Key Laboratory for Carcinogenesis & Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, The Chinese Ministry of Education, Shanghai, People's Republic of China.
Ann Surg Oncol. 2013 Jan;20(1):267-76. doi: 10.1245/s10434-012-2487-z. Epub 2012 Jul 18.
Interferon regulatory factor (IRF)-1 and IRF-2 are transcriptional factors that mediate interferons functions; the loss of IRF-1 expression and gain of IRF-2 expression were associated with malignant phenotype in multiple cancers. However, their roles in the progression of hepatocellular carcinoma (HCC) remain poorly described.
Immunohistochemistry was used to analyze the nuclear expression of IRF-1/2 in a cohort of 332 HCC patients. The expression of IRF-1/2 in HCC cell lines with stepwise metastasis potential was determined by immunoblotting. Downregulation of IRF-1 or IRF-2 expression was mediated by shRNAs; a series of experiments were conducted to determine the changes of invasion ability and downstream molecular events.
High expression of IRF-1 was associated with good outcome (p<.001 for OS/TTR), while high expression of IRF-2 was relevant to increased recurrence probability (p=.049) in HCC patients. The combination of the 2 IRFs showed better predictive power than either factor alone. Immunoblotting analysis revealed that IRF-2/IRF-1 ratio was positively correlated with the metastatic potential in human HCC cell lines. Downregulation of IRF-2 led to sharply attenuated invasion ability, paralleled with a decreased expression of STAT3, p-STAT3(Ser727), and MMP9. While downregulation of IRF-1 caused a concurrent decrease in IRF-2, little or no change was displayed in IRF-2/IRF-1 ratio, invasion ability, and MMP9 expression.
IRF-1 and IRF-2 expression were associated with prognosis of HCC patients with opposite predictive power. IRF-2/IRF-1 ratio was associated with tumor invasion, probably through modulation of MMP9 expression mediated by STAT3.
干扰素调节因子 (IRF)-1 和 IRF-2 是介导干扰素功能的转录因子；IRF-1 表达缺失和 IRF-2 表达获得与多种癌症的恶性表型相关。然而，它们在肝细胞癌 (HCC) 进展中的作用仍描述不足。
采用免疫组织化学法分析 332 例 HCC 患者中 IRF-1/2 的核表达。采用免疫印迹法检测具有逐步转移潜能的 HCC 细胞系中 IRF-1/2 的表达。通过 shRNA 下调 IRF-1 或 IRF-2 的表达；进行一系列实验以确定侵袭能力的变化和下游分子事件。
IRF-1 高表达与良好的预后相关（OS/TTR 差异具有统计学意义，p<.001），而 IRF-2 高表达与 HCC 患者的复发概率增加相关（p=.049）。2 种 IRF 的组合比任何单一因素都具有更好的预测能力。免疫印迹分析显示，IRF-2/IRF-1 比值与人类 HCC 细胞系的转移潜能呈正相关。下调 IRF-2 导致侵袭能力急剧减弱，同时 STAT3、p-STAT3(Ser727) 和 MMP9 的表达降低。下调 IRF-1 导致 IRF-2 同时减少，但 IRF-2/IRF-1 比值、侵袭能力和 MMP9 表达几乎没有变化。
IRF-1 和 IRF-2 的表达与 HCC 患者的预后相关，具有相反的预测能力。IRF-2/IRF-1 比值与肿瘤侵袭有关，可能通过 STAT3 介导的 MMP9 表达调节。
