title: Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer.
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.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
authors.forename: Swapna
authors.initials: S
authors.lastname: Asuthkar
authors.forename: Victoria
authors.initials: V
authors.lastname: Stepanova
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lebedeva
authors.forename: Aixuan L
authors.initials: AL
authors.lastname: Holterman
authors.forename: Norman
authors.initials: N
authors.lastname: Estes
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Jasti S
authors.initials: JS
authors.lastname: Rao
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Gondi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D058985:Side-Population Cells / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D035683:MicroRNAs; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014568:Urokinase-Type Plasminogen Activator; D000093542:Gemcitabine; C485631:HEY1 protein, human; C489213:HOXA5 protein, human; C489783:LHX2 protein, human; C509207:MIRN124 microRNA, human; C495901:TP53 protein, human