Expression of microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4

Abstract

The microRNA miR-17-92 cluster plays a fundamental role in heart development. The aim of this study was to investigate the effect of a member of this cluster, miR-17, on cardiac senescence. We examined the roles of miR-17 in senescence and demonstrated that miR-17-3p attenuates cardiac aging in the myocardium by targeting Par4 (also known as PAWR). This upregulates the downstream proteins CEBPB, FAK, N-cadherin, vimentin, Oct4 and Sca-1 (also known as stem cell antigen-1), and downregulates E-cadherin. Par4 has been reported as a tumor suppressor gene that induces apoptosis in cancer cells, but not in normal cells. Repression of Par4 by miR-17-3p enhances the transcription of CEBPB and FAK, which promotes mouse cardiac fibroblast (MCF) epithelial-tomesenchymal transition (EMT) and self-renewal, resulting in cellular senescence and apoptosis resistance. We conclude that Par4 can bind to the CEBPB promoter and inhibit its transcription. Decreased Par4 expression increases the amount of CEBPB, which binds to the FAK promoter and enhances FAK transcription. Par4, CEBPB and FAK form a senescence signaling pathway, playing roles in modulating cell survival, growth, apoptosis, EMT and self-renewal. Through this novel senescence signaling axis, miR-17-3p represses Par4 expression, acting pleiotropically as a negative modulator of cardiac aging and cardiac fibroblast cellular senescence.

MicroRNA-17-5p: At the Crossroads of Cancer and Aging - A Mini-Review

“…In addition, overexpression of pre-miR-17 in mouse cardiac fibroblasts enhances cell survival upon oxidative stress, increases proliferation and reduces senescence-associated β-galactosidase staining [33], whereby the miR-17-3p component of the pre-miR-17 activates a transcriptional program that promotes epithelial-to-mesenchymal transition and self-renewal while suppressing senescence, and might even act as a miR-17-5p antagomiR.…”

Non-Coding RNAs in Cardiac Aging

“…Cardiac fibroblasts are also required for cardiac remodeling [10,11]. Cardiac fibroblasts undergo senescence, growth-arrest and epithelial-mesenchymal transition (EMT) [12,13]. Cellular senescence is the universal and fundamental process of aging.…”

“…In addition, the expression of miR-17-3p in aging hearts was lower than the young hearts. Par-4 was demonstrated to be a direct target of miR-17 [13]. Par-4, known as pro-apoptotic protein, is a critical regulator of tumor cell survival and is also required for cell apoptosis [42,43].…”

“…Par4 negatively regulates its transcript factors, CEBPB and Focal Adhesion Kinase (FAK), which promotes MCF epithelial-mesenchymal transition (EMT) and self-renewal, resulting in cellular senescence and apoptosis-resistance. MiR-17-3p plays an anti-aging role by targeting Par4, and promoting CEBPB/FAK senescence related signaling pathway in the transgenic mice and transfected cells [13]. …”

Papel da expressão celular e extracelular do Par-4 na formação tumoral e sensibilidade a droga

“…Sendo assim, diversos estímulos são encontrados na literatura descritos como moduladores da expressão de Par-4, dentre eles: fatores de crescimento e hormonal (CASOLARI et al, 2011;CHAN et al, 1999;CHUNG et al, 2007); quimioterápicos (JAGTAP et al, 2014); diversas quinases (DE THONEL et al, 2014;GURUMURTHY;VASUDEVAN, 2005); membros da família RAS (DONNINGER et al, 2010);p53 (BURIKHANOV et al, 2014);Fbxo45 (CHEN et al, 2014); e miRNAs (DU et al, 2015). …”