MCPIP1 downregulation in clear cell renal cell carcinoma promotes vascularization and metastatic progression
| Autor: | Janusz Rys, Judyta Górka, Waclaw Wilk, Paulina Marona, Jolanta Jura, Marcin Majka, Katarzyna Miekus, Zofia Mazurek |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology medicine.medical_specialty Angiogenesis Down-Regulation Apoptosis Mice SCID Biology Proinflammatory cytokine Mice 03 medical and health sciences Ribonucleases Downregulation and upregulation Cell Movement Mice Inbred NOD Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Neoplasm Metastasis Phosphorylation Carcinoma Renal Cell Cell Proliferation Neoplasm Staging Inflammation Neovascularization Pathologic Cell growth Cell Cycle Cancer Cell cycle Prognosis medicine.disease Xenograft Model Antitumor Assays Kidney Neoplasms Clear cell renal cell carcinoma 030104 developmental biology Oncology Disease Progression Cancer research Female Neoplasm Grading Kidney cancer Signal Transduction Transcription Factors |
| Popis: | Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL6, IL1, and IL12. MCPIP1 is also a negative regulator of NFκB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patient-derived tumors and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumor outgrowth, and vascularity. MCPIP1 activity regulated secretion of VEGF, IL8, and CXCL12 leading to chemotaxis of microvascular endothelial cells, phosphorylation of VE-cadherin, and increased vascular permeability. Mechanistic investigations showed that MCPIP1 regulated ccRCC cell motility, lung metastasis, and mesenchymal phenotype by regulating key elements in the EMT signaling axis. Overall, our results illuminate how MCPIP1 serves as a key nodal point in coordinating tumor growth, angiogenesis, and metastatic spread in ccRCC. Cancer Res; 77(18); 4905–20. ©2017 AACR. |
| Databáze: | OpenAIRE |
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