Research Article: Transcriptome Sequencing Reveals Key Pathways and Genes Associated with Cisplatin Resistance in Lung Adenocarcinoma A549 Cells

Date Published: January 23, 2017

Publisher: Public Library of Science

Author(s): Yani Fang, Cheng Zhang, Tong Wu, Qi Wang, Jinhui Liu, Penggao Dai, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0170609

Abstract

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. 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. These results support previous studies demonstrating that the pathways regulating cell proliferation and invasion confer resistance to chemotherapy. Furthermore, the results proved that cell adhesion and cytoskeleton regulation is associated with cisplatin resistance in human lung cancer. Our study provides new promising biomarkers for lung cancer prognosis and potential therapeutic targets for lung cancer treatment.

Partial Text

Lung cancer is the most prevalent malignancy worldwide, accounting for the highest incidence and mortality rates of all cancer types[1]. In the clinical treatment of lung cancer, chemotherapy can be used as adjuvant therapy either alone or in combination with radiation[2]. For decades, cisplatin has been used as the first-line drug for chemotherapeutic administration in cases of advanced and metastatic lung cancer[3]. However, the prognosis for patients with advanced lung cancer remains poor, with a median survival time of 8–11 months, a 1-year survival rate of 30–45%, and a 5-year survival rate of <5%[4]. Acquired resistance after prolonged exposure to cisplatin is considered as one of the primary reasons for the failure of chemotherapy[5]. In this study, we aimed to identify the genes associated with acquired resistance to cisplatin for the development of targeted therapy in the clinical treatment of lung cancer. First, we screened DEGs between the A549/DDP and A549 cell lines by transcriptome sequencing. Our results showed that 1214 genes were significantly differentially expressed between the cisplatin-resistant cell line and its parental cell line, 656 of which were upregulated and 558 were downregulated. Second, the function of the DEGs was annotated by reference to the COG, GO, and KEGG databases, and the top 5 DEGs-enriched pathways in the KEGG database were analyzed to elucidate the resistance mechanism. Finally, qRT-PCR was used to validate all of the RNA sequencing results.   Source: http://doi.org/10.1371/journal.pone.0170609

 

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