Ligeza Janusz, Marona Paulina, Gach Natalia, Lipert Barbara, Miekus Katarzyna, Wilk Waclaw, Jaszczynski Janusz, Stelmach Andrzej, Loboda Agnieszka, Dulak Jozef, Branicki Wojciech, Rys Janusz, Jura Jolanta
Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland.
Center of Oncology, Maria Skłodowska-Curie Memorial Institute, Garncarska 11, 31-115, Krakow, Poland.
Angiogenesis. 2017 Aug;20(3):325-340. doi: 10.1007/s10456-017-9540-2. Epub 2017 Feb 14.
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.
单核细胞趋化蛋白诱导蛋白1（MCPIP1），也称为Regnase-1，由ZC3H12a基因编码，它通过调节促炎细胞因子编码转录本的稳定性以及控制转录因子（如NF-κB和AP1）的活性来介导炎症过程。我们发现，与周围正常组织相比，在接受肾癌手术治疗的患者来源的透明细胞肾细胞癌（ccRCC）样本中，MCPIP1转录本和蛋白水平显著下调。以Caki-1细胞为模型，我们分析了MCPIP1在癌症发展中的作用。我们发现MCPIP1的表达依赖于蛋白酶体活性；然而，缺氧和缺氧诱导因子2α（HIF2α）是降低MCPIP1表达的关键因素。此外，我们发现MCPIP1负向调节HIF1α和HIF2α的水平，对于后者，其机制基于对HIF2α编码转录本半衰期的调节。Caki-1细胞中MCPIP1表达的增强导致VEGFA、GLUT1和IL-6编码转录本的下调。此外，在常氧条件下，MCPIP1降低mTOR和蛋白激酶B（Akt）的活性。综上所述，MCPIP1促进了ccRCC的发展。
