The anti-inflammatory protein MCPIP1 inhibits the development of ccRCC by maintaining high levels of tumour suppressors
| Autor: | Janusz Rys, Oliwia Kwapisz, Judyta Górka, Paulina Marona, Katarzyna Miekus, Jolanta Jura |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine PTEN TIMP3 tumour suppressors Mice SCID Matrix metalloproteinase law.invention Proinflammatory cytokine Mice 03 medical and health sciences Ribonucleases 0302 clinical medicine Mice Inbred NOD law Cell Line Tumor medicine Animals Humans RECK Carcinoma Renal Cell Aged Aged 80 and over Inflammation Pharmacology biology Tumor Suppressor Proteins Monocyte MCPIP1 Middle Aged medicine.disease Regnase-1 Clear cell renal cell carcinoma 030104 developmental biology medicine.anatomical_structure Apoptosis Cell culture Cancer research biology.protein Suppressor Female MMPs 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | European Journal of Pharmacology. 888:173591 |
| ISSN: | 0014-2999 |
| Popis: | Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. It is highly vascularized and largely resistant to traditional chemo- and radiotherapy. Decreases in tumour suppressors and low levels of the anti-inflammatory Monocyte Chemoattractant Protein-Induced Protein 1 (MCPIP1) play important roles in the development and progression of ccRCC. MCPIP1, also called Regnase-1, possesses endonuclease activity and degrades the mRNA of proinflammatory cytokines such as IL-6, IL-1β, IL-12 and IL-2. We previously showed that the level of MCPIP1 decreases with ccRCC progression. In this study, we explored the role of MCPIP1 in regulating the levels of tumour suppressors. We found low levels of the suppressors PTEN, RECK and TIMP3 and high levels of MMPs in patients with ccRCC who had already been shown to have low MCPIP1 expression. We demonstrated that MCPIP1 regulates the expression levels of PTEN, RECK and TIMP3 in ccRCC cell lines as well as in vivo models of ccRCC. MCPIP1 overexpression increased the expression of tumour suppressors. Moreover, we observed that the RNase activity of MCPIP1 is responsible for the modulation of apoptosis and activation of prometastatic signalling pathways. Furthermore, we found a negative correlation between high levels of IL6, a direct target of MCPIP1 RNase activity, and TIMP3 in patients, indicating that MCPIP1 and TIMP3 might collectively cause the high levels of IL6 in ccRCC patients. Taken together, our results show the importance of MCPIP1 in regulating the level of tumour suppressors and, consequently, in ccRCC development and progression. |
| Databáze: | OpenAIRE |
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