title: Protease-activated receptor 2 signaling upregulates angiogenic growth factors in renal cell carcinoma.
abstract: Renal cell carcinoma (RCC) is a highly vascular tumor associated with expression of various angiogenic growth factors. The precise process of how these growth factors are regulated in RCC is not fully understood. Recent evidence suggests that protease activated receptors (PARs), a new family of G-protein coupled receptors, play a crucial role in vascular development and tumor progression through a variety of mechanisms. However, the nature of PAR expression in human RCC tissues and its function in regulating angiogenesis in RCC are largely unknown. In this study, we investigated the expression and function of PAR-2 in RCC. RT-PCR and immunohistochemistry assays show that PAR-2 expression is significantly increased in human RCC tissue compared with the adjacent non-neoplastic kidney tissue. In RCC derived cells, PAR-2 is functional as evidenced by robust signaling through MAP kinases including ERK1/2 and JNK. Furthermore, activation of PAR-2 significantly upregulates several angiogenic cytokines, including interleukin-6 (IL-6), IL-8, monocytes chemotactic protein-1 (MCP-1) and growth-related oncogene (GRO). To our knowledge, this is the first report that characterized PAR-2 expression in RCC tissue and further demonstrated that PAR-2 has a critical role in regulating angiogenesis in RCC.
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington 98195, United States. xiaotun@u.washington.edu
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wang
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Mize
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Takayama
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000378:metabolism*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007680:Kidney Neoplasms / Q000098:blood supply / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009389:Neovascularization, Pathologic; D044464:Receptor, PAR-2 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D042501:Angiogenic Proteins; C111835:CCL2 protein, human; C475829:CXCL1 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D015850:Interleukin-6; D016209:Interleukin-8; D044464:Receptor, PAR-2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases