Hypoxia-inducible factor-2α and its missense mutations: potential role in HCC diagnosis, progression, and prognosis and underlying mechanism

Abstract

Abstract Objective This study aims to gain further the potential mechanisms of HIF-2α in tumor progression and tumorigenesis. Methods Mined The Cancer Genome Atlas (TCGA) dataset. In total, 421 participants were enrolled in the TCGAHepatocellular Carcinoma (HCC) study, comprising 371 patients with cancer and 50 healthy controls. From the 371 tumor samples, three samples containing the missense mutation of the HIF-2α gene were compared with 368 wild-type samples to identify differentially expressed genes (DEGs). Results After filtering, univariate Cox regression and multivariate Cox regression analyses showed that the differentially expressed genes (DEGs) progestagen-associated endometrial protein (PAEP) PNLIPRP2, MIR147B, and pregnancy zone protein (PZP) were significantly correlated with the survival times of patients with HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8 database to detect the functional annotation of these four DEGs as well as hub genes obtained from protein-protein interaction (PPI) network analysis using the STRING v10 database. Our analysis focused on the PAEP and PZP genes, whose protein expressions were downregulated in samples with HIF-2α missense mutation. The hub genes of PAEP and PZP were identified using PPI network analysis. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that PAEP and its hub genes were highly enriched in the TGF-β pathway, which is consistent with the analysis of PZP. Conclusion Our study proved that the missense mutation of HIF-2α induces the upregulation of PAEP, which is positively related to the poor prognosis of patients with HCC, as it may upregulate the TGF-β pathway. In contrast, PZP downregulation showed the opposite phenomenon, as it may downregulate the TGF-β pathway.