Background and Aims: The dysregulation of oncogenes and tumor suppressors is a critical factor for the initiation and progression of hepatocellular carcinoma (HCC). Previous studies demonstrated that G-protein-signaling modulator 2 (GPSM2) functions as a tumor suppressor in lung cancer, while acts as an oncogene in breast cancer and pancreatic cancer. However, the expression of GPSM2 in HCC and its biological functions have not been reported yet. This study aimed to investigate the expression GPSM2 in HCC tissues and its effects on cell proliferation and glycolysis. 
Methods: The GPSM2 mRNA and protein expressions in HCC tissues and adjacent non-tumor tissues qRT-PCR and Western blot. The relations of GPSM2 expression in HCC tissues with the clinicopathologic features and prognosis of the patients were analyzed. In HCC Huh7 cells after GPSM2 knockdown by a specific small interfering RNA (siRNA), the changes in cell proliferation as well as the glucose consumption and lactate production were determined by CCK-8 assay and corresponding kits, and the changes in protein levels of the key rate-limiting enzymes of glycolysis hexokinase 2 (HK2), phosphofructokinase, liver type (PFKL) and pyruvate kinase M2 (PKM2) were examined by Western blot. The difference in GPSM2 expression in Huh7 cells between normoxic and hypoxic conditions was compared. 
Results: Both GPSM2 mRNA and protein levels in HCC tissue were significantly higher than those in adjacent nontumor tissue (both P<0.000 1). Results of clinical data analysis indicated that GPSM2 mRNA expression was significantly associated with tumor sized, Edmondson-Steiner grading and TNM stage (all P<0.05). TCGA data analysis based on the GEPIA platform showed that HCC patients with high GPSM2 mRNA level had a significantly lower overall survival and disease-free survival than those with low GPSM2 mRNA level (both P<0.000 1). In Huh7 cells after GPSM2 knockdown, the proliferation was significantly inhibited, and glucose consumption and lactate production were significantly reduced, furthermore, the protein level of HK2 was significantly decreased (all P<0.05). In addition, protein level of GPSM2 was significantly upregulated in hypoxic condition compared with those in normoxic condition (P<0.05). 
Conclusion: The GPSM2 expression is increased in HCC tissue, and is closely related to the unfavorable prognosis of the patients. GPSM2 is a hypoxia response gene, which promotes the proliferation and glycolysis of HCC cells probably by enhancing HK2 expression. These results indicate that GPSM2 is a potential prognostic biomarker and therapeutic target for HCC.