Limning of HIF-2 and HIF-3 in the Tumor Microenvironment: Developing Concepts for the Treatment of Hypoxic Cancer

Hypoxia, characterized by insufficient oxygen supply to tissues, is a significant factor in tumor growth and resistance to treatment. The hypoxia-inducible factor (HIF) signaling pathway is activated when oxygen levels decline, influencing cell activities and promoting tumor progression. HIF-1 alpha and HIF-2 alpha are the main targets for therapeutic intervention in tumors. Nevertheless, the significance of HIF-2 alpha is often overlooked. This review examines the physiological role of HIF-2 alpha in tumor growth and its involvement in tumor growth. HIFs, composed of hypoxia-responsive alpha and oxygen-insensitive beta subunits, play a crucial role in controlling gene expression in both normal and solid tumor tissues under low oxygen levels. HIF-3 alpha, formerly considered a detrimental modulator of HIF-regulated genes, exerts a transcriptional regulatory role by inhibiting gene expression through competition with HIF-1 alpha and HIF-2 alpha for binding to transcriptional sites in target genes under hypoxia. Recent research indicates that various HIF-3 variants exhibit distinct and potentially contrasting functionalities. Hypoxia often occurs during the initiation and progression of cancer formation. Recent research has discovered that HIF-2 alpha, also known as endothelial PAS domain protein 1, has a significant impact on tumors. HIF-2 alpha is a significant cancer-causing gene and a crucial predictor of prognosis in non-small cell lung cancer. However, due to limited research investigating the relationship between HIF-2 alpha and small-cell lung cancer, it is not possible to reach a definitive conclusion. HIF-2 alpha plays a vital function in cancer by preserving the stemness of cancer cells. This review provides a comprehensive overview of HIF-2 and the role of HIF-3 in various cancer-related processes, as well as its potential as a targeted therapeutic approach.