Abstract
BackgroundHypoxia plays an indispensable role in the development of hepatocellular carcinoma (HCC). However, there are few studies on the application of hypoxia molecules in the prognosis predicting of HCC. We aim to identify the hypoxia-related genes in HCC and construct reliable models for diagnosis, prognosis and recurrence of HCC patients as well as exploring the potential mechanism.MethodsDifferentially expressed genes (DEGs) analysis was performed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database and four clusters were determined by a consistent clustering analysis. Three DEGs closely related to overall survival (OS) were identified using Cox regression and LASSO analysis. Then the hypoxia-related signature was developed and validated in TCGA and International Cancer Genome Consortium (ICGC) database. The Gene Set Enrichment Analysis (GSEA) was performed to explore signaling pathways regulated by the signature. CIBERSORT was used for estimating the fractions of immune cell types.ResultsA total of 397 hypoxia-related DEGs in HCC were detected and three genes (PDSS1, CDCA8 and SLC7A11) among them were selected to construct a prognosis, recurrence and diagnosis model. Then patients were divided into high- and low-risk groups. Our hypoxia-related signature was significantly associated with worse prognosis and higher recurrence rate. The diagnostic model also accurately distinguished HCC from normal samples and nodules. Furthermore, the hypoxia-related signature could positively regulate immune response. Meanwhile, the high-risk group had higher fractions of macrophages, B memory cells and follicle-helper T cells, and exhibited higher expression of immunocheckpoints such as PD1and PDL1.ConclusionsAltogether, our study showed that hypoxia-related signature is a potential biomarker for diagnosis, prognosis and recurrence of HCC, and it provided an immunological perspective for developing personalized therapies.
Highlights
Hypoxia plays an indispensable role in the development of hepatocellular carcinoma (HCC)
Acquisition of hypoxia‐related genes associated with Hepatocellular carcinoma (HCC) The mRNA expression profiles and corresponding clinical information associated with HCC patients were obtained from The Cancer Genome Atlas—Liver Hepatocellular Carcinoma dataset (TCGA‐LIHC)
Gene set enrichment analysis Gene set enrichment analysis (GSEA) [24] was performed using prognosis index with Clusterprofiler package to identify signaling pathways regulated by the Identification of Differentially expressed genes (DEGs) related to hypoxia in HCC We identified DEGs (|LogFC|> 1, P < 0.05) using the mRNA expression profile between HCC and adjacent noncancerous tissues from TCGA database (Additional file 1: Table S1)
Summary
Hypoxia plays an indispensable role in the development of hepatocellular carcinoma (HCC). There are few studies on the application of hypoxia molecules in the prognosis predicting of HCC. We aim to identify the hypoxia-related genes in HCC and construct reliable models for diagnosis, prognosis and recurrence of HCC patients as well as exploring the potential mechanism. It is of great significance to search for molecular markers for early diagnosis, survival prediction and recurrence monitoring of HCC, which can improve patients’ stratification and optimize medical intervention. The low rate of early diagnosis and high rate of metastasis and recurrence have considerable impact on the prognosis of HCC patients, which are mainly related to the invasiveness and high proliferative activity of tumor cells [5]. The mechanism of tumor progression has not been completely realized
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