Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects

Yuqi Jing, Krisztina Kovacs, Vittal Kurisetty, Zhijie Jiang, Nicholas Tsinoremas, Jaime R Merchan

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Abstract

Tumor proteases and inhibitors have been associated with paradoxical effects on tumor progression in preclinical and clinical settings. We previously reported that urokinase (uPA) overexpression delays tumor progression in mammary cancer. This study aimed to determine the role of plasminogen activator inhibitor-1 (PAI-1) on uPA's paradoxical in vivo effects. Using syngeneic murine models, we found that stable uPA overexpression promoted in vivo growth of colon tumors (MC-38) naturally expressing high PAI-1, whereas growth inhibition was observed in renal tumors (RENCA) expressing lower PAI-1 levels. In murine mammary carcinoma (4T1), uPA overexpression shifted the uPA/PAI-1 balance in favor of the protease, resulting in significantly reduced tumor growth and metastases in vivo. Conversely, increased tumor progression was observed in stable PAI-1 overexpressing 4T1 tumors as compared with uPA-overexpressing and control tumors. These effects were associated with downregulation of metastases promoting genes in uPA-overexpressing tumors, such as metalloproteinases, CXCL-1, c-Fos, integrin α-5, VEGF-A, PDGF-α, and IL-1β. In PAI-1-overexpressing tumors, many of the above genes were upregulated. PAI-1 overexpressing tumors had increased total and new tumor microvessels, and increased tumor cell proliferation, whereas the opposite effects were found in uPA-overexpressing tumors. Finally, PAI-1 downregulation led to significant inhibition of 4T1 tumor growth and metastases in vivo. In conclusion, uPA's dual effects on tumor progression occur in the context of its interactions with endogenous PAI-1 expression. Our studies uncover novel mechanisms of in vivo tumor control by modulation of the balance between tumor proteases and inhibitors, which may be exploited therapeutically.

Original languageEnglish
Pages (from-to)1271-1281
Number of pages11
JournalMolecular Cancer Research
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2012

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Plasminogen Activator Inhibitor 1
Urokinase-Type Plasminogen Activator
Neoplasms
Growth
Neoplasm Metastasis
Protease Inhibitors
Down-Regulation
Breast Neoplasms
Metalloproteases

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects. / Jing, Yuqi; Kovacs, Krisztina; Kurisetty, Vittal; Jiang, Zhijie; Tsinoremas, Nicholas; Merchan, Jaime R.

In: Molecular Cancer Research, Vol. 10, No. 10, 01.10.2012, p. 1271-1281.

Research output: Contribution to journalArticle

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