In this study, we sought to predict the effects of a certain circular RNA (circRNA), hsa_circ_101280 (also known as hsa_circ_0100929 and hsa_circ_SLAIN1), on hepatocellular carcinoma (HCC) cells and to determine the potential mechanism. After screening differentially expressed circRNAs in HCC tissues through Gene Expression Omnibus data analysis, hsa_circ_101280 was found to be highly expressed, and its high expression was verified in HCC cell lines with qRTāPCR along with the low expression of its downstream miRNA miRā375. Colony formation and flow cytometry assays showed that both hsa_circ_101280 silencing and miRā375 overexpression restrained proliferation and promoted apoptosis in HCC cells. JAK2 was identified as a downstream mRNA target of miRā375 by RNA pullādown and dualāluciferase reporter gene assays, its expression in HCC cell lines were positively regulated by hsa_circ_101280 and negatively by miRā375 expression. Furthermore, the silencing of hsa_circ_101280 significantly inhibited the growth of HCC xenografts in nude mice, with the downregulated expression of JAK2. Overall, both the inĀ vitro and inĀ vivo studies revealed that hsa_circ_101280 largely facilitated the tumorigenesis of HCC, characterized by the promoted proliferation and suppressed apoptosis of HCC cells, by sponging miRā375 and upregulating JAK2.