Study Of The Molecular Mechanism Of Acquired Cisplatin Resistance Of Lung Adenocarcinoma A549 Cells Based On Whole Transcriptome Sequencing

Acquired resistance to cisplatin-based chemotherapy frequently occurs in patients with non-small cell lung cancer,and the underlying molecular mechanisms are not well understood.The aim of this study was to investigate whether a distinct gene expression pattern is associated with acquired resistance to cisplatin in human lung adenocarcinoma.Whole-transcriptome sequencing was performed to compare the genome-wide gene expression patterns of the human lung adenocarcinoma A549 cisplatin-resistant cell line A549/DDP with those of its progenitor cell line A549.A total of 1214 differentially expressed genes(DEGs)were identified,656 of which were upregulated and 558 were downregulated in A549/DDP cells.Functional annotation of the DEGs in the Kyoto Encyclopedia of Genes and Genomes database revealed that most of the identified genes were enriched in the PI3K/AKT,mitogen-activated protein kinase,actin cytoskeleton regulation,and focal adhesion pathways in A549/DDP cells,suggesting that these pathways play vital roles in the regulation of cisplatin resistance in lung cancer.Meanwhile,we also noticed that three genes of the AKR1 family,including AKR1C1,AKR1C3 and AKR1B1 were significantly upregulated in A549/DDP cells.Based on functional experiments results,we found that combination of cisplatin and inhibitor of AKR1C1 or AKR1B1 significantly enhanced the drug sensitivity of A549/DDP cells.Also,co-knockdown of AKR1C1 and AKR1B1 significantly enhanced the cyto-toxicity and apoptosis effect induced by cisplatin,suggesting that these genes were closely associated with cisplatin resistance.Our study provides new promising therapeutic targets for lung cancer treatment,and validation in clinical patients is warranted.