Clinical Trials Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2015; 21(13): 3983-3993
Published online Apr 7, 2015. doi: 10.3748/wjg.v21.i13.3983
Decreased STAT4 indicates poor prognosis and enhanced cell proliferation in hepatocellular carcinoma
Gang Wang, Jia-Hui Chen, Yong Qiang, Dong-Zhi Wang, Zhong Chen
Gang Wang, Yong Qiang, Dong-Zhi Wang, Zhong Chen, Department of General Surgery, Medical School of Nantong University, Nantong 226000, Jiangsu Province, China
Jia-Hui Chen, Department of Cardiology, Medical School of Fudan University, Shanghai 200000, China
Author contributions: Wang G designed the study; Wang G and Chen JH performed the study; Wang DZ and Qiang Y contributed reagents or analysis tools; and Wang G analyzed the data and wrote the manuscript; all the authors contributed to this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Zhong Chen, Professor, Department of General Surgery, Medical School of Nantong University, West Temple Road, Nantong 226000, Jiangsu Province, China.
Telephone: +86-513-81161001
Received: September 22, 2014
Peer-review started: September 23, 2014
First decision: October 14, 2014
Revised: November 1, 2014
Accepted: December 5, 2014
Article in press: December 8, 2014
Published online: April 7, 2015

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.

Keywords: Signal transduction and activation of transcription 4, Prognosis, Proliferation, Hepatocellular carcinoma

Core tip: In this study, we assessed the role of signal transduction and activation of transcription 4 in hepatocellular carcinoma (HCC) and discussed the possible function of this protein in the development of HCC.