Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.