Intratumoral Restoration of miR-137 Plus Cholesterol Favors Homeostasis of the miR-137/Coactivator p160/AR Axis and Negatively Modulates Tumor Progression in Advanced Prostate Cancer

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Pimenta, Ruan ; Mioshi, Carolina Mie ; Goncalves, Guilherme L. ; Candido, Patricia ; Camargo, Juliana A. ; Guimaraes, Vanessa R. ; Chiovatto, Caroline ; Ghazarian, Vitoria ; Romao, Poliana ; da Silva, Karina Serafim ; dos Santos, Gabriel A. ; Silva, Iran A. ; Srougi, Miguel ; Nahas, William C. ; Leite, Katia R. ; Viana, Nayara I. ; Reis, Sabrina T.

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 24, n. 11, p. 16-pg., 2023-06-01.

Abstract

MicroRNAs (miRNAs) have gained a prominent role as biomarkers in prostate cancer (PCa). Our study aimed to evaluate the potential suppressive effect of miR-137 in a model of advanced PCa with and without diet-induced hypercholesterolemia. In vitro, PC-3 cells were treated with 50 pmol of mimic miR-137 for 24 h, and gene and protein expression levels of SRC-1, SRC-2, SRC-3, and AR were evaluated by qPCR and immunofluorescence. We also assessed migration rate, invasion, colony-forming ability, and flow cytometry assays (apoptosis and cell cycle) after 24 h of miRNA treatment. For in vivo experiments, 16 male NOD/SCID mice were used to evaluate the effect of restoring miR-137 expression together with cholesterol. The animals were fed a standard (SD) or hypercholesterolemic (HCOL) diet for 21 days. After this, we xenografted PC-3 LUC-MC6 cells into their subcutaneous tissue. Tumor volume and bioluminescence intensity were measured weekly. After the tumors reached 50 mm3, we started intratumor treatments with a miR-137 mimic, at a dose of 6 mu g weekly for four weeks. Ultimately, the animals were killed, and the xenografts were resected and analyzed for gene and protein expression. The animals' serum was collected to evaluate the lipid profile. The in vitro results showed that miR-137 could inhibit the transcription and translation of the p160 family, SRC-1, SRC-2, and SRC-3, and indirectly reduce the expression of AR. After these analyses, it was determined that increased miR-137 inhibits cell migration and invasion and impacts reduced proliferation and increased apoptosis rates. The in vivo results demonstrated that tumor growth was arrested after the intratumoral restoration of miR-137, and proliferation levels were reduced in the SD and HCOL groups. Interestingly, the tumor growth retention response was more significant in the HCOL group. We conclude that miR-137 is a potential therapeutic miRNA that, in association with androgen precursors, can restore and reinstate the AR-mediated axis of transcription and transactivation of androgenic pathway homeostasis. Further studies involving the miR-137/coregulator/AR/cholesterol axis should be conducted to evaluate this miR in a clinical context. (AU)

• FAPESP's process: 18/26528-5 - Adaptive mechanisms of renal function in a model of adriamycin-induced nephrotoxicity: participation of sirtuin 1 and claudin-1
• Grantee: Guilherme Lopes Gonçalves
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/19906-3 - Genomic edition with CRISPR/Cas9 to evaluate the role of MMP9 and the regulator miR21 in Prostate Cancer
• Grantee: Juliana Alves de Camargo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/19138-9 - Study of the effect of miR-137 on cell line of castration resistant prostate cancer in a hypercholesterolemic environment
• Grantee: Vitória Ghazarian Nunes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 22/09284-0 - Searching for alterations in the expression of mismatch-type repair proteins (MLH1, MSH2, MSH6, and PMS2) in Prostate Cancer
• Grantee: Karina Serafim da Silva
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 19/00156-7 - In vivo study of co-activators and co-repressors of androgen receptor in Prostate Câncer
• Grantee: Ruan César Aparecido Pimenta
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/02341-6 - Establishment of the animal model of Peyronie's disease fibrin-induced
• Grantee: Caroline Brandão Chiovatto
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/01317-1 - Evaluation of the role of microRNAs -17-5p and -137 on androgen receptor cofactors in castration-resistant prostate cancer: in vitro and in vivo study in a hypercholesterolemic model
• Grantee: Sabrina Thalita dos Reis Faria
• Support Opportunities: Regular Research Grants