Fig. 5
From: Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape
The role of HIFs in cancer invasiveness and metastasis. HIF1A regulates the sonic hedgehog signaling pathway to promote the invasive abilities of cancer cells. Under hypoxic conditions, HIF1A upregulates differentiated embryonic chondrocyte gene 2 (DEC2) at the transcriptional level, which in turn promotes HIF1A activation, ultimately contributing to cancer cell metabolic reprogramming, angiogenesis, and invasiveness. HIF2A directly induces transcription of the stem cell factor (SCF) gene via the hypoxia response element in the SCF promoter and upregulates SCF expression, thereby promoting angiogenesis and metastasis. Zinc finger MYND-type containing 8 (ZMYND8) is regarded as a direct target gene of HIF1A and HIF2A. The ZMYND8/HIF axis increases breast tumor angiogenesis and decreases cancer cell death to promote cancer metastasis. Protein kinase growth arrest-specific 6 (GAS6)/AXL is activated by HIF1A and HIF2A. The SRC proto-oncogene nonreceptor tyrosine kinase is a direct target of GAS6/AXL signaling; it activates MET proto-oncogenes, thereby regulating the epithelial-mesenchymal transition (EMT) and tumor metastasis. Overexpression of HIF1A promotes production of CD24, which leads to tumor growth and metastasis, and HIFs regulate EMT to promote cancer metastasis. Hypoxia-induced HIFs promote EMT by enhancing snail, β-catenin, Wnt, and Notch signaling, thereby inducing cancer cell survival, metastasis, and immune escape. EMT promotes expression of PD-L1, facilitating tumor cells escape and recognition and attack by immune cells