HIF1α: A key emerging player in pancreatic cancer

Abstract

Pancreatic cancer is the world’s fourth leading vulnerable cancerous disease with poor diagnosis and low survival rate. Intratumoral hypoxia is the characteristic feature of pancreatic cancer. Hypoxia-inducible factor 1a (HIF1α) is a well-known transcriptional molecule which is associated with aggravation of the pancreatic cell proliferation, invasion, metastasis, and apoptosis. HIF1α belongs to a family of Per-ARNT-Sim (PAS) with heterodimeric basic helix-loop-helix (bHLH) transcriptional proteins. Under oxygen depletion conditions, catalytic function of prolyl hydroxylases is downregulated, thereby inhibiting the binding to von Hippel-Lindau protein (pVHL); thus HIF1α does not undergo ubiquitin-proteasomal degradation and gets accumulated in the cancerous tissue. It may also stimulate many signaling molecules and lead to lymph node metastasis. HIF1α may induce invadopodia formation through reactive oxygen species mediated by NADPH oxidases involving the stimulation of Notch signaling, thus leading to pancreatic cancer cell invasiveness. HIF1α also stimulates the production of anti-angiogenic factors which might be one of the probable reasons for poor therapeutic response toward pancreatic cancer. Future studies may focus on the development of new therapeutic pathway toward inhibition of hypoxia-induced HIF1α signaling to reduce the risk for the incidence of pancreatic cancer.