Analysis of the clinicopathological data of 76 HBV-HCC cases revealed that the medium-to-high expression rates of RSK2 and CREB were significantly higher in the tumor diameter ≥5 cm group than in the tumor diameter <5 cm group, suggesting that RSK2 and CREB expression may be associated with the development of tumors. This evidence concerns the gene CREB1 and hepatocellular carcinoma.