| Jun Li,Yibo Yan,Ganxin Wang,Zaozao Huang. Hypoxia-inducible factor-2α and its missense mutations: potential role in HCC diagnosis, progression, and prognosis and underlying mechanism. Oncol Transl Med, 2022, 8: 267-275. |
| HIF-2α和错义突变HIF-2α对HCC的诊断、进展和预后的预测价值及其前瞻性机制 |
| Hypoxia-inducible factor-2α and its missense mutations: potential role in HCC diagnosis, progression, and prognosis and underlying mechanism |
| Received:September 17, 2022 Revised:December 31, 2022 |
| DOI：10.1007/s10330-022-0598-8 |
| 中文关键词: HIF-2α；TGF-β途径；ECM；PZP；PAEP；缺氧 |
| 英文关键词: HIF-2α; TGF-β pathway; ECM; PZP; PAEP; Hypoxia |
| 基金项目: |
| Author Name | Affiliation | Department | | Jun Li | Liyuan Hospital of Tongji Medical College of Huazhong University of Science and Technology | Emergency Department | | Yibo Yan | | | | Ganxin Wang* | Liyuan Hospital of Tongji Medical College of Huazhong University of Science and Technology | Division of Oncology | | Zaozao Huang | Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology | Yangchunhu Community Hospital |
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| 中文摘要: |
| HIF-2α是一种内皮细胞特异性的HIF-1α异构体，在肿瘤进展和肿瘤发生中具有矛盾的作用。为了进一步了解其潜在机制，我们挖掘了癌症基因组图谱（TCGA）数据集。总共有421人参加了TCGA-肝癌（HCC）研究，包括371名癌症患者和50名健康对照。从371个肿瘤样本中，将含有HIF-2α基因错义突变的三个样本与368个野生型样本进行比较，以确定差异表达基因（DEGs）。经过筛选，单变量Cox回归和多变量Cox回归分析显示，DEGs PAEP、PNLIPRP2、MIR147B和PZP与HCC患者的生存时间显著相关。使用注释、可视化和综合发现数据库（DAVID）v6.8数据库进行GO和KEGG分析，以检测这4个DEGs的功能注释，以及使用STRING v10数据库从蛋白质-蛋白质相互作用（PPI）网络分析中获得的枢纽基因。我们的分析集中在PAEP和PZP基因上，这两个基因的蛋白表达在HIF-2α错义突变的样本中被下调。通过PPI网络分析得到PAEP和PZP的中心基因。随后的KEGG通路分析显示，PAEP及其中心基因在TGF-β通路中高度富集，这与PZP的分析一致。总之，我们的研究证明，HIF-2α的错义突变诱导PAEP的上调，与HCC患者的预后不良呈正相关，因为它可能上调TGF-β通路。相反，PZP的下调则显示出相反的现象，因为它可能下调TGF-β途径。 |
| 英文摘要: |
| 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 proteinprotein
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. |
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