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Clinicopathological significance of STAT4 in hepatocellular carcinoma and its effect on cell growth and apoptosis

Authors Li J, Liang L, Liu Y, Luo Y, Liang X, Luo D, Feng ZB, Dang Y, Yang L, Chen G

Received 7 November 2015

Accepted for publication 9 January 2016

Published 21 March 2016 Volume 2016:9 Pages 1721—1734

DOI https://doi.org/10.2147/OTT.S100040

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Wei An

Peer reviewer comments 2

Editor who approved publication: Dr Faris Farassati


Jianjun Li,1,* Lu Liang,2,* Yongru Liu,2 Yihuan Luo,2 Xiaona Liang,2 Dianzhong Luo,2 Zhenbo Feng,2 Yiwu Dang,2 Lihua Yang,3 Gang Chen2

1
Department of General Surgery, Western Branch, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Pathology, 3Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China

*These authors contributed equally to this work

Background: Recent studies showed that signal transducer and activator of transcription 4 (STAT4) was downregulated in hepatocellular carcinoma (HCC) tissues. However, the role of STAT4 in HCC is still unknown. The aim of this study is to explore the association between STAT4 expression and other clinicopathological features in HCC and to test the effect of STAT4 on cell growth and apoptosis in vitro.
Methods: STAT4 was evaluated by immunohistochemistry in 171 HCC and corresponding paraneoplastic liver, 37 cirrhosis, and 33 normal liver tissues. Association between STAT4 and clinicopathological parameters was analyzed. Meta-analysis on STAT4 in cancer was performed. The effect of STAT4 small interfering RNA (siRNA) on cell growth and cell apoptosis was also detected.
Results: Positive rate of STAT4 was 29.2% (50/171) in HCC tissues, 53.2% (91/171) in paraneoplastic liver tissues, 64.9% (24/37) in cirrhosis tissues, and 72.7% (24/33) in normal liver tissues. STAT4 was upregulated in younger patients who were female, with single tumor node, early TNM stage, without portal vein tumor embolus, and α-fetoprotein (AFP)-positive tumors compared with the groups comprising older patients, males, and those with multiple tumor nodes, advanced TNM stage, with portal vein tumor embolus, and AFP negative tumors. Meta-analysis showed STAT4 was correlated with TNM stage (OR =0.50, 95% CI =0.30, 0.83, P=0.008) and age (OR =0.58, 95% CI =0.38, 0.95, P=0.032) in malignant tissues, and with AFP level (OR =1.76, 95% CI =1.06, 2.94, P=0.03) in HCC. STAT4 siRNA promoted growth and suppressed apoptosis of HepG2 cells.
Conclusion: STAT4 might play a vital role in development of HCC, via influencing cell growth and apoptosis, as a tumor suppressor.

Keywords: hepatocellular carcinoma, HCC, signal transducers and activators of transcription 4, STAT4, clinicopathological features, immunohistochemistry, meta-analysis, in vitro

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