UNIVERSITY OF TEXAS M.D. ANDERSON CANCER CENTER, THE
Grant: $335,032 - National Institutes of Health - Jul. 17, 2009
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Award Description: 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 purpose of this application is to decipher the roles of ncRNAs during the metastatic process of CRC. The long-term goal of our investigation is to understand the 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 EST 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 metastases. Third, the proved interactor miRNAs::mRNA pairs will be tested in vivo in colon cancer cells for biological effects, including apoptosis or proliferation. Fourth, we will investigate the biological functions related to the metastasis process for some very significantly differentially expressed miRNAs. Based on our preliminary data, we will include as the top candidates for such studies mir-192, miR-215, miR-21 and miR-222, as well as the non-coding UCGs 160, 170A and 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. PUBLIC HEALTH RELEVANCE: 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.
Project Description: As this project is already under development in the PI laboratory in the last two years, in the five weeks timeframe after the project become active (8/20/09) till end of reporting period (9/30/09), we continued the Aim 1 experiments, specifically the confirmation by quantitative RT-PCR of a remaining set of 35 colorectal (CRC) patients equally divided between non-metastasis and metastatic cases for the abnormally expressed microRNAs. We have performed qRT-PCR on macrodissected tissues for 20 microRNAs and found that 15 miRNAs were significantly differentially expressed between the CRC that did recurred (and therefore metastasized) and the CRCs that did not recurred. Also, as proposed in Aim 1b, we investigated the expression correlations between these miRNAs and ultraconserved genes (UCGs). Furthermore, the in vitro studies proposed in Aim 3 for two of the confirmed microRNAs (miR-192 and miR-215) as well as for one ultraconserved gene were already started by using the migration assay in two CRC cell lines, one metastatic (SW620) and one non-metastatic (Colo320) after induction or down-regulation of specific miRNAs. The results of triplicate experiments will be shortly available.
Jobs Summary: Retained - Senior Investigator in charge of performing the quantitative RT-PCR profiling and the functional studies described in this grant related to the abnormally expressed miRNAs. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
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