Abstract
Oxoglutarate dehydrogenase like (OGDHL) is involved in tricarboxylic acid cycle and has been reported as a candidate tumor suppressor in some other tumors. We first explored the role of OGDHL in human pancreatic ductal adenocarcinoma (PDAC) progression. OGDHL was frequently down-regulated in human PDAC and predicted poor prognosis. OGDHL suppressed PDAC growth though G1 cell cycle arrest and also inhibited migration and invasion ability of PDAC both in vivo and in vitro. Compared with non-tumor tissues, PDAC tissues showed down-regulation of OGDHL and up-regulation of miR-214 and TWIST1. The results showed that OGDHL was a target gene of miR-214 and always negatively regulated by miR-214 and the decreased expression level of OGDHL was on account of the increased expression level of miR-214 in PDAC. In addition, TWIST1 was frequently up-regulated in PDAC and induces miR-214 expression. However OGDHL could inhibit TWIST1 expression via both promoting ubiquitin-mediated proteasomal degradation of HIF1a and regulating AKT pathways. The effect of OGDHL/HIF1a/TWIST1/miR-214 signaling pathway in pancreatic carcinogenesis and metastasis was also determined both in vivo and in vitro. A combination of down-regulation OGDHL and over-expression miR-214 and TWIST1 predicts a poorer overall survival in PDAC patients. Finally, we demonstrated that the relationship of expression among OGDHL, miR-214 and TWIST1 may be a significant predictor of prognosis in PDAC patients. It is a novel pathway in OGDHL-regulated inhibition of PDAC tumorgenesis and metastasis. It may be a brand new targeted therapy in PDAC through OGDHL, TWIST1, miR-214, and HIF1a for prevention, treatment and prognosis.
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