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Osteopontin regulates ubiquitin-dependent degradation of Stat1 in murine mammary epithelial tumor cells.

ABSTRACT: BACKGROUND:Osteopontin (OPN) is a secreted glycoprotein that mediates cell-matrix interactions and cellular signaling by binding with integrin (primarily alpha(v)beta(3)) and CD44 receptors. OPN regulates cell adhesion, chemotaxis, macrophage-directed IL-10 suppression, stress-dependent angiogenesis, apoptosis prevention, and anchorage-independent growth of tumor cells. However, the molecular mechanisms that define the role of OPN in tumor progression and metastasis are incompletely understood. METHODS:In this study, we use a system of 4T1 and 4T07 murine mammary epithelial tumor cell lines that are divergent in both metastatic phenotype and OPN expression. 4T1 expresses OPN and hematogeneously metastasizes, whereas 4T07 does not express OPN and is highly tumorigenic but fails to metastasize. RESULTS:Our results demonstrate that OPN regulates Stat1 protein degradation through the ubiquitin-proteasome pathway to alter interferon-gamma-dependent growth inhibition and p21 expression. We identify Stat-interacting LIM protein as the critical Stat ubiquitin E3 ligase in this setting. CONCLUSIONS:OPN regulates Stat1-dependent functions, such as growth inhibition and p21 expression, in the murine mammary epithelial cells lines 4T1 and 4T07. This relationship between OPN and Stat1 in the context of tumor biology has not been previously examined.

SUBMITTER: Gao C

PROVIDER: S-EPMC1993854 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Osteopontin regulates ubiquitin-dependent degradation of Stat1 in murine mammary epithelial tumor cells.

Gao Chengjiang C Mi Zhiyong Z Guo Hongtao H Kuo Paul C PC

Neoplasia (New York, N.Y.) 20070901 9

<h4>Background</h4>Osteopontin (OPN) is a secreted glycoprotein that mediates cell-matrix interactions and cellular signaling by binding with integrin (primarily alpha(v)beta(3)) and CD44 receptors. OPN regulates cell adhesion, chemotaxis, macrophage-directed IL-10 suppression, stress-dependent angiogenesis, apoptosis prevention, and anchorage-independent growth of tumor cells. However, the molecular mechanisms that define the role of OPN in tumor progression and metastasis are incompletely unde ...[more]

PMID: 17898865

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Project description:BackgroundOsteopontin is a secreted phosphoglycoprotein that is expressed by a number of normal cells as well as a variety of tumor cells. With respect to breast cancer, osteopontin has been implicated in regulating tumor cell proliferation and migration/metastasis and may serve as a prognostic indicator. However it remains unclear whether osteopontin has the same impact in all breast cancer subtypes and in particular, osteopontin's effects in claudin-low breast cancer are poorly understood.MethodscDNA microarrays and qRT-PCR were used to evaluate osteopontin expression in mammary tumors from MTB-IGFIR transgenic mice and cell lines derived from these tumors. siRNA was then used to determine the impact of osteopontin knockdown on proliferation, apoptosis and migration in vitro in two murine claudin-low cell lines as well as identify the receptor mediating osteopontin's physiologic effects.ResultsOsteopontin was expressed at high levels in mammary tumors derived from MTB-IGFIR transgenic mice compared to normal mammary tissue. Evaluation of cell lines derived from different mammary tumors revealed that mammary tumor cells with claudin-low characteristic expressed high levels of osteopontin whereas mammary tumor cells with mixed luminal and basal-like features expressed lower levels of osteopontin. Reduction of osteopontin levels using siRNA significantly reduced proliferation and migration while increasing apoptosis in the claudin-low cell lines. Osteopontin's effect appear to be mediated through a receptor containing ITGAV and not through CD44.ConclusionsOur data suggests that mammary tumors with a mixed luminal/basal-like phenotype express high levels of osteopontin however this osteopontin appears to be largely produced by non-tumor cells in the tumor microenvironment. In contrast tumor cells with claudin-low characteristics express high levels of osteopontin and a reduction of osteopontin in these cells impaired proliferation, survival and migration.

Dataset Information

Osteopontin regulates ubiquitin-dependent degradation of Stat1 in murine mammary epithelial tumor cells.

Publications

Osteopontin regulates ubiquitin-dependent degradation of Stat1 in murine mammary epithelial tumor cells.

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