Abstract
BackgroundThe efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer is limited by the acquired drug resistance. Identification the RNAs related to the cisplatin resistance may help to improve clinical response rates.MethodsMicroarray expression profiling of mRNAs, lncRNA and miRNA was undertaken in A549 cells and cisplatin resistant A549/CDDP cells. Differentially expressed mRNAs, lncRNAs and miRNAs, verified by realtime RT-PCR, were subjected to pathway analysis. Expression of NKD2 and β-catenin was assessed by realtime RT-PCR and western blot analysis. The effect of lncRNA AK126698 on cisplatin induced apoptosis was investigated by annexin-V/PI flow cytometry.ResultsIn total, 1471 mRNAs, 1380 lncRNAs and 25 miRNAs differentially expressed in A549/CDDP and A549 cells. Among them, 8 mRNAs, 8 lncRNAs and 5 miRNAs differentially expressed in gene chip analysis were validated. High-enrichment pathway analysis identified that some classical pathways participated in proliferation, differentiation, avoidance of apoptosis, and drug metabolism were differently expressed in these cells lines. Gene co-expression network identified many genes like FN1, CTSB, EGFR, and NKD2; lncRNAs including BX648420, ENST00000366408, and AK126698; and miRNAs such as miR-26a and let-7i potentially played a key role in cisplatin resistance. Among which, the canonical Wnt pathway was investigated because it was demonstrated to be targeted by both lncRNAs and miRNAs including lncRNA AK126698. Knockdown lncRNA AK126698 not only greatly decreased NKD2 which can negatively regulate Wnt/β-catenin signaling but also increased the accumulation and nuclear translocation of β-catenin, and significantly depressed apoptosis rate induced by cisplatin in A549 cells.ConclusionCisplatin resistance in non-small-cell lung cancer cells may relate to the changes in noncoding RNAs. Among these, AK126698 appears to confer cisplatin resistance by targeting the Wnt pathway.
Highlights
Lung cancer is one of the most common human cancers worldwide and continues to be associated with the highest incidence and mortality rates of all cancers [1,2]
Microarray of A549 and A549/CDDP cell lines First, the cisplatin-resistance of A549/CDDP cell line was identified by evaluating the IC50-value of A549/CDDP against wild A549 cell line
A gene chip study was performed in these two cell lines to investigate the possible RNA expression changes in cisplatin resistance in lung adenocarcinoma cells using the Arraystar probe dataset which included 33,045 Long noncoding RNAs (lncRNAs) and 30,215 coding transcripts
Summary
Lung cancer is one of the most common human cancers worldwide and continues to be associated with the highest incidence and mortality rates of all cancers [1,2]. According to the WHO GLOBOCAN project, 1.6 million new cases of lung cancer, accounting for 12.7% of the world’s total cancer incidence, were diagnosed in 2008 [3]. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases [4]. The most effective therapy for NSCLC is complete lung resection. The survival rate after complete lung resection is far from satisfactory and most patients are offered chemotherapy as an alternative, in particular cisplatin (CDDP; cis-diamminedichloroplatinum II)-based chemotherapy. The ability of cancer cells to become resistant to CDDP remains a significant impediment to successful chemotherapy. There is an ongoing need to pinpoint the exact mechanisms involved in order to find new targets to prevent drug resistance. The efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer is limited by the acquired drug resistance. Identification the RNAs related to the cisplatin resistance may help to improve clinical response rates
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