Systematic determination of microRNAs associated with chemosensitivity of 5-fluorouracil, CPT-11, and oxaliplatin in colorectal cancer

B13

Background: Non-coding small microRNAs (miRNAs) regulate gene expression at the posttranscriptional and translational level and altered miRNA expression has been linked to tumorigenesis. Previous studies from our laboratory have shown that tumor suppressor p53 mediated a number of miRNAs expression and several of these miRNAs were associated with patient’s response and survival in colorectal cancer. In this study, the involvement of miRNAs in chemosentitivity of several anticancer agents was systematically determined using miRNA expression profiling approach. Materials and Methods: We systematically examined the expression changes of miRNAs in response to genotoxic stress including 5-Fluorouracil (5-FU), CPT-11, and Oxaliplatin in human colon cancer HCT-116 (wt-p53) and HCT-116 (null-p53) cells. The miRNA expression profiles were quantified by miRCURY Locked Nucleic Acid (LNA) array analysis. ImaGene 7.0 and GeneSpring 7.2 Software were employed for data analysis with 2-fold cut-off for expression threshold. The impact of certain miRNAs on chemosensitivity was characterized based on the overexpression of miRNAs and the LD-50 changes were quantified using XTT assays. Results: Differential miRNA expression profiles related to chemosensitivity were discovered by comparing the profiles of miRNAs between HCT-116 (wt-p53) and HCT-116 (null-p53) cells treated with three different anticancer agents. The expression of 101 miRNAs was altered in response to 5-FU, 60 miRNAs were involved in CPT-11 treatment and 64 differentially regulated miRNAs were associated with Oxaliplatin exposure with 2-fold cut-off. Although each genotoxic agent yields unique miRNA expression profiles, there are 29 overlap miRNAs involved in all three different treatments exclusively in HCT-116 (wt-p53) cells. Some of them had been validated and determined to be related to chemosensitivity.
 Conclusion: This study provides a comprehensive understanding of miRNAs involved in response to several key anticancer agents in colorectal cancer. Some of them may become potential novel targets to overcome chemoresistance and benefit the personalized treatment in the colorectal cancer.