAs (siRNAs) against HER2. We demonstrated that amplification of HER2 or expression of HER2 positively correlated with the expression of EMT-related transcription factor Snail in 382 cases of gastric cancer, and HER2/Snail double positive patients had poorer patient outcome compared with single positive or double negative group
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