Up-regulation of vascular endothelial growth factor-D expression in clear cell renal cell carcinoma by CD74: A critical role in cancer cell tumorigenesis
Journal
Journal of Immunology
Journal Volume
181
Journal Issue
9
Pages
6584-6594
Date Issued
2008
Author(s)
Abstract
Elevation of CD74 is associated with a number of human cancers, including clear cell renal cell carcinoma (ccRCC). To understand the role of CD74 in the oncogenic process of ccRCC, we ectopically expressed CD74 in human embryonic kidney 293 cells (HEK/CD74) and evaluated its oncogenic potential. Through overexpression of CD74 in HEK293 and Caki-2 cells and down-regulation of CD74 in Caki-1 cells, we show that vascular endothelial growth factor-D (VEGF-D) expression is modified accordingly. A significant, positive correlation between CD74 and VEGF-D is found in human ccRCC tissues (Pearson's correlation, r = 0.65, p < 0.001). In HEK/CD74 xenograft mice, CD74 significantly induced the formation of tumor masses, increased tumor-induced angiogenesis, and promoted cancer cell metastasis. Blockage of VEGF-D expression by small interference RNA resulted in a decrease in cell proliferation, invasion, and cancer cell-induced HUVEC migration enhanced by CD74. Furthermore, we provide evidence that the intracellular signaling cascade responsible for VEGF-D up-regulation by CD74 is both PI3K/AKT- and MEK/ERK-dependent, both of which are associated with NF-κB nuclear translocation and DNA-binding activity. These results suggest that VEGF-D is crucial for CD74-induced human renal carcinoma cancer cell tumorigenesis. Copyright ? 2008 by The American Association of Immunologists, Inc.
SDGs
Other Subjects
cd74 protein; immunoglobulin enhancer binding protein; membrane protein; mitogen activated protein kinase; phosphatidylinositol 4 phosphate kinase; protein kinase B; small interfering RNA; unclassified drug; vasculotropin D; B lymphocyte antigen; HLA antigen class 2; vasculotropin D; angiogenesis; animal cell; animal experiment; animal model; animal tissue; article; cancer cell; carcinogenesis; cell invasion; cell migration; cell proliferation; cell strain HEK293; chromatin immunoprecipitation; clear cell carcinoma; controlled study; correlation coefficient; DNA binding; down regulation; endothelium cell; female; flow cytometry; human; human cell; human tissue; immunohistochemistry; kidney carcinoma; kidney cell; metastasis; mouse; nonhuman; oncogene; priority journal; protein expression; reverse transcription polymerase chain reaction; tumor promotion; umbilical vein; upregulation; Western blotting; xenograft; animal; biosynthesis; cell line; cell transformation; coculture; gene expression regulation; genetics; immunology; invariant chain; kidney carcinoma; kidney tumor; metabolism; mouse mutant; neovascularization (pathology); nonobese diabetic mouse; pathology; physiology; tumor cell line; upregulation; vascular endothelium; Animals; Antigens, Differentiation, B-Lymphocyte; Carcinoma, Renal Cell; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Coculture Techniques; Endothelium, Vascular; Female; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens Class II; Humans; Kidney Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neovascularization, Pathologic; Transplantation, Heterologous; Up-Regulation; Vascular Endothelial Growth Factor D
Publisher
American Association of Immunologists
Type
journal article