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Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway.

ABSTRACT: Alterations in the microenvironment collaborate with cell autonomous mutations during the transformation process. Indeed, cancer-associated fibroblasts and senescent fibroblasts stimulate tumorigenesis in xenograft models. Because senescent fibroblasts accumulate with age, these findings suggest that they contribute to age-related increases in tumorigenesis. Previously we showed that senescence-associated stromal-derived osteopontin contributes to preneoplastic cell growth in vitro and in xenografts, suggesting that it impacts neoplastic progression. Analysis of fibroblasts within premalignant and malignant skin lesions ranging from solar/actinic keratosis to squamous cell carcinoma revealed they express osteopontin. Given the stromal expression of osteopontin, we investigated how osteopontin impacts preneoplastic cell growth. We show that osteopontin promotes preneoplastic keratinocyte cellular proliferation and cell survival through the CD44 cell receptor and activation of the MAPK pathway. These data suggest that stromal-derived osteopontin impacts tumorigenesis by stimulating preneoplastic cell proliferation thus allowing expansion of initiated cells in early lesions.

SUBMITTER: Luo X

PROVIDER: S-EPMC3685505 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway.

Luo Xianmin X Ruhland Megan K MK Pazolli Ermira E Lind Anne C AC Stewart Sheila A SA

Molecular cancer research : MCR 20110614 8

Alterations in the microenvironment collaborate with cell autonomous mutations during the transformation process. Indeed, cancer-associated fibroblasts and senescent fibroblasts stimulate tumorigenesis in xenograft models. Because senescent fibroblasts accumulate with age, these findings suggest that they contribute to age-related increases in tumorigenesis. Previously we showed that senescence-associated stromal-derived osteopontin contributes to preneoplastic cell growth in vitro and in xenogr ...[more]

PMID: 21673011

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Project description:PurposeThe migration and proliferation of vascular smooth muscle cells play crucial roles in the development of atherosclerotic lesions. This study examined the effects of fatty acid binding protein 4 (FABP4), an adipokine that is associated with cardiovascular risk, endothelial dysfunction and proinflammatory effects, on the migration and proliferation of human coronary artery smooth muscle cells (HCASMCs).Methods and resultsA DNA 5-bromo-2'-deoxy-uridine (BrdU) incorporation assay indicated that FABP4 significantly induced the dose-dependent proliferation of HCASMCs with a maximum stimulatory effect at 120 ng/ml (13% vs. unstimulated cells, p<0.05). An anti-FABP4 antibody (40 ng/ml) significantly inhibited the induced cell proliferation, demonstrating the specificity of the FABP4 proliferative effect. FABP4 significantly induced HCASMC migration in a dose-dependent manner with an initial effect at 60 ng/ml (12% vs. unstimulated cells, p<0.05). Time-course studies demonstrated that FABP4 significantly increased cell migration compared with unstimulated cells from 4 h (23%vs. 17%, p<0.05) to 12 h (74%vs. 59%, p<0.05). Pretreatment with LY-294002 (5 µM) and PD98059 (10 µM) blocked the FABP4-induced proliferation and migration of HCASMCs, suggesting the activation of a kinase pathway. On a molecular level, we observed an up-regulation of the MAPK pathway without activation of Akt. We found that FABP4 induced the active forms of the nuclear transcription factors c-jun and c-myc, which are regulated by MAPK cascades, and increased the expression of the downstream genes cyclin D1 and MMP2, CCL2, and fibulin 4 and 5, which are involved in cell cycle regulation and cell migration.ConclusionsThese findings indicate a direct effect of FABP4 on the migration and proliferation of HCASMCs, suggesting a role for this adipokine in vascular remodelling. Taken together, these results demonstrate that the FABP4-induced DNA synthesis and cell migration are mediated primarily through a MAPK-dependent pathway that activates the transcription factors c-jun and c-myc in HCASMCs.

Dataset Information

Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway.

Publications

Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway.

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