title: High STAT4 expression is a better prognostic indicator in patients with hepatocellular carcinoma after hepatectomy.
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.
authors: Department of Surgery, The University of Tokushima, Tokushima, Japan.
authors: Gizachew Yismaw
authors: GY
authors: Wubetu
authors: Tohru
authors: T
authors: Utsunomiya
authors: Daichi
authors: D
authors: Ishikawa
authors: Shinichiro
authors: S
authors: Yamada
authors: Tetsuya
authors: T
authors: Ikemoto
authors: Yuji
authors: Y
authors: Morine
authors: Shuichi
authors: S
authors: Iwahashi
authors: Yu
authors: Y
authors: Saito
authors: Yusuke
authors: Y
authors: Arakawa
authors: Satoru
authors: S
authors: Imura
authors: Mami
authors: M
authors: Kanamoto
authors: Chengzhan
authors: C
authors: Zhu
authors: Yoshimi
authors: Y
authors: Bando
authors: Mitsuo
authors: M
authors: Shimada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001808:Blood Vessels / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006498:Hepatectomy; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics*; D008099:Liver / Q000737:chemistry; D008113:Liver Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D009367:Neoplasm Staging; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D012333:RNA, Messenger / Q000032:analysis; D050797:STAT4 Transcription Factor / Q000032:analysis / Q000235:genetics*; D047368:Tumor Burden
chemical_list: D015415:Biomarkers; C573415:IFNG protein, human; D011498:Protein Precursors; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C008208:acarboxyprothrombin; D007371:Interferon-gamma; D011516:Prothrombin