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01-12-2014 | Translational Research and Biomarkers

High STAT4 Expression is a Better Prognostic Indicator in Patients with Hepatocellular Carcinoma After Hepatectomy

Authors: Gizachew Yismaw Wubetu, BSc, MSc, Tohru Utsunomiya, MD, PhD, Daichi Ishikawa, MD, Shinichiro Yamada, MD, Tetsuya Ikemoto, MD, PhD, Yuji Morine, MD, PhD, Shuichi Iwahashi, MD, PhD, Yu Saito, MD, PhD, Yusuke Arakawa, MD, PhD, Satoru Imura, MD, PhD, Mami Kanamoto, MD, PhD, Chengzhan Zhu, MD, Yoshimi Bando, MD, PhD, Mitsuo Shimada, MD, PhD

Published in: Annals of Surgical Oncology | Special Issue 4/2014

Abstract

Background

Signal transducer and activator of transcription 4 (STAT4) mediates the intracellular effects of interleukin-12, leading to the production of interferon gamma (IFN-γ) and natural killer cells cytotoxicity. However, the clinical significance of STAT4 expression in patients with hepatocellular carcinoma (HCC) remains virtually unknown.

Methods

A total of 66 HCC patients who underwent hepatectomy were enrolled in this study. Quantitative real-time polymerase chain reaction was performed to determine STAT4 and IFNG mRNA expression levels. Tissue microarray-based immunohistochemistry was performed to examine CD8⁺ T cells, STAT4, and INF-γ proteins.

Results

STAT4 was differentially expressed in tumor and nontumor tissues (P = 0.001) and positively correlated with IFNG expression (R ² = 0.506, P < 0.05) and CD8⁺ T cell infiltration (R ² = 0.53, P < 0.001). Significant correlations were observed between STAT4 expression and tumor TNM stage (P = 0.043), hepatic venous invasion (P = 0.003), des-gamma-carboxy prothrombin (P = 0.011), tumor size (P = 0.036), and tumor differentiation (P = 0.034). Patients with high STAT4 expression had significantly better recurrence-free survival (P = 0.009). Low STAT4 expression (P = 0.030) and presence of portal venous invasion or hepatic venous invasion (P = 0.006) were independent risk factors for HCC recurrence.

Conclusions

Downregulation of STAT4 in HCC indicated aggressive tumor behavior and predicted a worse clinical outcome. STAT4 might be a useful biomarker to identify patients at high risk of recurrence after hepatectomy.

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Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–46.PubMedCrossRef

Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRef

El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol. 2002;35:72–8.CrossRef

Huang YH, Chen CH, Chang TT, et al. The role of transcatheter arterial embolization in patients with resectable hepatocellular carcinoma: a nation-wide, multicenter study. Liver Int. 2004;24:419–24.PubMedCrossRef

Yu H and Jove R. The STATs of cancer: new molecular targets come of age. Nature Rev Cancer. 2004;4:97–105.CrossRef

Bollrath J, Phesse TJ, von Burstin VA, et al. gp130 mediated STAT3 activation in enterocytes regulates cell survival and cell cycle progression during colitis associated tumorigenesis. Cancer Cell. 2009;15: 91–102.PubMedCrossRef

Takeda K, Akira S. STAT family of transcription factors in cytokine mediated biological responses. Cytokine Growth Factor Rev. 2000;11:199–207.PubMedCrossRef

Bruns HA, Kaplan MH. The role of constitutively active STAT6 in leukemia and lymphoma. Crit Rev Oncol Hematol. 2006;57:245–53.PubMedCrossRef

Good SR, Thieu VT, Mathur AN, et al. Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage specific programming. J Immunol. 2009;183:3839–47.PubMedCentralPubMedCrossRef

10.

Kaplan MH. STAT4: a critical regulator of inflammation in vivo. Immunol Res. 2005;31:231–42.PubMedCrossRef

11.

Jiang DK, Sun J, Cao G, Liu Y, Lin D, Gao YZ. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013;45:72–75.PubMedCentralPubMedCrossRef

12.

Chan H, Han L, Goswami R, et al. Impaired development of human Th1 cells in patients with deficient expression of STAT4. Blood. 2009;113:5887–90.CrossRef

13.

Street SE, Cretney E, Smyth MJ. Perforin and IFN-γ activities independently control tumor initiation, growth, and metastasis. Blood. 2001;97:192–97.PubMedCrossRef

14.

Dupre SA, Redelman D, Hunter KW. Microenvironment of the murine mammary carcinoma 4T1: Endogenous IFN-γ affects tumor phenotype, growth and metastasis. Exp Mol Pathol. 2008;85:174–88.PubMedCrossRef

15.

Beatty GL and Paterson Y. IFN-γ dependent inhibition of tumor angiogenesis by tumor infiltrating CD4⁺ T cells requires tumor responsiveness to IFN-γ. J Immunol. 2001;166:2276-82.PubMedCrossRef

16.

Dunn GP, Ikeda H, Bruce AT, et al. Interferon gamma and cancer immunoediting. Immunol Res. 2005;32:231–45.PubMedCrossRef

17.

Saha B, Prasanna S, Chandrasekar B, Nandi D. Gene modulation and immuno-regulatory roles of IFN-γ. Cytokine. 2010;50:1–14.PubMedCrossRef

18.

Horras CJ, Lamb CL, Mitchell KA. Regulation of hepatocyte fate by IFN-γ. Cytokine Growth Factor Rev. 2011;22:35–43.PubMedCentralPubMedCrossRef

19.

Jacob CO, Zang S, Li L, et al. Pivotal role of STAT4 and STAT6 in the pathogenesis of the lupus like disease in the New Zealand mixed 2328 mice. J Immunol. 2003;171:1564–71.PubMedCrossRef

20.

Thierfelder WE, Deursen JM, Yamamoto K. Requirement for STAT4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996;382:171–4.PubMedCrossRef

21.

Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in STAT4 deficient mice. Nature. 1996;382:174–7.PubMedCrossRef

22.

Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50.PubMedCrossRef

23.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: Int J Cancer. 2010;12:2893–917.CrossRef

24.

Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, OShea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004;202:139–56.PubMedCrossRef

25.

Frucht DM, Aringer M, Galon J, et al. STAT4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol. 2000;164:4659–64.PubMedCrossRef

26.

Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 2012;62:394–9.PubMedCrossRef

27.

Lim KC, Chow PK, Allen JC, et al. Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for Hepatocellular carcinoma compared to the Milan criteria. Ann Surg. 2011;254:108–13.PubMedCrossRef

28.

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedCrossRef

29.

Tang ZY. Hepatocellular carcinoma causes treatment and metastasis. World J Gastroenterol. 2001;7:445–54.PubMed

30.

Yuki K, Hirohashi S, Sakamoto M, Kanai T, Shimosato Y. Growth and spread of hepatocellular carcinoma. A review of 240 consecutive autopsy cases. Cancer. 1990;66:2174–9.PubMedCrossRef

31.

Cai G, Radzanowski T, Villegas EN, Kastelein R, Hunter CA. Identification of STAT4 dependent and independent mechanisms of resistance to Toxoplasma gondii. J Immunol. 2000;165:2619–27.PubMedCrossRef

32.

Lee IC, Huang YH, Chau GY, et al. Serum IFN-γ level predicts recurrence in hepatocellular carcinoma patients after curative treatments. Int J Cancer. 2013;133:2895–902.PubMedCrossRef

33.

Ikeda H, Old LJ, Schreiber RD. The roles of IFN gamma in protection against tumor development and cancer immunediting. Cytokine Growth Factor Rev. 2002;13:95–109.PubMedCrossRef

34.

Shankaran V, Ikeda H, Bruce AT, et al. IFN-γ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410:1107–11.PubMedCrossRef

35.

Tsuta K, Ishii G, Kim E, et al. Primary lung adenocarcinoma with massive lymphocyte infiltration. Am J Clin Pathol. 2005;123:547–52.PubMedCrossRef

36.

Canna K, McArdle PA, McMillan DC, et al. The relationship between tumour T lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer. 2005;92:651–4.PubMedCentralPubMedCrossRef

37.

Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8⁺ T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001;61:5132–6.PubMed

38.

Pedroza A, Verhoef C, Ijzermans JN, et al. Activated tumor infiltrating CD4⁺ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology. 2013;57:183–94.CrossRef

Title: High STAT4 Expression is a Better Prognostic Indicator in Patients with Hepatocellular Carcinoma After Hepatectomy
Authors: Gizachew Yismaw Wubetu, BSc, MSc
Tohru Utsunomiya, MD, PhD
Daichi Ishikawa, MD
Shinichiro Yamada, MD
Tetsuya Ikemoto, MD, PhD
Yuji Morine, MD, PhD
Shuichi Iwahashi, MD, PhD
Yu Saito, MD, PhD
Yusuke Arakawa, MD, PhD
Satoru Imura, MD, PhD
Mami Kanamoto, MD, PhD
Chengzhan Zhu, MD
Yoshimi Bando, MD, PhD
Mitsuo Shimada, MD, PhD
Publication date: 01-12-2014
Publisher: Springer US
Published in: Annals of Surgical Oncology / Issue Special Issue 4/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-014-3861-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

High STAT4 Expression is a Better Prognostic Indicator in Patients with Hepatocellular Carcinoma After Hepatectomy

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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