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Up-Regulation of Vascular Endothelial Growth Factor-D Expression in Clear Cell Renal Cell Carcinoma by CD74: A Critical Role in Cancer Cell Tumorigenesis¹

Yu-Huei Liu^*, Chang-Yueh Lin^*, Wei-Chou Lin, Sai-Wen Tang^*, Ming-Kuen Lai and Jung-Yaw Lin^2,*

^* Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pathology and Department of Urology, National Taiwan University Hospital, Taipei, Taiwan

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-B nuclear translocation and DNA-binding activity. These results suggest that VEGF-D is crucial for CD74-induced human renal carcinoma cancer cell tumorigenesis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Science Council 96-2320-B-002-084 Grant from the National Science Council of Taiwan.

² Address correspondence and reprint requests to Dr. Jung-Yaw Lin, Room 942, Number 1, Jen-Ai Road, First Section, Taipei, Taiwan. E-mail address: linjy{at}ntu.edu.tw

³ Abbreviations used in this paper: RCC, renal cell carcinoma; ccRCC, clear cell RCC; VEGF, vascular endothelial growth factor; MHC-II, MHC class II; MIF, macrophage inhibitory factor; q, quantitative; TPT1, translationally-controlled 1; siRNA, short interference RNA; ChIP, chromatin immunoprecipitation; Ct, cycle threshold.