Studying a possible functional circuitry involving microRNAs, MITF, MYO5A/DLC2, RA...
| Grant number: | 16/09179-1 |
| Support type: | Scholarships abroad - Research Internship - Doctorate |
| Effective date (Start): | September 08, 2016 |
| Effective date (End): | September 07, 2017 |
| Field of knowledge: | Biological Sciences - Biochemistry - Molecular Biology |
| Principal Investigator: | Miriam Galvonas Jasiulionis |
| Grantee: | Ana Carolina Monteiro |
| Supervisor abroad: | Regine Schneider-Stock |
| Home Institution: | Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil |
| Local de pesquisa : | Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany |
| Associated to the scholarship: | 13/04829-0 - MicroRNAs associated with the metastatic phenotype of melanoma, BP.DR |
Abstract MicroRNAs (miRNAs) are one of the most abundant classes of gene regulatory molecules. They are small non-coding RNAs of approximately 22 nucleotides that have important regulatory function in animals and plants by regulating gene expression negatively and post-transcriptionally. In animals, miRNAs binds to mRNAs leading to its destabilization or its translation repression. It is estimated that 30% of all protein coding human genes are regulated by miRNAs, and miRNAs are essential components in the regulation of several physiological processes. Therefore, alterations in miRNAs expression are involved in various diseases, such as cancer. MiRNAs participate in tumorigenesis by regulating important processes, such as cell differentiation, adhesion, apoptosis, tumor growth, invasion and metastasis. Signatures of miRNA expression are being developed for several cancers and it can be used to identify tumor types, subtypes and cancer prognosis. MiR-298 is an extremely poorly characterized miRNA, however some studies have suggested it as a regulator of tumor progression. It has been observed alterations in miR-298 expression mainly among aggressive and non-aggressive tumor samples. So, these studies indicate that this miRNA can be associated with the acquisition of tumor aggressiveness characteristics, as drug resistance and tumor recurrence. Melanoma is one the most aggressive cancers and its incidence and mortality are rising worldwide. It is also the most aggressive, treatment-resistant and metastatic skin cancer, and it has been responsible for 80% of all deaths caused by skin malignancies. Importantly, metastasis is one of the most important parameters that affect cancer patient´s prognosis. It is associated with resistance to treatments, high recurrence rates and poor cancer patient survival rates. However, there is still limited information about the involvement of miRNAs in the development and progression of melanoma. At Miriam Jasiulionis' laboratory, by submitting non-tumorigenic melanocytes to sequential cycles of anchorage blockade it was developed a murine model that allows the study of the different phases of melanoma progression. In this model, we have detected miRNAs that appears to be implicated in the transformation of the non-metastatic melanoma cell 4C11- to the metastatic cell 4C11+. Among these, miR-298 stood-out. MiR-298 presents a significantly reduced expression in the metastatic lineage 4C11+ in comparison with the less aggressive lineage 4C11-. Functional assays have shown that this miRNA regulates cell proliferation, migration and clonogenicity in this melanoma cells. Also, a preliminary subcutaneous tumorigenic assay in mice showed that miR-298 can regulate the occurrence of spontaneous metastasis. These results associated with other groups results suggest that miR-298 can participate in the aggressive phenotype of melanoma. In this context, the main aim of this project is to elucidate the role of miR-298 in melanoma cells, mainly through two activities. The first focus on identifying the miRNA's targets, while the second intends to determinate the contribution of the miR-298 and its targets deregulation on melanoma progression. The present study also aims to evaluate miRNA-298 and its targets expression in human melanoma primary cells and human tumor samples. (AU) | |