A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma
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 prol...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/3/795 |
| _version_ | 1797488633098272768 |
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| author | Marine Goujon Justine Woszczyk Kelly Gaudelot Thomas Swierczewski Sandy Fellah Jean-Baptiste Gibier Isabelle Van Seuningen Romain Larrue Christelle Cauffiez Viviane Gnemmi Sébastien Aubert Nicolas Pottier Michaël Perrais |
| author_facet | Marine Goujon Justine Woszczyk Kelly Gaudelot Thomas Swierczewski Sandy Fellah Jean-Baptiste Gibier Isabelle Van Seuningen Romain Larrue Christelle Cauffiez Viviane Gnemmi Sébastien Aubert Nicolas Pottier Michaël Perrais |
| author_sort | Marine Goujon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T00:05:05Z |
| format | Article |
| id | doaj.art-31e08578c135436e8296bbdf752f65e6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T00:05:05Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-31e08578c135436e8296bbdf752f65e62023-11-23T16:08:47ZengMDPI AGCancers2072-66942022-02-0114379510.3390/cancers14030795A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell CarcinomaMarine Goujon0Justine Woszczyk1Kelly Gaudelot2Thomas Swierczewski3Sandy Fellah4Jean-Baptiste Gibier5Isabelle Van Seuningen6Romain Larrue7Christelle Cauffiez8Viviane Gnemmi9Sébastien Aubert10Nicolas Pottier11Michaël Perrais12Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, FranceClear 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.https://www.mdpi.com/2072-6694/14/3/795miR-21PPAR-αrenal cancerccRCClipidNF-κB |
| spellingShingle | Marine Goujon Justine Woszczyk Kelly Gaudelot Thomas Swierczewski Sandy Fellah Jean-Baptiste Gibier Isabelle Van Seuningen Romain Larrue Christelle Cauffiez Viviane Gnemmi Sébastien Aubert Nicolas Pottier Michaël Perrais A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma Cancers miR-21 PPAR-α renal cancer ccRCC lipid NF-κB |
| title | A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma |
| title_full | A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma |
| title_fullStr | A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma |
| title_full_unstemmed | A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma |
| title_short | A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma |
| title_sort | double negative feedback interaction between mir 21 and ppar α in clear renal cell carcinoma |
| topic | miR-21 PPAR-α renal cancer ccRCC lipid NF-κB |
| url | https://www.mdpi.com/2072-6694/14/3/795 |
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