MCPIP1 contributes to clear cell renal cell carcinomas development

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. Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-017-9540-2) contains supplementary material, which is available to authorized users.

MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression

“…It is in concordance with previous findings showing that MCPIP1 regulates the level of IL6 and IL8 transcripts by binding to stem-loop structures present in 3 0 UTRs (13,39). VEGF expression is induced by HIF (hypoxia-inducible factors), and we have previously demonstrated that MCPIP1 overexpression reduces the level of HIFs and transcripts for VEGF (25). However, it was suggested that HIF1-independent mechanisms regulating VEGF expression may also exist.…”

“…23,24). Our recent findings have suggested that MCPIP1 may decrease the level of HIFs in tumor cells, and we showed that MCPIP1 is downregulated in ccRCC samples compared with normal tissue (25). In this study, we demonstrate that decreasing the MCPIP1 protein level correlates with renal cancer progression and better tumor vascularity.…”

“…Moreover, the same study showed that MCPIP1 expression in breast cancer samples was reduced compared with that in healthy tissue, and low MCPIP1 expression was associated with tumor progression and poor survival (22). Our group has already demonstrated that ccRCC tumors have a lower level of MCPIP1 than normal renal tissues, and MCPIP1 overexpression decreases viability and proliferation of ccRCC cells (25). These findings led us to evaluate the level of MCPIP1 during tumor progression and the influence of MCPIP1 downregulation on ccRCC.…”

“…There is growing evidence that MCPIP1 plays a role during the process of tumorigenesis. It has been already demonstrated that MCPIP1 regulates the viability and proliferation of neuroblastoma (20), HeLa, HepG2 (19), ccRCC (25), and breast cancer cells (21). Previous findings have demonstrated that MCPIP1 degrades the mRNA of antiapoptotic gene transcripts in breast cancer cells, leading to apoptosis and tumor regression (22).…”

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

“…Brain ischaemia-reperfusion injury and neuronal apoptosis are also related to Mst1 activation [24, 25]. Mst1 also participates in atherosclerosis progression via autophagy inhibition and macrophage apoptosis [26]. Many researchers have attempted to demonstrate the promotive effects of Mst1 on acute cell death.…”