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-1α) and HIF-2α (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3α (HIF3A) has not been investigated. Therefore, HIF-1α, HIF-2α, and HIF-3α expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3α expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3α expression on cell invasion and migration was investigated in vitro and in vivo, as well as the underlying mechanisms. Under hypoxic conditions, HIF-3α expression was stimulated in pancreatic cancer cells to a greater degree than HIF-1α and HIF-2α expression. HIF-3α 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-3α, under hypoxic conditions, suppressed pancreatic cancer cell invasion and migration. Under normoxia, HIF-3α overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3α 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.Implications: HIF3α is overexpressed in pancreatic cancer, and targeting the HIF3α/RhoC-ROCK1 signaling pathway may be a novel therapeutic approach for the treatment of pancreatic cancer invasion and metastasis. Mol Cancer Res; 16(1); 124-34. ©2017 AACR.