PTEN and cancer: However, the role of HIFs in cancer cells goes beyond mediating the response to hypoxia: In fact, HIF-1-a can be upregulated through growth factors or oncogenic signaling cascades such as the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT serine/threonine kinase 1 (Akt) and Ras/Raf/mitogen-activated protein kinase (MAPK) pathway as well as through inactivation of tumor suppressors like the phosphatase and tensin homolog (PTEN) protein [12, 13].