Han Zhao, Gao Yanling, Li Zhifeng, Liu Zhao, Zhang Jianzhong, Jing Tingting, Xv Yanyan, Miao Guoying, Li Xiaojing, Chen Aijun
Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Yuanjiagang Youyi Road No. 1, Yuzhong District, Chongqing, 400010, China.
Department of Dermatology, The Affiliated Hospital of Hebei Engineering University, Congtai Road No. 81, Congtai District, Handan, 056000, Hebei, China.
Sci Rep. 2025 Jul 1;15(1):21446. doi: 10.1038/s41598-025-02384-2.
Melanoma is a highly heterogeneous and aggressive malignancy. Hypoxia within the tumor microenvironment is closely associated with tumor progression. However, the role of hypoxia-inducible factor 2α (HIF2α), a key transcription factor, in melanoma remains poorly understood. In this study, transcriptome analysis compared HIF2α expression between melanoma patient and control samples. Single-cell RNA sequencing categorized cells into high- and low-HIF2α expression groups. Ligand-receptor interactions (CellChat), enrichment analysis (GSEA/GSVA), immune regulatory network, and metabolic pathway analyses were performed. The correlation between HIF2α and genes involved in hypoxia, autophagy, and epithelial-mesenchymal transition (EMT) was explored, alongside its relationship with clinical stage. Experimentally, A375 cells were cultured under normoxic and hypoxic conditions, transfected with ShRNA-NC or ShRNA-HIF2α, and mRNA levels of HIF2α, E-cadherin, N-cadherin, and Vimentin were quantified using real-time PCR. Differential expression analysis showed significant upregulation of HIF2α in melanoma samples. Ligand-receptor interaction analysis emphasized its role in modulating the tumor microenvironment. Enrichment analyses (GSEA/GSVA) revealed HIF2α involvement in key oncogenic pathways. Correlation analysis linked HIF2α to genes related to hypoxia, autophagy, and EMT, and its expression was associated with advanced clinical stages. In vitro, hypoxia increased HIF-2α, N-cadherin, and Vimentin mRNA levels, while decreasing E-cadherin. HIF-2α knockdown reversed these effects, promoting E-cadherin and suppressing N-cadherin and Vimentin under hypoxia. This study underscores the critical role of HIF2α in melanoma progression, suggesting its involvement in regulating the tumor microenvironment and associated metabolic pathways. As a potential biomarker and therapeutic target, HIF2α offers new insights into the clinical management and treatment of melanoma.
黑色素瘤是一种高度异质性和侵袭性的恶性肿瘤。肿瘤微环境中的缺氧与肿瘤进展密切相关。然而，关键转录因子缺氧诱导因子2α（HIF2α）在黑色素瘤中的作用仍知之甚少。在本研究中，转录组分析比较了黑色素瘤患者样本与对照样本中HIF2α的表达。单细胞RNA测序将细胞分为高HIF2α表达组和低HIF2α表达组。进行了配体-受体相互作用（CellChat）、富集分析（GSEA/GSVA）、免疫调节网络和代谢途径分析。探讨了HIF2α与缺氧、自噬和上皮-间质转化（EMT）相关基因之间的相关性，以及它与临床分期的关系。在实验中，将A375细胞在常氧和缺氧条件下培养，用ShRNA-NC或ShRNA-HIF2α转染，并使用实时PCR定量HIF2α、E-钙黏蛋白、N-钙黏蛋白和波形蛋白的mRNA水平。差异表达分析显示黑色素瘤样本中HIF2α显著上调。配体-受体相互作用分析强调了其在调节肿瘤微环境中的作用。富集分析（GSEA/GSVA）揭示HIF2α参与关键致癌途径。相关性分析将HIF2α与缺氧、自噬和EMT相关基因联系起来，其表达与晚期临床分期相关。在体外，缺氧增加了HIF-2α、N-钙黏蛋白和波形蛋白的mRNA水平，同时降低了E-钙黏蛋白。HIF-2α敲低逆转了这些效应，在缺氧条件下促进E-钙黏蛋白表达并抑制N-钙黏蛋白和波形蛋白。本研究强调了HIF2α在黑色素瘤进展中的关键作用，表明其参与调节肿瘤微环境和相关代谢途径。作为一种潜在的生物标志物和治疗靶点，HIF2α为黑色素瘤的临床管理和治疗提供了新的见解。
