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Integrin-linked kinase regulates osteopontin-dependent MMP-2 and uPA expression to convey metastatic function in murine mammary epithelial cancer cells.

Publication ,  Journal Article
Mi, Z; Guo, H; Wai, PY; Gao, C; Kuo, PC
Published in: Carcinogenesis
June 2006

Metastasis-supporting physiological alterations are regulated by cell signaling molecules, which target signal transduction pathways and gene expression. Osteopontin (OPN) overexpression may represent a key molecular event in cancer metastasis. In this study, using metastatic 4T1 and non-metastatic 4T07 murine mammary cancer cell lines, we demonstrate that 4T1 cells exhibit significantly increased OPN, integrin-linked kinase (ILK), matrix metalloproteinase-2 (MMP-2) and urokinase-type plasminogen activator (uPA) expression in contrast to 4T07 cells. Blockade of OPN binding to 4T1 cell-surface integrins by the competitive ligand inhibitor, RGD, or a blocking antibody to alphavbeta3 integrin decreases OPN, ILK, MMP-2 and uPA expression. Conversely, exposure of 4T07 cells to exogenous OPN increases ILK, MMP-2 and uPA levels. Further experiments demonstrate that OPN-alphavbeta3 integrin binding in 4T1 with subsequent activation of ILK results in binding of AP-1 to MMP-2 and uPA promoter and increased in vitro promoter activation, as measured by transient transfection assays using MMP-2 and uPA promoter-reporter constructs. AP-1 activity is ablated by co-transfection of DN-ILK or exposure to RGD. Finally, functional correlative assays demonstrate that inhibition of ILK activity or RGD-mediated blockade of alphavbeta3 integrin binding significantly inhibits in vitro invasion, migration and invasion properties of 4T1 cells. In addition, uPA and MMP-2 have overlapping contributions to 4T1 migration and invasion characteristics. However, OPN and ILK activities contribute to 4T1 adhesion activities via mechanisms that are independent of uPA and MMP-2. Our results indicate that binding of an RGD-bearing ligand, such as OPN, to integrin receptors in metastatic 4T1 cells transcriptionally mediates MMP-2, uPA and OPN expression through ILK-dependent AP-1 activity and significantly increases in vitro functional correlates of metastasis. In 4T1 murine mammary cancer cells, we conclude that OPN mediates metastatic behavior, in part, through upregulation of MMP-2 and uPA protein expression.

Duke Scholars

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Published In

Carcinogenesis

DOI

ISSN

0143-3334

Publication Date

June 2006

Volume

27

Issue

6

Start / End Page

1134 / 1145

Location

England

Related Subject Headings

  • Urokinase-Type Plasminogen Activator
  • Sialoglycoproteins
  • Protein Serine-Threonine Kinases
  • Osteopontin
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Mice
  • Matrix Metalloproteinase 2
  • Mammary Neoplasms, Animal
 

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Mi, Z., Guo, H., Wai, P. Y., Gao, C., & Kuo, P. C. (2006). Integrin-linked kinase regulates osteopontin-dependent MMP-2 and uPA expression to convey metastatic function in murine mammary epithelial cancer cells. Carcinogenesis, 27(6), 1134–1145. https://doi.org/10.1093/carcin/bgi352
Mi, Zhiyong, Hongtao Guo, Philip Y. Wai, Chengjiang Gao, and Paul C. Kuo. “Integrin-linked kinase regulates osteopontin-dependent MMP-2 and uPA expression to convey metastatic function in murine mammary epithelial cancer cells.Carcinogenesis 27, no. 6 (June 2006): 1134–45. https://doi.org/10.1093/carcin/bgi352.
Mi, Zhiyong, et al. “Integrin-linked kinase regulates osteopontin-dependent MMP-2 and uPA expression to convey metastatic function in murine mammary epithelial cancer cells.Carcinogenesis, vol. 27, no. 6, June 2006, pp. 1134–45. Pubmed, doi:10.1093/carcin/bgi352.
Journal cover image

Published In

Carcinogenesis

DOI

ISSN

0143-3334

Publication Date

June 2006

Volume

27

Issue

6

Start / End Page

1134 / 1145

Location

England

Related Subject Headings

  • Urokinase-Type Plasminogen Activator
  • Sialoglycoproteins
  • Protein Serine-Threonine Kinases
  • Osteopontin
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Mice
  • Matrix Metalloproteinase 2
  • Mammary Neoplasms, Animal