title: Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin.
abstract: Because of the early onset of local invasion and distant metastasis, pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 5-year survival rate of less than 5%. In this study, we investigated the role of fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, and the molecular mechanisms underlying fascin overexpression in PDAC. Our data showed that the expression levels of fascin were higher in cancer tissues than in normal tissues, and fascin overexpression correlated with the PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cell migration and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin regulated MMP-2 expression through protein kinase C and extracellular signal-regulated kinase. Importantly, our data showed that hypoxia induced fascin overexpression in PDAC cells by promoting the binding of hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1α expression levels in PDAC patient specimens significantly correlated with fascin expression. Moreover, immunohistochemistry staining of consecutive sections demonstrated colocalization between HIF-1α and fascin in PDAC specimens, suggesting that hypoxia and HIF-1α were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1α knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. Our data suggested that the hypoxic tumor microenvironment in PDAC might promote invasion and metastasis by inducing fascin overexpression, and fascin might be targeted to block PDAC progression.
authors.affiliation: Authors' Affiliations: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; and Department of Tumor Biology and Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhao
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.forename: He
authors.initials: H
authors.lastname: Ren
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianwei
authors.initials: J
authors.lastname: Sun
authors.forename: Shengyu
authors.initials: S
authors.lastname: Yang
authors.forename: Jihui
authors.initials: J
authors.lastname: Hao
mesh_terms: D000368:Aged; D001665:Binding Sites; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015533:Transcriptional Activation
chemical_list: D002352:Carrier Proteins; C502658:FSCN1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008840:Microfilament Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2