757 HYPERTENSION-RELATED, CALCIUM-REGULATED GENE (HCaRG/COMMD5) INHIBITS KIDNEY CANCER DEVELOPMENT

Abstract

Introduction: Hypertension is an individual risk factor not only for renal failure but also for renal cell carcinoma (RCC). Hypertension-related, calcium-regulated gene (HCaRG/COMMD5)is more expressed in kidneys of the genetically hypertensive rats than normotensive controls. Transgenic mice overexpressing HCaRG in proximal tubules are more resistant to ischemic kidney injury. HCaRG accelerates tubular repair after injury by controlling cell proliferation and facilitating re-differentiation through the induction of p21 via p53-independent pathway. HCaRG expression is lower in RCCs compared to normal adjacent tissues in humans. Hypothesis: HCaRG could be a factor linking hypertension with the risk of RCC. Methods: To elucidate whether HCaRG can inhibit RCC development, we examined the effect of HCaRG overexpression in Renca cells (murine RCC cell line) and a murine RCC homograft model. Results: HCaRG-overexpressing Renca cells exhibited lower cell proliferation rate and more differentiated phenotype compared to Neo-Renca cells. Experimental RCC derived from HCaRG-Renca cells were significantly smaller than tumors of Neo-Renca cells after 10 days of subcutaneous implantation. In the HCaRG-overexpressing tumors, PI3K/Akt and MAPK pathways were inhibited compared to controls. HCaRG overexpression dramatically decreased the expression of EGFR and ErbB3, thus inhibiting the phosphorylation of HER2. Tumor angiogenesis was also reduced in HCaRG-overexpressing tumors and serum VEGF concentrations were lower in mice implanted with HCaRG-Renca cells. Conclusion: HCaRG overexpression inactivated ErbB pathway by inhibiting the expression of EGFR and HER3, and the phosphorylation of HER2, resulting in reduced RCC progression. HCaRG deficiencies may be involved in the risk of RCC in hypertensive patients.