AbstractBackgroundHepatocelluar carcinoma (HCC) is one human cancer with obvious gender disparity. This study investigated the association of aberrant prolactin levels with HCC risk and the potential impacts on HCC of the prolactin receptor (PRLR)/Janus kinase 2 (JAK2) signaling.MethodsSerum prolactin of 63 HCC patients and 162 subjects without HCC was measured by radioimmunoassay. The expressions of PRLR and phosphorylated JAK2 (p‐JAK2) in 82 retrospectively collected HCC specimens were evaluated by immunohistochemistry and further incorporated into the survival analysis. The immunoblotting and proliferation assays were used to analyze the effects of PRLR/JAK2 signaling on liver cancer cells with prolactin treatment.ResultsSerum prolactin level was significantly higher in HCC patients than in controls. Hepatocellular carcinoma patients with high p‐JAK2 expression had a significantly higher postoperative risk than those with low p‐JAK2 expression. Moreover, results from the multivariate analysis indicated the prognostic role of p‐JAK2 expression with respect to overall survival in HCC patients. In addition, the Kaplan–Meier survival curve showed that high p‐JAK2 expression was associated with poor survival in HCC patients with high PRLR expression. The immunoblotting assay showed that prolactin induced the expression of both p‐JAK2 and cyclin D1 in Hep‐G2 cells. Importantly, the proliferative effects induced by prolactin could be effectively attenuated by adding AG490, a JAK2 inhibitor.ConclusionsIncreased circulating prolactin was found in HCC patients and high p‐JAK2 expression could predict poor overall survival in those patients expressing high PRLR. In addition, prolactin contributed to the proliferation of liver cancer cells through PRLR/JAK2 signaling.