Expression of FOXM1 and Aurora-A predicts prognosis and sorafenib efficacy in patients with hepatocellular carcinoma

Abstract

Background: Effective prognostic biomarkers and powerful target-therapeutic drugs are needed for improving the treatment of Hepatocellular carcinoma (HCC).

Objective: This study aimed to evaluate the expression of FOXM1 and Aurora-A and their prognostic value in HCC.

Methods: We determined the differentially expressed genes signature in HCC using the Gene Set Enrichment Analysis (GSEA), and then evaluated the expression of FOXM1 and Aurora-A in TCGA and KMUH cohort. Associations between co-expression of FOXM1 and Aurora-A and clinical variables were calculated. Overall survival (OS) and recurrence-free survival (RFS) were estimated with different FOXM1 and Aurora-A expression status.

Results: FOXM1-related gene sets were mostly associated with cell cycle regulation in HCC tissues. We found a positive correlation between the expression of FOXM1 and Aurora-A. Overexpression of FOXM1 and Aurora-A was associated with larger tumor size, advanced stage, higher grade, and double-positive for HBV and HCV. The coordinated overexpression of FOXM1 and Aurora-A was the most significant independent prognostic factor for OS and RFS. Furthermore, the concomitant high expression of FOXM1 and Aurora-A predicted the worst OS of sorafenib-treated patients with HCC.

Conclusions: The co-expression of FOXM1 and Aurora-A could be a reliable biomarker to predict the sorafenib response and prognosis of HCC patients.

Keywords: Aurora-A; FOXM1; hepatocellular carcinoma (HCC); sorafenib.

Supplementary Fig. 1.

Effect of FOXM1 knockdown on the expression of cell cycle-regulating proteins in HCC cells. HepG2 and Hep3B cells were transfected with control siRNA or with FOXM1 siRNA. The expression of the indicated cell cycle-regulating proteins was analyzed by western blotting.

Fig. 1.

FOXM1 expression is positively correlated with Aurora-A expression in human HCC. (a) The expression of FOXM1 and Aurora-A in HCC and adjacent liver tissues by transcriptome sequencing from the TCGA dataset (Left). The expression levels of the FOXM1 and Aurora-A mRNAs were validated in 40 paired HCC from KMUH using RT-qPCR (Right). The horizontal lines depict the mean $\pm$ S.D. (b) The level of FOXM1 and Aurora-A in HCC tissues from the TCGA and KMUH datasets and the correlation between their expression levels was analyzed using Fisher’s exact test ($p<$ 0.001). (c) The relationship between FOXM1 and Aurora-A expression in HCC (black dot, $n=$ 341) and adjacent liver tissues (red dot, $n=$ 44) was analyzed using Pearson’s correlation. RSEM, RNA-seq by Expectation Maximization.

Fig. 2.

Overexpression of FOXM1 and Aurora-A are associated with poor prognosis in HCC. KaplanMeier curves of OS (Left) and RFS (Right) were estimated with different FOXM1 and Aurora-A expression status in the TCGA ($n=$ 341) (a–b), and OS in KMUH ($n=$ 30) datasets (c–d). KaplanMeier curves for OS (Left) and RFS (Right) among three subgroups according to FOXM1 and Aurora-A expression status in the TCGA ($n=$ 341) (e), and OS in KMUH ($n=$ 30) datasets (f).

Fig. 3.

FOXM1 and Aurora-A expression predict the prognosis of sorafenib-treated patients in HCC. KaplanMeier curves of overall survival probability were estimated with different FOXM1 (a), Aurora-A (b), and FOXM1/Aurora-A (c) expression status in sorafenib-treated patients obtained from the TCGA dataset ($n=$ 29).