As reported in many research, LncRNA CTBP1 divergent transcript (CTBP1-AS2) remarkably affects the progression of several tumors. However, the precise role and function of CTBP1-AS2 in hepatocellular carcinoma (HCC) remained unknown. We found that CTBP1-AS2 expressions were increased in HCC samples and cells. After treatment with microwave ablation (MWA), CTBP1-AS2 was distinctly up regulated in residual HCC tissues compared with HCC samples. CTBP1-AS2 was upregulated under the induction of the nuclear transcription factor SP1. As revealed by the clinical assays, high CTBP1-AS2 expression usually related to lymph node metastasis, clinical stage and weaker prognosis specific to HCC patients. Functionally, CTBP1-AS2 knockdown suppressed HCC cells in terms of the proliferation, migration, invasion, chemotherapy resistance as well as EMT progress, but promoted apoptosis. Mechanistically, CTBP1-AS2 was a sponge of miR-195-5p for elevating CEP55 expression, a target of miR-1955p, and thereby exhibited its oncogenic roles in HCC progression. Overall, an emerging regulatory mechanism of SP1/CTBP1-AS2/miR-195-5p/CEP55 axis was reported in the paper, which possibly served as a new therapeutic HCC treatment target. (c) 2020 Elsevier Inc. All rights reserved.