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Data: 26-feb-2013
Autori: Statello, Luisa
Titolo: Specific Alterations of miRNA Transcriptome and Global Network Structure in Colorectal Cancer After Inhibition of MAPK/ERK Signaling Pathway
Abstract: Colorectal cancer (CRC) is one of the most frequent malignancies affecting western societies. Currently, the gold standard of CRC treatment is cetuximab, a monoclonal antibody, alone or in combination with chemotherapy. Not all patients positively respond to cetuximab: the analysis of KRAS mutational status at tumor site, a highly invasive analysis, is the only universally accepted genetic predictor for patient s response. However, some KRAS wild type patients, potential good responders, don t benefit from this therapy. To overcome these obstacles, research is focusing on the identification of new biomarkers detectable in circulating blood or other body fluids that can be used for diagnosis as well as for predicting the response to certain therapies. miRNAs, small RNA molecules involved in all aspects of cellular metabolism through regulation of gene expression, have been identified as new biomarkers for many diseases and cancers, including CRC. On the other hand, the scientific research is investigating on new molecules providing high specificity for the key players of the main cellular pathway affected in cancer. The main pathway involved in CRC is MAPK/ERK signaling pathway, which members are good targets for designing new specific inhibitors that could help to overcome the problems related to non-responsive patients to EGFR-targeted therapy. This thesis is focused on the relationship between the response to certain drugs and miRNA transcriptome changes in CRC human cellular models, based on KRAS mutational status. We profiled the expression of 667 miRNAs in 2 human CRC cell lines (Caco-2, KRAS wild type, and HCT-116, KRAS mutated), and 745 miRNAs in 3 CRC cell lines (Caco-2, HCT-116 and SW-620, another KRAS mutated cell line) after treatment with cetuximab and three specific inhibitors of MAPK pathway, respectively. Our aim was the identification of typical miRNA transcription profiles associated to cetuximab response, as well as the investigation on the global involvement of miRNAs within MAPK/ERK pathway. In the first analysis we identified substantially unique subsets of differentially expressed miRNAs in the sensitive cell line compared to the resistant one. Global network functional analysis on their targets suggested a role of these miRNAs in cancer related processes and identified hubs involved in EGFR internalization. In the second analysis we identified six differentially expressed miRNAs, that we have demonstrated to be involved in cell proliferation, migration, apoptosis, and to globally affect the regulation circuits centered on MAPK/ERK signaling. We evaluated the expression of the main candidate miRNAs identified in both studies in biopsies from CRC patients, previously categorized for their KRAS status: two miRNAs from the first study (miR-146b-3p and miR-486-5p) and four from the second (miR-92a-1*, miR-135b*, miR-372, miR-720) resulted highly expressed in biopsies from CRC patients than in normal controls. Moreover, the last four miRNAs are also overexpressed in CRC patients with mutated KRAS than in wild-type genotypes. The identification of miRNAs, which expression is linked to the efficacy of therapy, should help to predict the patients response to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response. Our results contribute to deepen current knowledge on some features MAPK/ERK pathway, pinpointing new oncomiRs in CRC and allowing their translation into clinical practice and CRC therapy. Data shown in this thesis were published in 2010 and 2012 (Ragusa M, Majorana A, Statello L, et al. Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment. Mol Cancer Ther. 2010 Dec; 9:3396-409; Ragusa M, Statello L, Maugeri M, et al. Specific alterations of the microRNA transcriptome and global network structure in colorectal cancer after treatment with MAPK/ERK inhibitors. J Mol Med (Berl). 2012 Jun 4).
InArea 06 - Scienze mediche

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