Six1 is negatively correlated with poor prognosis and reduces 5-fluorouracil sensitivity via attenuating the stemness of hepatocellular carcinoma cells.

The promoting roles of transcriptional factor six1 have been shown in various tumors, such as breast cancer and colorectal Cancer. However, its roles in hepatocellular carcinoma (HCC) cell stemness and chemotherapeutic sensitivity are never been revealed. In the present study, we showed that six1 expression was negatively correlated the overall survival of HCC patients and significantly increased in HCC tissues. Analysis on normal hepatic cells and HCC cells obtained the consistent result. Functional experiments revealed that six1 knockdown enhanced 5-fluorouracil (5-FU) sensitivity and reduced the stemness of HCC cells. Additionally, six1 knockdown partially reversed 5-FU resistance and attenuated the stemness in 5-FU-resistant HCC cells. Furthermore, we demonstrated that six1 directly bound to sox2 (a stemness master regulator) promoter, enhanced its transcription and expression. Overexpression of sox2 rescued the inhibitory effects of six1 knockdown on the stemness and 5-FU sensitivity of HCC cells. Thus, our work identified a novel six1/sox2 axis in regulating the stemness of HCC cells.