AbstractWe aimed to explore the function and underlying mechanism of highly upregulated in liver cancer (HULC; an long noncoding RNAs) in hepatocellular carcinoma (HCC) and chemosensitivity of oxaliplatin (Oxa). The expression of HULC, miR‐383‐5p, and vesicle‐associated membrane protein‐2 (VAMP2) was detected by quantitative real‐time polymerase chain reaction. Western blot assay was applied for measuring the protein expression of cyclinD1, cleaved‐caspase‐3, light Chain 3 I/II, p62, and VAMP2. Cell viability and Oxa IC50 value were determined by Cell Counting Kit‐8 assay. A colony formation assay was conducted to evaluate colony formation ability. Cell apoptosis was assessed by flow cytometry. The interaction between miR‐383‐5p and HULC or VAMP2 was predicted by bioinformatics analysis and verified by dual‐luciferase reporter assay and RNA immunoprecipitation assay. The mice xenograft model was established to investigate the roles of HULC in vivo. HULC and VAMP2 were overexpressed whereas miR‐383‐5p was lowly expressed in HCC tissues. HULC overexpression promoted the progression of HCC cells and inhibited chemosensitivity of Oxa by increasing cell proliferation and protective autophagy and inhibiting apoptosis, whereas HULC silence presented opposite effects. Moreover, miR‐383‐5p was a direct target of HULC and miR‐383‐5p reversed the effects of HULC on the progression of HCC cells and chemosensitivity of Oxa. Besides, HULC acted as a molecular sponge of miR‐383‐5p to regulate VAMP2 expression. HULC promoted the progression of HCC and inhibited Oxa sensitivity by regulating miR‐383‐5p/VAMP2 axis, elucidating a novel regulatory mechanism for chemosensitivity of Oxa and providing a potential lncRNA‐targeted therapy for HCC.