Abstract 683: NaDC3: a potential tumor suppressor and biomarker in renal cell carcinoma

Introduction and Objective: The five-year survival rate for patients with metastatic renal cell carcinoma (mRCC) is less than 10%, with the highest incidence found among African American males. Addressing racial disparities in renal cell carcinoma (RCC) are essential for the development of biomarkers and targeted therapies. NaDC3, a succinate/citrate transporter expressed in kidney epithelial cells, has not yet been studied in relation to any diseases. In our research, we assessed NaDC3 expression in both normal and RCC tissues and examined its correlation with clinical outcomes and racial disparities. Additionally, we investigated the biological functions and molecular signaling pathways influenced by NaDC3 in RCC cells. Methods: Differences in gene expression in the matched normal and RCC tissues (n=6/category) was evaluated using microarray analysis; results were then validated by QPCR and immunoblotting in tissues from 83 patients (White=46; Hispanic=24; AA=13). VHL+ and VHL- RCC cells were stably transfected with a NaDC3 construct. Transfectants were assessed for cell proliferation, cell cycle, motility, succinate/citrate transport and reactive oxygen species (ROS) measurement assays under normoxic and hypoxic conditions. SDCT2 induction was evaluated following 5-azacytidine plus Trichostatin A treatment. Results: NaDC3 was 63- and 100-fold downregulated in low- and high-stage RCC tissues respectively. QPCR validation showed 40-fold downregulation of NaDC3 in RCC tissues when compared to normal kidney (P< 0.0001). Downregulation was 40-fold in White and Hispanic patients, but 198-fold in AA patients (P=0.0049) and correlated with tumor stage and metastasis (P=0.009). Under hypoxic conditions, NaDC3 expression caused 3-4-fold inhibition of proliferation, cell-cycle, and motility in both VHL+ and VHL- cells (P<0.01); only VHL+ cells were inhibited under normoxia. NaDC3 expression induced ROS levels and succinate transport by >3-fold (P<0.01) and activated the p16INK4a-RB pathway and apoptosis (caspase-3 and PARP activation). NaDC3 expression was silenced in patient-derived primary cell lines from AA patients. Conclusion: This is the first study on a functional biomarker in RCC, NaDC3, that is a possible novel tumor suppressor gene. NaDC3 loss promotes RCC growth and survival and inhibits cellular senescence, while its downregulation correlates with metastasis and racial disparity. Support: 1R01CA227277-05A1; 1R01CA283699-01 Citation Format: Miswakumari Lad, Tianyu Yang, Karina Aguilar, Vinata Lokeshwar. NaDC3: a potential tumor suppressor and biomarker in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 683.