Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer

Peter Büchler, Howard A. Reber, James S. Tomlinson, Oliver Hankinson, Georgios Kallifatidis, Helmut Friess, Ingrid Herr, Oscar J. Hines

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Angioinvasion is critical for metastasis with urokinase-type plasminogen activator receptor (uPAR) and tumor hypoxiaactivated hypoxia-inducible factor 1 (HIF-1) as key players. Transcriptional control of uPAR expression by HIF has never been reported. The aim of the present study, therefore, was to test whether tumor hypoxia-induced HIF expression may be linked to transcriptional activation of uPAR and dependent angioinvasion. We used human pancreatic cancer cells and a model of parental and derived HIF-1β-deficient mouse liver cancer cell lines and performed Northern blot analysis, nuclear runoff assays, electrophoreticmobility shift assay, polymerase chain reaction-generated deletionmutants, luciferase assays, Matrigel invasion assays, and in vivo angioinvasion assays in the chorioallantoic membrane of fertilized chicken eggs. Urokinase-type plasminogen activator receptor promoter analysis resulted in four putative HIF binding sites. Hypoxia strongly induced de novo transcription of uPARmRNA.With sequential deletion mutants of the uPAR promoter, it was possible to identify one HIF binding site causing a nearly 200-fold increase in luciferase activity. Hypoxia enhanced the number of invading tumor cells in vitro and in vivo. In contrast, HIF-1β-deficient cells failed to upregulate uPAR expression, to activate luciferase activity, and to invade on hypoxia. Taken together, we show for the first time that uPAR is under transcriptional control of HIF and that this is important for hypoxia-induced metastasis.

Original languageEnglish (US)
Pages (from-to)196-206
Number of pages11
JournalNeoplasia
Volume11
Issue number2
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

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Urokinase Plasminogen Activator Receptors
Hypoxia-Inducible Factor 1
Liver Neoplasms
Pancreatic Neoplasms
Luciferases
Binding Sites
Neoplasm Metastasis
Chorioallantoic Membrane
Zygote
Northern Blotting
Transcriptional Activation
Chickens
Up-Regulation
Cell Line
Polymerase Chain Reaction
Hypoxia

ASJC Scopus subject areas

  • Cancer Research

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Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer. / Büchler, Peter; Reber, Howard A.; Tomlinson, James S.; Hankinson, Oliver; Kallifatidis, Georgios; Friess, Helmut; Herr, Ingrid; Hines, Oscar J.

In: Neoplasia, Vol. 11, No. 2, 01.01.2009, p. 196-206.

Research output: Contribution to journalArticle

Büchler, Peter ; Reber, Howard A. ; Tomlinson, James S. ; Hankinson, Oliver ; Kallifatidis, Georgios ; Friess, Helmut ; Herr, Ingrid ; Hines, Oscar J. / Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer. In: Neoplasia. 2009 ; Vol. 11, No. 2. pp. 196-206.
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