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| Author(s): |
Leonardo Augusto Marson
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2018-12-14 |
| Examining board members: |
Murilo Vieira Geraldo;
Cristina Pontes Vicente;
Gianna Maria Griz Carvalheira
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| Advisor: | Murilo Vieira Geraldo |
| Abstract | |
Papillary thyroid carcinoma (PTC) is the most prevalent histotype of thyroid carcinomas and its incidence has increased globally. More recently, the aberrant expression of microRNAs (miRNAs), small non-protein-coding RNAs, emerged as promising diagnostic and prognostic tools for PTC. However, its therapeutic potential for PTC remains poorly explored. Several miRNAs located along the DLK1-DIO3 genomic region present an overall reduction in PTC expression. Thus, this project aims to evaluate the tumor suppressor activity of DLR1-DIO3 miRNAs in vitro. To this purpose, we performed the computational prediction of the targets of the 102 mature miRNAs from the DLK1-DIO3 region, combined with the gene expression data mining from PTC tissue samples and normal thyroid tissue from Gene Expression Omnibus (GEO) and from The Cancer Project Genome Atlas (TCGA). A matrix of interactions between the miRNAs and their predicted targets was subsequently constructed, where the miRNAs were ranked according to (i) the total number of predicted targets; (ii) the number of targets already characterized as oncogenes and (iii) the number cancer-related genes targeted, indicated miR-485-5p as a promising candidate for subsequent functional analyses. This list of targets of this miRNA is enriched for biological processes important for tumor progression, such as cell migration, MAPK signal transduction and control of gene expression. Functional analyses showed that transfection of commercial mimetic of miR-485-5p in PTC lines (TPC-1 and BCPAP) decreased cell migration, invasion, proliferation and cell viability in vitro, corroborating the bioinformatic analyses. Interestingly, these effects were observed only in the BRAFT1799A-positive cell line (BCPAP), indicating the influence of the tumor genetic background on the mechanism of action of miR-485-5p. Indeed, the transfection of miR-485-5p decreased the levels of its putative target genes GAB2, RAC1 and ICAM1, key members of pathways related to tumor progression, only in BCPAP cell line. Thus, our results allow us to conclude that miR-485-5p is involved in the modulation of genes involved in important processes related to tumor progression, pointing this molecule as a promising element in the elucidation of papillary thyroid cancer. The exploration of these molecular mechanisms may contribute to new therapeutic strategies for PTC, especially for BRAF1799A-positive patients, which tend to progress to metastatic cancer and have fewer therapeutic options (AU) | |
| FAPESP's process: | 16/09107-0 - Evaluation of the tumor suppressor role of microRNAs situated at DLK1-DIO3 genomic region in papillary thyroid carcinoma |
| Grantee: | Leonardo Augusto Marson |
| Support Opportunities: | Scholarships in Brazil - Master |