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Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer

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posted on 05.11.2013 by Swapna Asuthkar, Victoria Stepanova, Tatiana Lebedeva, AiXuan L. Holterman, Norman Estes, Douglas B. Cines, Jasti S. Rao, Christopher S. Gondi
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.

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Funding

National Cancer Institute (1R21CA141228-01 to V.S.) for this research is acknowledged.

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Publisher Statement

© 2013 Asuthkar et al. This article is distributed by The American Society for Cell Biology under license from the author(s). This is a copy of an article published in the Molecular Biology of the Cell © 2013 American Society for Cell Biology. The final publication is available at http://www.molbiolcell.org/.

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American Society for Cell Biology

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en_US

issn

1939-4586

Issue date

01/09/2013

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