HIF-1A as a prognostic biomarker related to invasion, migration and immunosuppression of cervical cancer

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.