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

Abstract

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-α (PPAR- α), 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-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α 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-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

The Molecular Mechanism of Hepatic Lipid Metabolism Disorder Caused by NaAsO2 through Regulating the ERK/PPAR Signaling Pathway

“…In addition, the content of TG in cells decreased with the increase in arsenic exposure dose. In the study of lipid metabolism in mice exposed to low-dose arsenic, it was found that chronic arsenic exposure could induce the decrease in SREBP-1c expression in the liver, which decreased TG synthesis in hepatocytes [36], and it was consistent with the results of this study. Although the expression levels of SREBP-1c and its downstream gene FASN were decreased, hepatocyte steatosis still occurred in animal experiments.…”

The Versatile Role of miR-21 in Renal Homeostasis and Diseases

“…In this context, miR-21 has been shown to be involved in the resistance to conventional chemotherapies (paclitaxel, 5-Fluorouracil, topotecan and platinum-based therapy) and targeted therapies such as dovitinib and sorafenib by controlling the expression of genes associated with multi-drug resistance (MDR) and the apoptotic pathway (PTEN, PDCD4) [ 85 , 105 , 106 ]. Similar to renal fibrosis, miR-21 seems to also be involved in the metabolic shift characterizing renal cancer by targeting PPAR-α, a master regulator of lipid metabolism [ 107 ]. miR-21 silencing using antisense oligonucleotide or miR-21 sponge strategies decreases the proliferation, invasion and migration of cRCC cells and also increases the expression of pro-apoptotic markers.…”

Determination of in vitro immunotoxic potencies of a series of perfluoralkylsubstances (PFASs) in human Namalwa B lymphocyte and human Jurkat T lymphocyte cells

“…The PFAS-induced decreased expression on RAG1 and RAG2 in Namalwa cells and decreased activity of IL-2 reporter activity in Jurkat cells described here are potentially also mediated by PPARs. Upon activation, PPARs are reported to negatively interfere with nuclear factor κB (NF-κB) and (activator protein-1) AP-1 signaling pathways ( Chinettl et al, 2000 ; Harmon et al, 2011 ; Goujon et al, 2022 ) and in addition, activated PPAR-γ is reported to physically associate with nuclear factor of activated T-cells (NFAT). Upon activation of the T-cell receptor (TCR), NF-kB, AP-1, and NFAT are stimulated and bind to the canonical response element in the promoter of IL-2, leading to transcriptional regulation of IL-2 gene expression.…”