For three decades, alterations of protein-coding oncogenes and tumor suppressors genes have been considered as the causes of tumorigenesis. Recent advances proved without doubts that cancer is a complex genetic disease involving structural and expression abnormalities of both coding and non-coding genes. We pioneered the idea that small non-coding RNAs (ncRNAs) named microRNAs (miRNAs) and other larger ncRNAs named ultraconserved genes are involved in human tumorigenesis and particularly in colorectal cancers (CRC). The pathogenetic mechanisms of the final steps of tumorigenesis, the metastases, is still largely unknown. The broad, long-term purposes of this application are to decipher the roles of ncRNAs during the metastatic process of CRC and to understand the ncRNAs genetic abnormalities in the set of patients that will represent the initial target of miRNA-based gene therapy. To achieve this, we will use a four-aimed strategy applied to a large panel of patients divided in two arms: one without and the other having metastases. First, based on microarray experiments with genome-wide miRNA and expressed sequence tags (ESTs) profiling and on bioinformatics studies, we will develop a large database of miRNAs, ultraconserved genes and large ncRNAs expression and correlate this with databases of expressed ESTs. Second, based on the negative correlations that we will found using bioinformatics tools, we will analyze the possible interactions between ncRNAs and messenger RNAs of protein coding genes significant for mestatases. Third, we will investigate the biological functions related to the metastasis process for some verry significantly differentially expressed miRNAs and UCGs by using in vitro models of colon cancer metastases. Based on our preliminary data, we will include as the top candidates for such studies miR-21, miR-192, miR-215, and miR-222, as well as the non-coding UCGs uc.160, uc.170A and uc.310, and the top three miRNAs and top three UCGs selected according to statistical criteria obtained from the patient study (if different from the previous genes). The final results of the described tasks will reveal new markers for molecular diagnosis and prognosis and new targets for drug therapy.
The broad, long-term purpose of this application is to decipher the roles of ncRNAs during the metastatic process of CRC by using bioinformatics, genome-wide microarray and functional studies in human cancer cells. The final results of the described tasks will reveal new markers for molecular diagnosis and prognosis and new targets for drug therapy.
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