HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC-ROCK1 Signaling Pathway

Hypoxia contributes to pancreatic cancer progression and promotes its growth and invasion. Previous research principally focused on hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-2 alpha (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3 alpha (HIF3A) has not been investigated. Therefore, HIF-1 alpha, HIF-2 alpha, and HIF-3 alpha expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3 alpha expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3 alpha expression on cell invasion and migration was investigated in vitro and in vivo, as well as the underlying mechanisms. Under hypoxic conditions, HIF-3 alpha expression was stimulated in pancreatic cancer cells to a greater degree than HIF-1 alpha and HIF-2 alpha expression. HIF-3 alpha protein levels were also elevated in pancreatic cancer tissues and correlated with reduced survival and greater local invasion and distant metastasis, whereas knockdown of HIF-3 alpha, under hypoxic conditions, suppressed pancreatic cancer cell invasion and migration. Under normoxia, HIF-3 alpha overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3 alpha promotes pancreatic cancer cell invasion and metastasis in vivo and promotes pancreatic cancer cell invasion and metastasis by transcriptionally activating the RhoC-ROCK1 signaling pathway. (C) 2017 AACR.