miRNA-378 reverses chemoresistance to cisplatin in lung adenocarcinoma cells by targeting secreted clusterin

Lung cancer is the leading cause of cancer-related death in both males and females worldwide1. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80–85% of all lung cancer cases2. Cisplatin, a DNA-damaging cytotoxic agent, is the first-line therapy in NSCLC treatment, but its efficacy is often impaired by the development of drug resistance3. Although lots of studies have been done on the resistance to cisplatin3,4, the mechanisms involved are not fully understood, so further study is needed. Clusterin (CLU) is a secreted glycoprotein which is involved in many physiological processes, such as apoptosis, cell cycle regulation, and DNA repair5,6,7. It has two main isoforms: secreted form (sCLU) and nuclear form (nCLU). A previous study in our lab showed that sCLU is associated with resistance to cDDP in NSCLC8. Other reports have also demonstrated that sCLU is a key contributor to chemoresistance to anticancer agents6. sCLU is expressed in aggressive late stage tumors. Its expression can lead to the development of broad-based resistance to different chemotherapeutic agents. Inhibition of sCLU could improve the effect of chemotherapy on human tumor cells9. MicroRNAs are a class of short, non-coding RNA molecules involved in numerous biological processes, such as cell self-renewal and cancer development10. By binding with the 3′ untranslated region (UTR) of target mRNAs, miRNA works as a guide molecule in post-transcriptional gene silencing, leading to degradation of target mRNA, or repression of translation11. A growing body of evidence suggests that miRNAs may be involved in the development of chemoresistance, and may also play a role in the modulation of drug resistance-related pathways in cancer cells12,13,14. In this report, we demonstrated that miR-378 targets sCLU, and explored its possible roles in chemoresistance to cDDP in lung adenocarcinoma cells. With TargetScan software, we found a group of miRNAs (including miR-378) that target CLU. Meanwhile, we found two sets of observations that helped us to focus our research on miR-378. Using the microRNA microarray to examine tumor microRNA expression patterns, Eitan et al. found that seven microRNAs had significantly different expressions in tumors from platinum-sensitive vs. platinum-resistant patients15. In another article, Lu discovered that 34 miRNAs were differentially expressed between the A549 and A549/cDDP cell line16. Both reports demonstrated that miR-378 might be important in the chemoresistance to platinum, but the mechanisms for the effect remain poorly understood. Therefore, we selected miR-378 as the target of our research. Here we demonstrate that miRNA-378 regulates sCLU-mediated chemosensitivity to cDDP in non-small cell lung cancer cells.