Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80-90 % of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment. Here, we investigate the effects of CBFA2T2 on CSCs regulation in RCC, as well as to elucidate the possible mechanisms. We showed that CBFA2T2 expression can significantly predict the survival of RCC patients. Functional assays showed that knocking-down of CBFA2T2 can inhibit cell migration and invasion in 786-O and A-498 cells in vitro, and reduce ALDH high CSCs populations. Furthermore, CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines. Collectively, our data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of "stemness" through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment.KEYWORDS: CBFA2T2; renal cell carcinoma; cancer stem cells; OCT-4; NANOG INTRODUCTIONRenal cell carcinoma (RCC) represents one of the most common type of renal cancer, accounting for 90% of adult renal malignancies (1). The prognosis of advanced RCC is very poor, with a 5-year survival rate of 5-10% (2). In addition, around 20-40% of RCC patients developed recurrence after treatment (3). The mechanisms of how these metastasis and recurrence occur are largely uncharacterized. Recent studies have shown the presence of cancer stem cells (CSCs) in various solid tumor tissues (4-6). CSCs are undifferentiated multipotential tumor cells that have high tumorigenic activity and the capacity to self-renew (4, 5, 7). Moreover, CSCs promote cancer resistance to treatment and recurrence, leading to high mortality (5). Therefore, CSC-targeted therapy can be an essential part of cancer therapy.Previously, CSCs in RCC have been identified by using either stem cell markers (CD133, CD44, CXCR4 and CD105) (8-11) or functional assays (sphere-forming ability, side population and ALDH activity) (12)(13)(14). Especially, in RCC cell lines, ALDH high cells showed CSC properties in vitro, such as clonogenic and self-renewal ability and increased expression of OCT4 and NANOG (15). Importantly, in the metastatic RCC cell lines, ALDH high cells formed about 15% of the total number of cells and had higher Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: