Abstract 4038: Identification of microRNAs involved in colorectal cancer progression

Abstract

Abstract MicroRNAs (miRNAs) are negative regulators of gene expression during various basic biological processes such as development, cellular differentiation, proliferation and apoptosis. Altered expression of miRNAs is associated with development and progression of various human cancers, where they mainly regulate the translation of oncogenes and of tumor suppressor genes. In colorectal cancer (CRC), these regulators complement the Vogelstein multi-step model of pathogenesis and have the potential of becoming a novel class of tumor biomarkers and of therapeutic targets. To identify miRNAs deregulated in CRC that could be used for diagnosis and prognosis, we examined by Quantitative Real-Time PCR the global expression of 378 mature miRNAs in 40 CRCs and their paired non-tumor tissues. Non-parametric confidence intervals for each miRNA where calculated and twenty-four miRNAs whose expression is significantly altered in tumors respect to the normal tissue where identified (Bonferroni P<0.05). Part of them, such as miR-21, miR-31 or miR-183 has been previously reported in CRC. MiR-135b, with the highest expression in the tumors is a promising tumor related miRNA. We subsequently evaluated the association of the 24 miRNAs with different clinical characteristics of the samples such as tumor site, disease status, TNM staging, expression of CEA and CA199, and presence of alterations in the molecular markers of CRC progression (APC, TP53, KRAS and loss of 18q arm). MiRNAs differently expressed among colon and rectum or higher in late stage tumors were identified. Expression levels of miR-31 were correlated to that of CA199 and miR-18a, miR-21 and miR-31 were associated with mutations in APC gene. Gene target predictions of these miRNAs pointed mainly the pathways related to CRC progression such as Wnt/TGFb, MAPK and TP53 signaling pathways. In addition, many of these miRNAs were predicted to target genes in the Vogelstein model. This study has identified promising miRNAs to be used as biomarkers (for example in plasma) in diagnostic and prognostic settings of CRC. And, in addition it shows their direct involvement in the regulation of driving events of CRC carcinogenesis which should be explored further in biological models. 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 4038.