title: miR-495 enhances the sensitivity of non-small cell lung cancer cells to platinum by modulation of copper-transporting P-type adenosine triphosphatase A (ATP7A).
abstract: Copper-transporting P-type adenosine triphosphatase A (ATP7A) is associated with platinum drug resistance in non-small cell lung cancer (NSCLC). microRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression at post-transcriptional level. In this study, the aim is to explore which miRNAs might participate in the platinum resistance by targeting ATP7A in NSCLC. Using real-time PCR-based miRNA expression profiling and bioinformatics, we selected miR-495 as a candidate miRNA. EGFP reporter assay, real-time PCR, and Western blot validated that ATP7A was a direct target for miR-495. The drug sensitivity assay indicated that miR-495 enhanced the cell response to cisplatin (CDDP) in NSCLC cells, while inhibition of miR-495 led to the opposite effects. Importantly, either overexpression or knockdown of ATP7A could override the effect of miR-495 on chemosensitivity. We also demonstrated that miR-495 increased the intracellular CDDP accumulation and overexpression of ATP7A can reduce the increased drug concentration induced by miR-495. Finally, we discovered that there was a converse relationship between miR-495 and ATP7A levels in NSCLC tissues sensitive or resistant to CDDP. In conclusion, our data demonstrate that miR-495 regulates the multi-drug resistance by modulation of ATP7A expression in NSCLC and suggest that miR-495 may serve as a potential biomarker for the treatment of multi-drug resistant NSCLC patients with high ATP7A levels.
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Weina
authors.initials: W
authors.lastname: Li
authors.forename: Shouzhen
authors.initials: S
authors.lastname: Wu
authors.forename: Zhikui
authors.initials: Z
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics*; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D016190:Carboplatin / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003001:Cloning, Molecular; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D017239:Paclitaxel / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D027682:Cation Transport Proteins; C577768:MIRN495 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016190:Carboplatin; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D017239:Paclitaxel; D002945:Cisplatin
keywords: ATP7A; CISPLATIN (CDDP); PLATINUM; miR-495; microRNAs