Abstract
Abstract Background: Approximately half of the colorectal cancer (CRC) patients develop metastatic disease, either at diagnosis or during follow-up. 5-FU-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. MicroRNAs are short RNAs that post-transcriptionally regulate the gene expression of many genes. MicroRNA levels are frequently altered in cancer, and can affect expression of genes that modulate tumorigenesis. Objective: In this study, we explore the potential of microRNAs, and the microRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity in patients with metastatic colorectal cancer. Methods: We analyzed the levels of a selected panel of 22 miRNAs and the Dicer protein in primary CRC tumors from patients enrolled in the CAIRO study (a phase III study of the Dutch Colorectal Cancer Group). MiRNA levels were determined with Taqman microRNA assays and Dicer level with immunohistochemistry. Correlation between the expression status of microRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. In addition, we evaluated correlations between Dicer and miRNA levels. Results: Variable Dicer intensities were observed among the analyzed samples, but there was no significant association between Dicer levels and PFS. In addition, no clear correlation between Dicer and miRNA levels could be identified. We especially detected higher expression of miR-31 and miR-21 in tumors compared to matched normal tissue, whereas miR-137 and miR-215 were lower expressed. Interestingly, miR-143 expression was reduced in a subset of the primary CRC tumors, and this differential expression showed a relationship with PFS. The group with reduced miR-143 expression showed higher PFS. The median PFS for patients with reduced, neutral and increased miR-143 expression was 261, 167 and 142 days, respectively (p-value log-rank test=0.018). Conclusion: The expression level of miR-143 may have clinical utility as a biomarker for response to 5-FU-based chemotherapy. These findings warrant further studies to investigate the relationship between miR-143 expression and 5-FU. Citation Format: Femke Simmer, Jeroen Dijkstra, Sabine Venderbosch, Claudius Faber, Leonie Mekenkamp, Miriam Koopman, Ton de Haan, Cornelis Punt, Iris Nagtegaal. MicroRNA-143 is a putative predictive biomarker for 5-FU-based chemotherapy in patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 534. doi:10.1158/1538-7445.AM2014-534
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