Although chemotherapeutic agents are widely used in the treatment of lung cancer, their efficacy is often limited by the existence or development of chemoresistance. As one of the first-line chemotherapeutic agents for the treatment of NSCLC, cisplatin is a platinum-based compound that forms intra- and inter-strand adducts with DNA [14, 15]. Despite tremendous efforts, cisplatin treatment often results in the development of drug resistance, leading to therapeutic failure, and the molecular mechanisms leading to cisplatin chemoresistance are poorly understood. Factors that enhance the sensitivity of NSCLC cells to cisplatin may highlight predictive biomarkers or targets for therapy.
MiRNAs are thought to function as either tumor suppressors or oncogenes though target oncogenes or tumor suppressor genes during tumorigenesis and development of cancers [16–18]. miR-182 has been regarded as an oncogene in most contexts. In a cohort of 253 glioma patients, high miR-182 expression was found to be a negative prognostic factor . In melanoma cell lines, Segura and coworkers showed that high miR-182 expression stimulated migration and survival. The same group treated liver metastases in mice with anti -miR-182 and obtained a lower tumor burden and a lower mir-182-level than in untreated mice . Also in breast tumors and cervical cancers miR-182 seems to have an oncogenic impact [21, 22]. Previously, Wang M et al. found that miR-182 was markedly upregulated in human lung cancer cells. They conducted MTT and colony formation assays to further evaluate the effect of miR-182 on lung cancer cell growth, and they performed transwell and wound healing assays to evaluate its role in regulating invasion and migration activity. Their results demonstrate that miR-182 acts as an oncogene in lung cancer .
Previous studies demonstrated that the acquired drug resistance of cancer cells is related to deregulation of miRNAs such as miR21, miR-503, miR-181a and miR-620 [23–25]. In the present study, to explore whether the unregulated oncogene miR-182 was involved in the NSCLC cells resistant to cisplatin, we transfected miR-182 inhibitor and its negative control oligonucleotides into A549 cells. Then MTT assay showed that the miR-182-suppressed cells were significantly more sensitive to the therapy of cisplatin than control cells, indicating that overexpression of miR-182 may involve in chemoresistance of NSCLC cells to cisplatin.
In NSCLC tissues, many onco-miRs/tumor suppressor-target or tumor suppressor-miRs/onco-target pathways have been demonstrated to participate in the tumorigenesis of lung cancer, including miR7/BCL2 axis, miR-99b/FGFR3 axis, miR-101/EZH2 axis, miR-192/RB1 axis and miR-196/HOXA5 axis [26–30]. However, miRNA/target network was so complex that more and more miRNA/target axis needs to be elucidated in lung cancer especially NSCLC. In the present study, We transfected A549 cells with miR-182 inhibitor or a scrambled miR-182 inhibitor control. The PDCD4 mRNA and protein were overexpression in miR-182-suppressed cells compared with controls, indicating that miR-182 was a negative regulator of PDCD4. Furthermore, we found that when down regulated of PDCD4 expression by siRNAs, A549 cells became more resistant to the therapy of cisplatin. In addition, the enhanced growth-inhibitory effect by the miR-182 inhibitor transfection was weakened after the addition of PDCD4 siRNA, suggesting that PDCD4 was responsible for the miR-182-induced resistance to cisplatin. These results established that miR-182 transfer in combination with cisplatin therapy may be a target to reverse chemotherapeutic resistance. In addition, further research is needed to investigate whether the expression level of miR-182 in tumor tissue and plasma might be used as a biomarker to predict platinum based chemotherapy response in patients with NSCLC.