A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Simple SummaryClear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional systemic therapies and also known for abnormal lipid accumulation. Identifying the actors and deciphering the molecular mechanisms that lead to tumor progression is an important step in the development of new therapeutic strategies to cure ccRCC. In this context, we focused our attention on miR-21, an oncogenic miRNA upregulated in many solid tumors, and peroxysome proliferator-activated receptor-alpha (PPAR- alpha), the master regulator of lipid metabolism and one target of miR-21. In this study, our data show a double-negative feedback interaction between PPAR-alpha and miR-21. Thus, miR-21 silencing could be therapeutically exploited to restore PPAR-alpha expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.& nbsp;Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-alpha (PPAR- alpha), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-alpha downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-alpha overexpression (i) decreased miR-21 expression, AP-1 and NF-kappa B transcriptional activity, and the binding of AP-1 and NF-kappa B to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-alpha expression and transcriptional activity mediated by PPAR-alpha, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-alpha expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-alpha. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-alpha expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

Automated summary

Clear cell renal cell carcinoma (ccRCC) is a highly resistant type of kidney cancer with abnormal lipid accumulation. This study reveals a double-negative feedback interaction between miR-21 and PPAR-alpha, suggesting that miR-21 silencing could restore PPAR-alpha expression and inhibit the oncogenic events mediated by abnormal lipid metabolism in ccRCC.