Analysis of the miRNAs involved in the regulation of MMP2 and MMP9 and regulators,...
| Grant number: | 12/02267-1 |
| Support type: | Scholarships in Brazil - Doctorate (Direct) |
| Effective date (Start): | May 01, 2012 |
| Effective date (End): | May 31, 2014 |
| Field of knowledge: | Health Sciences - Medicine |
| Principal Investigator: | Kátia Ramos Moreira Leite |
| Grantee: | Betina Stifelman Katz |
| Home Institution: | Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
Abstract Prostate cancer is the most common cancer in men and the second leading cause of cancer-related mortality in Brazil. Although most patients with prostate cancer present with localized disease, 5% have metastatic disease at the time of diagnosis. Comprehension of the mechanisms involved in the progression of these tumors is of great importance, and understanding the process called epithelial-mesenchymal transition is crucial. Epithelial-Mesenchymal Transition (EMT) is a reversible cell-biological program in which an epithelial cell loses intercellular adhesion and acquires a mesenchymal phenotype. EMT is activated during tumorigenesis leading to acquisition of invasiveness and metastastic properties by cancer cells. The main event in EMT is the repression of E-cadherin gene expression by transcriptional factors including SNAIL (SNAI1), SLUG (SNAI2), ZEB1, ZEB2, E47 and Twist, which results in dissociation of cancer cells and promotes metastasis. It is thought that another key regulator of EMT are the microRNAs, and the most investigated miRNA is the miR-200 family, which are powerful inducers of epithelial differentiation able to revert the EMT. The miR-200 participates in a signaling network with the ZEB family, and both have opposite functions and form a double-negative feedback loop. This loop is involved in EMT and might be the crucial prerequisite for cancer progression. In prostate cancer, the role of ZEB/miR-200 loop is still unknown. Aggressive tumors have elevated expression of ZEB1, but the understanding of the miR-200 in EMT is too limited. Therefore, due to the lack of data and the importance of this issue in cancer progression there is a need of a broader and more complete investigation of the factors involved in EMT, including the miRNAs, in prostate cancer. Objectives: Analysis of gene expression and miRNA expression involved in epithelial-mesenchymal transition in specimens of localized prostate cancer of patients who underwent radical prostatectomy and correlation between the gene expression and miRNA expression profiles and Gleason histological grading system, pathological staging and biochemical recurrence. Material and Methods: Fifty-six patients with localized prostate cancer treated by radical prostatectomy between 2000 and 2002 will be included in the study. Surgical specimens were received fresh, and samples of suspected areas for tumor were obtained, frozen in liquid nitrogen and stored at -170ºC. The remaining specimen was fixed in 10% buffered formalin and sent for histopathological analysis. All patients had localized disease at the time of surgery and Gleason scores between d 6 and 10. Gene expression profiles of E-cadherin, cadherin-11, N-cadherin, TGF², SNAIL, ZEB and SNUD and expression profiles of the microRNAs 21, 155, 17-92, 7, 15a, 16, 34, 10b, 373, 520c, 126, 335 and 200 will be analyzed. For such, RNA, miRNA, cDNA synthesis for gene expression analysis and cDNA synthesis for miRNA expression analysis will be extracted from the frozen tissue. Eleven non-neoplastic tissues from benign prostatic hyperplasia will be included as controls. (AU) | |