■宫颈癌的发病率在女性恶性肿瘤中排名第二,对他们的生活质量和整体福祉产生重大影响。低氧微环境在肿瘤发生的发生和发展中起着关键作用。本研究旨在探讨缺氧诱导因子(HIF-1A)在宫颈癌中的相关基因和通路。旨在确定用于诊断和治疗目的的潜在下游靶标。
■我们从综合基因表达数据库(GEO)获得数据集GSE63514。数据集包括正常组的24名患者和肿瘤组的28名患者。基因集差异分析(GSVA)和基因集富集分析(GSEA)用于鉴定与HIF-1A表达相关的基因和涉及的特定信号通路。在TCGA数据集中检查HIF-1A与肿瘤免疫浸润之间的关联。构建WGCAN网络以识别蓝色模块中的关键基因,以及随后的基因本体论(GO)功能和京都基因和基因组百科全书(KEGG)途径富集分析进行以确定与HIF-1A相关的途径和功能注释。同时从STRING数据库获得HIF-1A基因的蛋白质相互作用网络,并使用Cytoscape进行可视化。在体内验证了HIF-1A的功能及其相关基因的表达。
■HIF-1A是宫颈癌患者单因素和多因素Cox回归分析的危险因素。通过相关性分析,共鉴定出344个与HIF-1A表达显著相关的基因,并获得了表现出最强相关性的基因。参与HIF-1A的主要信号通路包括TNF-α/NF-κB,PI3K/AKT/MTOR,TGF-β,JAK-STAT,和各种其他信号级联。通过qRT-PCR增强,我们鉴定了整合素β-1(ITGB1),C-C基序趋化因子配体2(CCL2),纹状体蛋白3(STRN3),和内皮素-1(EDN1)作为受HIF-1A影响的关键下游基因。HIF-1A与自然杀伤(NK)细胞的免疫浸润有关,肥大细胞,CD4+T细胞,M0巨噬细胞,中性粒细胞,滤泡辅助性T细胞,CD8+T细胞,和调节性T细胞(Treg)。HIF-1A与化疗药物的敏感性相关。HIF-1A途径及其功能的鉴定主要集中在细胞质翻译上,有氧呼吸,细胞呼吸,氧化磷酸化,产热,在其他人中。体内实验结果证实HIF-1A在促进宫颈癌细胞的迁移和侵袭中起着至关重要的作用。此外,HIF-1A的过表达导致ITGB1、CCL2、STRN3和EDN1的表达上调。
■通过生物信息学分析和实验验证相结合,确定了HIF-1A在宫颈癌中的作用。鉴定了可能与HIF-1A的肿瘤发生机制有关的基因。这些发现有可能增强我们对宫颈癌进展的理解,并为其临床管理提供有希望的治疗目标。
UNASSIGNED: The incidence of cervical cancer ranks second among malignant tumors in women, exerting a significant impact on their quality of life and overall well-being. The hypoxic microenvironment plays a pivotal role in the initiation and progression of tumorigenesis. The present study aims to investigate the fundamental genes and pathways associated with the hypoxia-inducible factor (HIF-1A) in cervical cancer, aiming to identify potential downstream targets for diagnostic and therapeutic purposes.
UNASSIGNED: We obtained dataset GSE63514 from the Comprehensive Gene Expression Database (GEO). The dataset comprised of 24 patients in the normal group and 28 patients in the tumor group. Gene set difference analysis (GSVA) and gene set enrichment analysis (GSEA) were used to identify the genes related to HIF-1A expression and the specific signaling pathways involved.The association between HIF-1A and tumor immune infiltration was examined in the TCGA dataset. The WGCAN network was constructed to identify key genes within the blue module, and subsequent gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to determine the pathways and functional annotations associated with HIF-1A. The protein interaction network of the HIF-1A gene was obtained from the STRING database and visualized using Cytoscape in the meantime.The function of HIF-1A and its related gene expression were verified in vivo.
UNASSIGNED: HIF-1A was a risk factor in both univariate and multivariate Cox regression analysis of cervical cancer patients. A total of 344 genes significantly correlated with the expression of HIF-1A were identified through correlation analysis, and the genes exhibiting the strongest correlation were obtained. The major signaling pathways involved in HIF-1A encompass TNF-α/NF-κB, PI3K/AKT/MTOR, TGF-β, JAK-STAT, and various other signaling cascades. Reinforced by qRT-PCR, we identified Integrin beta-1 (ITGB1), C-C motif chemokine ligand 2 (CCL2), striatin 3 (STRN3), and endothelin-1 (EDN1) as pivotal downstream genes influenced by HIF-1A. HIF-1A is associated with immune infiltration of natural killer (NK) cells, mast cells, CD4+T cells, M0 macrophages, neutrophils, follicular helper T cells, CD8+T cells, and regulatory T cells (Treg). HIF-1A is associated with sensitivity to chemotherapy drugs. The identification of the HIF-1A pathway and its function primarily focuses on cytoplasmic translation, aerobic respiration, cellular respiration, oxidative phosphorylation, thermogenesis, among others. The results of in vivo experiments have confirmed that HIF-1A plays a crucial role in promoting the migration and invasion of cervical cancer cells. Moreover, the overexpression of HIF-1A led to an upregulation in the expressions of ITGB1, CCL2, STRN3, and EDN1.
UNASSIGNED: The role of HIF-1A in cervical cancer was determined through a combination of bioinformatics analysis and experimental validation. The genes potentially implicated in the tumorigenesis mechanism of HIF-1A were identified. These findings has the potential to enhance our comprehension of the progression of cervical cancer and offer promising therapeutic targets for its clinical management.