AIM: To investigate the role of signal transduction and activation of 
transcription 4 (STAT4) in the development and progression of human 
hepatocellular carcinoma (HCC).
METHODS: Recent genetic investigations have identified that a genetic variant of 
STAT4 is associated with hepatitis B virus (HBV)-related HCC. The level of STAT4 
in 90 HCC patients was examined via Western blot and immunohistochemical 
analyses. The correlation between STAT4 expression and the clinicopathological 
characteristics of the patients was analyzed. The level of STAT4 expression in 
the HCC liver tissues was significantly lower than that in the non-HCC liver 
tissues and correlated with tumor size, histological grade of HCC and serum 
hepatitis B surface antigen level in HCC patients. The data were statistically 
analyzed using SPSS. Furthermore, siRNA oligos targeting STAT4 were employed to 
investigate the influence of STAT4 RNA interference on HCC cell physiology. 
Based on Cell Counting Kit-8 and flow cytometric assays, we found that depletion 
of STAT4 expression significantly enhanced the proliferation of L02 cells.
RESULTS: STAT4 protein expression was significantly lower in HCC tissues than in 
normal liver tissues. Immunohistochemistry followed by statistical analysis 
revealed that the expression of STAT4 negatively correlated with Ki67 expression 
(r = 0.851; P < 0.05) and positively correlated with maximal tumor size (P < 
0.05), HBV (P = 0.012) and histological grade (P < 0.05). Kaplan-Meier analysis 
revealed significant differences in the survival curves between HCC patients 
expressing low and high levels of STAT4 and Ki67 (P < 0.05). Based on a 
multivariate Cox proportional hazard model, STAT4 expression was an independent 
prognostic indicator for HCC patients who underwent curative resection. In 
vitro, following the release of L02 cell lines from serum starvation, the 
expression of STAT4 was downregulated, and transfection of L02 cells with siRNA 
targeting STAT4 inhibited cell proliferation.
CONCLUSION: Our data indicate that STAT4 may inhibit HCC development by 
modulating HCC cell proliferation.