Abstract
Monocyte Chemoattractant protein-induced protein 1 (MCPIP1), also known as Regnase-1, is encoded by the ZC3H12a gene, and it mediates inflammatory processes by regulating the stability of transcripts coding for proinflammatory cytokines and controlling activity of transcription factors, such as NF-κB and AP1. We found that MCPIP1 transcript and protein levels are strongly downregulated in clear cell renal cell carcinoma (ccRCC) samples, which were derived from patients surgically treated for renal cancer compared to surrounded normal tissues. Using Caki-1 cells as a model, we analyzed the role of MCPIP1 in cancer development. We showed that MCPIP1 expression depends on the proteasome activity; however, hypoxia and hypoxia inducible factor 2 alfa (HIF2α) are key factors lowering MCPIP1 expression. Furthermore, we found that MCPIP1 negatively regulates HIF1α and HIF2α levels and in the case of the last one, the mechanism is based on the regulation of the half time of transcript coding for HIF2α. Enhanced expression of MCPIP1 in Caki-1 cells results in a downregulation of transcripts encoding VEGFA, GLUT1, and IL-6. Furthermore, MCPIP1 decreases the activity of mTOR and protein kinase B (Akt) in normoxic conditions. Taken together, MCPIP1 contributes to the ccRCC development.
Highlights
Kidney cancer is among the ten most common cancers in both men and women
We showed that Monocyte Chemoattractant protein-induced protein 1 (MCPIP1) expression depends on the proteasome activity; hypoxia and hypoxia inducible factor 2 alfa (HIF2a) are key factors lowering MCPIP1 expression
We found that MCPIP1 levels are substantially lower in clear cell renal cell carcinoma (ccRCC) samples than in the surrounding tissues
Summary
More than 90% of kidney cancers originate from epithelial cells and are referred to as renal cell carcinoma (RCC). In more than 90% of ccRCC samples, the loss of short arm chromosome 3 is observed [2]. This deletion includes the locus for the von Hippel–Lindau (VHL) tumor suppressor gene, responsible for regulating the stability of hypoxia inducible factors, HIF-1a and HIF-2a. The VHL protein forms a stable complex with other proteins, possessing E3 ubiquitin ligase activity. This complex is responsible for targeting HIFs for polyubiquitination and subsequent proteasomal degradation [3]. Further studies have shown that other genes in the short arm of chromosome 3, which are responsible for the chromatin remodeling and epigenetic modifications, are crucial for ccRCC development [5,6,7]
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