Abstract
Pancreatic ductal adenocarcinoma (PDAC) is almost always lethal. One of the underlying reasons for this lethality is believed to be the presence of cancer stem cells (CSC), which impart chemoresistance and promote recurrence, but the mechanisms responsible are unclear. Recently the poor prognosis of PDAC has been correlated with increased expression of urokinase plasminogen activator (uPA). In the present study we examine the role of uPA in the generation of PDAC CSC. We observe a subset of cells identifiable as a side population (SP) when sorted by flow cytometry of MIA PaCa-2 and PANC-1 pancreatic cancer cells that possess the properties of CSC. A large fraction of these SP cells are CD44 and CD24 positive, are gemcitabine resistant, possess sphere-forming ability, and exhibit increased tumorigenicity, known characteristics of cancer stemness. Increased tumorigenicity and gemcitabine resistance decrease after suppression of uPA. We observe that uPA interacts directly with transcription factors LIM homeobox-2 (Lhx2), homeobox transcription factor A5 (HOXA5), and Hey to possibly promote cancer stemness. uPA regulates Lhx2 expression by suppressing expression of miR-124 and p53 expression by repressing its promoter by inactivating HOXA5. These results demonstrate that regulation of gene transcription by uPA contributes to cancer stemness and clinical lethality.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Carcinoma, Pancreatic Ductal / drug therapy
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Carcinoma, Pancreatic Ductal / genetics
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Carcinoma, Pancreatic Ductal / metabolism*
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Carcinoma, Pancreatic Ductal / pathology*
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Cell Cycle Proteins / metabolism
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Drug Resistance, Neoplasm
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Gemcitabine
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Gene Expression Regulation, Neoplastic
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Homeodomain Proteins / metabolism
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Humans
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LIM-Homeodomain Proteins / metabolism
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MicroRNAs / metabolism
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Neoplastic Stem Cells / pathology
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Neoplastic Stem Cells / physiology*
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism*
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Pancreatic Neoplasms / pathology*
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Side-Population Cells / drug effects
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Side-Population Cells / physiology
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism
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Urokinase-Type Plasminogen Activator / genetics
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Urokinase-Type Plasminogen Activator / metabolism*
Substances
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Antineoplastic Agents
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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HEY1 protein, human
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HOXA5 protein, human
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Homeodomain Proteins
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LHX2 protein, human
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LIM-Homeodomain Proteins
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MIRN124 microRNA, human
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MicroRNAs
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TP53 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Deoxycytidine
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Urokinase-Type Plasminogen Activator
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Gemcitabine