Background: Gastric cancer (GC) is a common malignant tumor with poor prognosis. Patients are mainly treated by chemotherapy, but it usually fails in patients with advanced GC due to multidrug resistance (MDR).
Methods: We obtained microarray data in GEO datasets combined with TCGA data analysis to determine the common differentially expressed genes (DEGs) of MDR in GC. Function enrichment analysis and gene-interaction relationship of these genes were performed. Expression of LAMA4 in GC patients was detected by real-time PCR. In addition, cisplatin (DDP) resistance was examined in GC cells with overexpression or knockdown of LAMA4 in vitro, and in xenograft nude mouse model in vivo. By luciferase assay and Chromatin immunoprecipitation (ChIP) assay, mechanism of the up-regulated LAMA4 was further studied.
Results: LAMA4 was up-regulated in Gemcitabine-, Adriamycin-, Trastuzumab-, Cisplatin- and Vincristine-resistant GC cells and had the largest fold increase in cisplatin-resistant GC cells. Higher LAMA4 expression was correlated with higher histological state and poorer survival of GC patients. Overexpression of LAMA4 enhanced cisplatin resistance of GC cells both in vitro and in vivo, while LAMA4 knockdown led to opposite results. Moreover, increased LAMA4 expression was activated by AR through direct binding of AR to LAMA4 promoter.
Conclusion: LAMA4 was up-regulated by AR through directly binding to its specific promoter region, and was associated with the enhanced cisplatin resistance in GC, which provided new mechanism and better understandings for treating drug-resistant GC.
Keywords: Androgen receptor; Cisplatin resistance; Gastric cancer; LAMA4.
Copyright © 2019 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.