Background <p>Long non-coding RNAs (lncRNAs) play an important regulatory role in tumorigenesis and progression. However the role of TAF1A-AS1 in hepatocellular carcinoma (HCC) remains unclear. Therefore, this study aimed to clarify the specific role of TAF1A-AS1 in regulating tumorigenesis and progression of HCC.</p> Methods <p>Quantitative real-time PCR (qRT-PCR) was used to determine the expression of TAF1A-AS1, miR-664b-3p and USP22 in tissue samples and cell lines. Functional assays, including Cell Counting Kit-8 (CCK-8) assay, colony formation assay, transwell assays and chemoresistance assay, were performed to study the effects of TAF1A-AS1 in HCC cells. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to examine the interaction between TAF1A-AS1 and miR-664b-3p, as well as between miR-664b-3p and USP22. A nude mouse xenograft model was established for the in vivo experiments.</p> Results <p>TAF1A-AS1 was remarkably upregulated in HCC tissues, and patients with high TAF1A-AS1 expression had poorer prognosis. Both in vitro and in vivo experiments showed that TAF1A-AS1 promoted the proliferation, invasion and tumorigenicity of HCC cells. Furthermore, mechanism study revealed that TAF1A-AS1 served as a sponge of miR-664b-3p, and USP22 was identified as a downstream target of miR-664b-3p. Additionally, TAF1A-AS1 affected HCC cells sensitivity to sorafenib and activated mTOR signaling through USP22.</p> Conclusion <p>Our study demonstrated that TAF1A-AS1 regulated the progression of HCC by sponging miR-664b-3p to activate USP22. These results suggest that TAF1A-AS1 could be a novel HCC prognostic biomarker and a potential therapeutic target.</p>