Abstract 1549: Prognostic significance and tumor suppressive functions of SDCT2 in renal cell carcinoma
Authors: Andre R. Jordan, Martin Hennig, Daley S. Morera, Soum D. Lokeshwar, Asif Talukder, Lokeshwar Vinata
Journal: Cancer Research (2017)

Abstract Introduction: Five-year survival of metastatic renal cell carcinoma (mRCC) patients is &amp;lt; 10% and African American (AA) males have the highest incidence. Identification of the molecular determinants of mRCC and racial disparity in RCC is critical for biomarker development and targeted therapy. SDCT2 is expressed in kidney epithelial cells and is a succinate and citrate transporter, but its role has not been examined in any benign diseases or cancer. We examined SDCT2 expression in normal and RCC tissues and correlated it with clinical outcome and racial disparity. We also evaluated the biological functions and molecular signaling regulated by SDCT2 in RCC cells. Methods: Differential gene expression in the matched normal and RCC tissues (n=6/category) was evaluated by microarray analysis; results were validated by quantitative-PCR and immunoblotting in normal and RCC tissues from 53 patients (White=21; Hispanic=19; AA=13). VHL+ and VHL- RCC cells were stably transfected with a Flag-tagged SDCT2 construct. Transfectants were characterized for cell proliferation, cell cycle, motility, succinate/citrate transport and reactive oxygen species (ROS) measurement assays under normoxia and hypoxia (1% O2); cell death and senescence pathway markers were also evaluated. SDCT2 induction was evaluated following 5-azacytidine plus Trichostatin A treatment Results: SDCT2 was 63- and 100-fold downregulated in low- and high-stage RCC tissues, respectively. Q-PCR validation showed that SDCT2 levels were 40-fold downregulated in tumor tissues when compared to normal kidney (P&amp;lt;0.0001 Mann-Whitney test). Downregulation was 40-fold in White and Hispanic patients, but 198-fold in AA patients (P=0.0049) and also correlated with tumor stage and metastasis (P=0.009). Under hypoxia, SDCT2 expression caused over 3-fold inhibition of proliferation, cell-cycle (G1-S block), and motility in both VHL+ and VHL- cells (P&amp;lt;0.01), only VHL+ cells were inhibited under normoxia. SDCT2 expression induced ROS levels and succinate transport by 3-fold in RCC cells (P&amp;lt;0.01). SDCT2 expression induced the p16INK4a-RB pathway and apoptosis (caspase-3 and PARP activation). 5-AZA+TSA treatment caused a 50-fold induction (P&amp;lt;0.0001) of SDCT2 expression. Conclusion: This is the first study on a functional biomarker in RCC, SDCT2, that is a possible novel tumor suppressor gene. SDCT2 loss promotes RCC growth, survival and inhibits cellular senescence and its downregulation correlates with metastasis and racial disparity. Support: Grant NCI/NIH 5R01CA72821; 5R01CA176691 Citation Format: Andre R. Jordan, Martin Hennig, Daley S. Morera, Soum D. Lokeshwar, Asif Talukder, Lokeshwar Vinata. Prognostic significance and tumor suppressive functions of SDCT2 in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1549. doi:10.1158/1538-7445.AM2017-1549