Effects of CD74 on Proliferation and Metastasis in Human clear Cell Renal Cell Carcinoma: Involvement of Vascular Endothelial Growth Factor-D Upregulation

• Main Authors: Yu-Huei Liu, 呂郁蕙
• Other Authors: Jung-Yaw Lin
• Format: Others
• Language: en_US
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/15186865060094166994

博士 === 國立臺灣大學 === 生物化學暨分子生物學研究所 === 97 === According to GLOBALCAN 2002, the recent estimates of the cancer incidence, mortality and prevalence of all the countries of the world, worldwide about 208,000 new cases of kidney cancer have been diagnosed (1.9% of the world total), and 102,000 persons died because of kidney cancer in 2002. Kidney cancer has the highest rates in America, Australia and Europe. Kidney cancer is the 9th most common cancer in the European Union and the 7th most common cancer in men and the 9th in women in the United States. In Taiwan, there are 522 persons died because of kidney cancer in 2007, which is the 14th most common cause of cancer death in men and the 13th in women. Incidence and mortality rates are approximately 1.5 fold as high for men as for women worldwide. Although some factors, such as tobacco smoking, obesity, and environmental chemicals especially arsenic have been thought to be involved in tumorigenesis of kidney cancer, the precise mechanism needs to be identified. Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer (~70%) in adults, which characterized by a high microvascular density produced by tumor-induced neoangiogenesis. Studies have revealed that the major cause of ccRCC is due to loss of the von Hippel-Lindau (VHL) gene, which causes an upregulation of hypoxia-inducible factor-alpha (HIF-alpha) activity, and subsequencely leads to overexpression of VEGF-A. The other groups suggest that link between chronic inflammation and carcinogenesis may play an important role in renal cell carcinoma (RCC), but are not well understood. The undergoing therapies for metastatic ccRCC that include the use of the tyrosine kinase inhibitors as well as anti-EGFR and anti-VEGF agents demonstrate minimal efficacy, therefore to discover new targets for combined cancer therapy is required. 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. By overexpression of CD74 in HEK293 and Caki-2 cells, and downregulation of CD74 in Caki-1 cells, we show that 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 upregulation by CD74 is both PI3K/AKT- and MEK/ERK-dependent, both of which are associated with NF-kappaB nuclear translocation and DNA-binding activity. These results suggest that VEGF-D is crucial for CD74-induced human renal carcinoma cancer cell tumorigenesis.