Abstract
Background In addition to their involvement in mechanisms underlying cancer initiation and progression, emerging evidence has highlighted a key role for microRNAs in resistance to a number of anti-cancer therapies. Methods MicroRNA profiling and validation was carried out on a panel of age-matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines using 7th generation miRCURY LNA™ arrays (Exiqon). Transient transfections were used to either inhibit or over-express these microRNAs using antagomirs or pre-miRs, respectively. The effects of modulating these miRNAs on cell proliferation, apoptosis and clonogenic survival were examined in response to cisplatin. The translational relevance of these miRNAs in lung cancer was confirmed in a cohort of chemo-naive matched normal and tumour lung tissues and sera from NSCLC patients. MicroRNAs were also assessed in mouse xenograft FFPE tissues from H460 CisR-derived ALDH1+ and ALDH1– cancer stem cell subpopulations. Results A 5-miRNA signature consisting of members of the miR-30 family, miR-34a and miR-4286 was identified and validated. MicroRNAs were significantly up-regulated in all CisR cell lines relative to their parental counterparts, in contrast to miR-4286 which was significantly down-regulated. Inhibition of the miR-30 family and miR-34a and forced over-expression of miR-4286 significantly reduced the clonogenic survival ability of CisR cells in response to cisplatin. The miR-30 family was significantly decreased in AD and SCC tissues. MiR-34a expression was significantly lower in SCC tissues while miR-4286 levels were significantly increased in AD tissues only. A significant-fold increase in miR-4286 was found in sera from SCC lung cancer patients. Similar to that found at the in vitro level, the miR-30 family and miR-34a were up-regulated in mouse xenograft FFPE tissues derived from CisR and PT cell lines in vivo. Conclusions In this study, a 5-microRNA signature was identified using an in vitro model of cisplatin resistance. Differential expression of these microRNAs was found between matched normal and tumour lung tissues from NSCLC patients. These may offer potential as diagnostic markers in NSCLC and in predicting response to cisplatin chemotherapy.
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