Abstract

BackgroundTumor metastasis is one of the leading reasons of the dismal prognosis of hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is closely associated with tumor metastasis including HCC. The purpose of this study is to construct and validate an EMT-related gene signature for predicting the prognosis of HCC patients.MethodsGene expression data of HCC patients was downloaded from The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was performed to found the EMT-related gene sets which were obviously distinct between normal samples and paired HCC samples. Cox regression analysis was used to develop an EMT-related prognostic signature, and the performance of the signature was evaluated by Kaplan–Meier curves and time-dependent receiver operating characteristic (ROC) curves. A nomogram incorporating the independent predictors was established. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of the hub genes in HCC cell lines, and the role of PDCD6 in the metastasis of HCC was determined by functional experiments.ResultsAn EMT-related 5-gene signature (PDCD6, TCOF1, TRIM28, EZH2 and FAM83D) was constructed using univariate and multivariate Cox regression analysis. Based on the signature, the HCC patients were classified into high- and low-risk groups, and patients in high-risk group had a poor prognosis. Time-dependent ROC and Cox regression analyses suggested that the signature could predict HCC prognosis exactly and independently. The predictive capacity of the signature was also validated in two external cohorts. GSEA results showed that many cancer-related signaling pathways such as PI3K/Akt/mTOR pathway and TGF-β/SMAD pathway were enriched in high-risk group. The result of qRT-PCR revealed that PDCD6, TCOF1 and FAM83D were highly expressed in HCC cancer cells. Among them, PDCD6 were found to promote cell migration and invasion.ConclusionThe EMT-related 5-gene signature can serve as a promising prognostic biomarker for HCC patients and may provide a novel mechanism of HCC metastasis.

Highlights

  • Tumor metastasis is one of the leading reasons of the dismal prognosis of hepatocellular carcinoma (HCC)

  • The Epithelial-mesenchymal transition (EMT)-related 5-gene signature can serve as a promising prognostic biomarker for HCC patients and may provide a novel mechanism of HCC metastasis

  • The results indicated that high-risk score was significantly associated with a dismal prognosis in young subgroup (HR = 1.810, 95% confidence interval (CI) 1.019–3.216, P = 0.043), elder subgroup

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Summary

Introduction

Tumor metastasis is one of the leading reasons of the dismal prognosis of hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is closely associated with tumor metastasis including HCC. The purpose of this study is to construct and validate an EMT-related gene signature for predicting the prognosis of HCC patients. In advanced carcinoma, tumor cells present mesenchymal properties with highly aggressive, which are associated with metastatic dissemination [7, 8]. These mesenchymal features can reverse through mesenchymal-epithelial transition process, which make tumor cells restore the epithelial phenotype and enable them relocate into the metastasis sites [9]. EMT programs are closely associated with the development and progression of various malignancies including hepatocellular carcinoma. With the easy accessibility of many public databases, accumulating signatures or biomarkers has been developed to predict the prognosis of patients, whereas the EMTrelated prognostic model for HCC patients is still lacking

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