Abstract
FOXM1 (Forkhead box M1) is a key regulator of tumorigenesis. Previous studies demonstrated that FOXM1 overexpression was strongly correlated with poor prognosis in various cancers, including hepatocellular carcinoma (HCC). In this study, we examined an association between the gene expression signature of FOXM1 and HCC patient outcome. The co-expressed gene set of FOXM1, which is significantly associated with the prognosis of HCC patients, was identified by analyzing the gene expression profiles of 100 patients with HCC, and this gene set was validated in two independent HCC patient cohorts (n=573). In multivariate analysis, the co-expressed gene set of FOXM1 was the most significant prognostic factor for overall survival in patients with HCC (hazard ratio=1.706, 95% confidence intervals=1.176–2.475, P=0.005). We also analyzed different types of cancer, including pancreatic adenocarcinoma, lung adenocarcinoma, breast carcinoma and bladder urothelial carcinoma, to verify the association between the co-expressed gene set of FOXM1 and patient prognosis, and we found a consistent prognostic significance, regardless of tumor type. Finally, we identified a putative signaling pathway in which miR-34a acts as an upstream regulator of the FOXM1-MYC signaling network; this pathway may be ultimately responsible for the poor prognosis of HCC patients. The prognostic subgroups defined by the gene expression signature of FOXM1 could help predict high-risk patients and may guide selection of the best treatment strategy.
Highlights
Hepatocellular carcinoma (HCC) is a major public health problem; it is the primary malignancy of the liver, one of the most common tumors worldwide, and one of the fastest growing causes of cancer-related death
Prognostic utility of FOXM1 and its associated genes on HCC patients in the exploration data set We first tried to identify a gene set that was highly correlated with FOXM1 expression, used that gene set to predict the prognosis of HCC patients
It has been shown that the overexpression of FOXM1 is associated with aggressive tumor features and with the eventual prognosis of cancer patients, including those with HCC.[7]
Summary
Hepatocellular carcinoma (HCC) is a major public health problem; it is the primary malignancy of the liver, one of the most common tumors worldwide, and one of the fastest growing causes of cancer-related death. In 2012, 782,500 new cases of liver cancer were diagnosed, and 745,500 deaths occurred worldwide.[1] Because of the clinical heterogeneity of this malignant disease, precisely predicting the prognosis of HCC patients remains challenging. Several studies have shown that FOXM1 overexpression was associated with poor outcomes in many types of cancer,[7,8,9,10] its clinical relevance as a prognostic and predictive biomarker is not yet fully understood. No studies have examined the prognostic impact of the co-expressed gene set of FOXM1 and whether it can provide additional insights on the potential signaling pathway that is responsible for the poor prognosis of HCC patients
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