Abstract 2045: microRNA expression patterns associated with resistance to platinum-based chemotherapy in human cancer cell lines
Authors: Fan-Yu He, Jang-Yang Chang, Ching-Chuan Kuo, Wen-Yu Pan, Li-Tzong Chen, Wen-Hui Weng
Journal: Cancer Research (2010)

Abstract Platinum-based compounds, for example cisplatin and oxaliplatin, are the common anti-tumor drugs that have been used worldwide effective against a multitude of cancers. However, their clinical usage is impeded by toxic side effects or by the occurrence of drug resistance. MicroRNAs (miRNAs) are a group of the non-coding RNAs that play a role in controling the post-transcriptional expression of genes. Herein, we aimed to reveal the potential role of miRNAs in platinum-based drug resistance, and analyzed the miRNAs target genes that are supposed to be related with regulating the drug resistant mechanisms. The two human cancer resistant cell lines HONE-1 and TSGH were established by treating with the platinum-based compounds up to 6µm and 15µm, respectively. We then compared the expression level of genes among the parental lines and their resistant lines series using fluorescence in situ hybridization, miRNA array, expression microarray and western blot approach. The results showed the higher proteins expression level of p53 and p21 were presented in both resistant cell lines series while compared to the parental lines. However, there was no mutation occurred in both genes, either in gene structure or gene copy number change. Moreover, four miRNAs were detected from miRNA microarray by combining the results of both resistant cell line series. They included one high-regulated hsa-miR-193b; and three low-regulated hsa-miR-202, hsa-miR-509 and hsa-miR-575. Interestingly, corresponding genes that related to these miRNAs were also identified in the expression array. These genes included DNA replication related gene CDC34; cell cycle associated genes RRM2,S100A2,CCND1,CCNE1,CDC34; apoptotic pathway correlated gene CCND1; and RRM2 which is associated with DNA synthesis. In summary, as the high-expression level of protein p53 and p21 were observed on both resistant lines series without showing the gene status aberrations or RNA expression difference, we speculated that alteration could be occurred during the period of post-translational modification, and it may further regulate signal transduction of the resistant-associated genes. Therefore, genes that were targeted by hsa-miR-202, hsa-miR-509 and hsa-miR-575 should be highly noticed, and are worthwhile to further verify their potential role as the platinum-based compounds resistant biomarkers. Besides, the overexpressed gene IL-6, down stream gene Bcl-2 was known to be involved in the formation of chemoresistance, was also observed in the resistant lines. Therefore, further understanding of the regulatory pathways of IL-6 and Bcl-2 might provide novel insight into the platinum-drug resistance in clinical pharmacotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2045.