Explore The Mutual Regulation Mechanism Of HIF-1 And Notch Signaling Pathway In Pancreatic Cancer

IntroductionPancreatic cancer(PC)has been well known as a lethal malignant neoplasm with high mortality and poor survival rate.Due to the low sensitivity and specificity of early diagnosis,most patients are diagnosed with an advanced stage of pancreatic cancer.So far there has been no effective treatment strategy for these patients.Hypoxia inducible factor 1(HIF-1)is a hypoxic-mediated transcription factor.Fibrosis of pancreatic cancer can cause hypoxia in localized pancreatic tissues and activate HIF-1 signal.It has been well knowm that the Notch signaling pathway is a relatively conservative signal transduction pathway in evolution.Activating the Notch signaling pathway can induce early pathological changes in pancreatic cancer.The HIF-1 and Notch signals can be activated by each other in a variety of solid tumor and disease models.In this study,we aim to investigate whether the HIF-1 and Notch signals have the same regulation mechanism in pancreatic cancer through human pancreatic cancer tissue and cell lines.We also hope to find the bridging molecule between two pathways,which can provide a theoretical basis for the clinical use of inhibitors of these two pathways in the treatment of pancreatic cancer.MethodsTo explore the expression of HIF-1 a and HES1 in human pancreatic cancer,we analyzed the TCGA database and the mean optical density of immune histochemical staining of human pancreatic cancer tissue chip.Three pancreatic cancer cell lines(MIA,PANC-1 and BxPC-3)were chosen to investigate the expression and transcription of HIF-1? under a hypoxia condition induced by CoCl2,as well as to investigate whether the Notch signaling pathway was regulated by the HIF-1 signal.In order to investigate whether the HIF-1 signal was regulated by the Notch signaling pathway and find specific regulatory mechanisms between them,we used the DAPT to inhibit the Notch signaling pathway of MIA,PANC-1 and BxPC-3.ResultsIn human pancreatic tissues,HIF-1 a and HES1 have a positive correlation in both expression and transcription levels.CoCl2 can mimic a hypoxia condition in pancreatic cancer cell lines,which can inhibit HIF-1 a degradation and upregulate the protein level of HIF-1?,and consequently upregulate the Notch signaling pathway.The activation level of HIF-1 was down regulated by the down regulation of the Notch signal through DAPT.ConclusionsIn human pancreatic tissues,the HIF-1 signal and the Notch signaling pathway share a same changing trend in both protein expression and transcription levels.In human pancreatic cell lines,the HIF-1 signal and the Notch signaling pathway can activate each other.HIF-1? may stabilize the NICD or upregulate the transcription level of the ligands or receptors of the Notch signaling pathway,and therefore activate this pathway.