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Oct4 and Nanog are two major transcription factors related to the stem cell self-renewal and differentiation. The aim of this study was to evaluate the correlation between these two stemness markers with recurrence, metastasis, and prognosis of hepatocellular carcinoma (HCC).Expression of Oct4 and Nanog was evaluated by immunohistochemistry in a random cohort of 228 HCC patients (cohort A), predominantly hepatitis B related, and validated in another independent cohort of 95 patients (cohort B). Survival analysis was performed by univariate and multivariate analyses. Oct4 and Nanog expression levels in 5 HCC cell lines with different metastatic potential were detected by Western blot assay and quantitative real-time PCR assay.In tissue microarrays, coexpression of Oct4 and Nanog was dramatically associated with big tumor size (P = .001) and vascular invasion (P = .02) and was an independent predictor of postoperative recurrence (hazard ratio [HR] = 1.57, 95 % confidence interval [95 % CI] 1.21-2.04, P = .01) and poor prognosis (HR = 2.20, 95 % CI 1.71-2.88, P.001). This association was further validated in patients in cohort B. Importantly, this correlation remained significant in patients with early-stage HCC or alpha-fetoprotein (AFP) negative HCC. In addition, expression of Oct4 and Nanog increased in a concordant manner with the increase of metastatic potential in human HCC cell lines.Coexpression of stemness markers Oct4 and Nanog in HCC indicated the aggressive tumor behaviors and predicted a worse clinical outcome, which may be a useful biomarker to identify patients at high risk of postoperative recurrence.

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.