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      Targeting the hypoxia pathway to treat pancreatic cancer

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          Abstract

          The correlation between hypoxia and pancreatic cancer has long been discussed. Hao’s research team made many efforts on revealing the oncogenic function of hypoxic inducible factor-1 (HIF-1) in pancreatic cancer progression and development in recent years. Based on their research, they linked micro-environmental regulation of pancreatic cancer and its clinical significance. Hao’s research team suggests it is a promising approach to target HIF-1 for the management of pancreatic cancer progression and invasion.

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          Most cited references 8

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          Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

          The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK: Copyright © 2014 Elsevier Inc. All rights reserved.
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            Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin.

            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.
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              LASP1 is a HIF1α target gene critical for metastasis of pancreatic cancer.

              LASP1 is an actin-binding protein associated with actin assembly dynamics in cancer cells. Here, we report that LASP1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) where it promotes invasion and metastasis. We found that LASP1 overexpression in PDAC cells was mediated by HIF1α through direct binding to a hypoxia response element in the LASP1 promoter. HIF1α stimulated LASP1 expression in PDAC cells in vitro and mouse tumor xenografts in vivo. Clinically, LASP1 overexpression in PDAC patient specimens was associated significantly with lymph node metastasis and overall survival. Overall, our results defined LASP1 as a direct target gene for HIF1α upregulation that is critical for metastatic progression of PDAC.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                08 April 2015
                : 9
                : 2029-2031
                Affiliations
                [1 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
                [2 ]University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA
                Author notes
                Correspondence: Jun Zhang, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA, Email zhang.jun@ 123456mayo.edu
                Article
                dddt-9-2029
                10.2147/DDDT.S80888
                4396576
                © 2015 Erickson et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Pharmacology & Pharmaceutical medicine

                pancreatic cancer, hif-1, hypoxia

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