HEY1-mediated cisplatin resistance in lung adenocarcinoma via epithelial-mesenchymal transition.

Abstract

Lung cancer is one of the most common malignancies and the leading cause of cancer-related death in the world. In patients with advanced lung adenocarcinoma who are negative for driver gene mutations, platinum-based chemotherapy represented by cisplatin remain the standard of care. Therefore, studying the mechanism behind inevitable cisplatin resistance in lung adenocarcinoma is still important. In this study, the potentially related differential expression gene for cisplatin resistance in lung adenocarcinoma was screened in the GEO database. The expression level of HEY1 in cell lines of lung adenocarcinoma was detected and HEY1 expression was up-regulated in cisplatin-resistant lung adenocarcinoma tissues and cell lines A549/DDP. Patients with high HEY1 expression have poor prognosis after cisplatin therapy. Gain and loss function assays uncovered that HEY1 could regulate the cisplatin sensitivity of NSCLC cells. In vivo experiments have confirmed that silence of HEY1 expression can induce cisplatin resistance, and epithelial-mesenchymal transition (EMT) changes occur during this process. Mechanically, HEY1 silencing significantly up-regulated E-cadherin expression and down-regulated Vimentin in A549/DDP cells. While up-regulation of HEY1 resulted in down-regulation of E-cadherin and up-regulation of Vimentin in A549 cells. Immunohistochemical experiments confirmed that E-cadherin was significantly decreased, and Vimentin expression was significantly up-regulated in cisplatin-resistant lung adenocarcinoma tissues. HEY1 can mediate the occurrence of cisplatin-acquired resistance in lung adenocarcinoma, and the possible mechanism is to regulate the EMT. The results of this study can provide a new direction and target for clinical research on the reversal of cisplatin resistance in lung adenocarcinoma.