Journal Article

Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by α<sub>v</sub>β<sub>3</sub> integrin signaling

Meng-Ru Shen, Yueh-Mei Hsu, Keng-Fu Hsu, Yih-Fung Chen, Ming-Jer Tang and Cheng-Yang Chou

in Carcinogenesis

Volume 27, issue 5, pages 962-971
Published in print May 2006 | ISSN: 0143-3334
Published online January 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi336
Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by αvβ3 integrin signaling

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Insulin-like growth factor 1 (IGF-1) has been implicated in promoting mitogenic, metastatic and antiapoptotic phenotypes in several types of cancer. But little is known about the signal interaction of IGF-1 and integrin in the regulation of cervical cancer development and progression. This study is to investigate the regulatory mechanism of IGF-1 receptor (IGF-1R) signaling and its importance in cervical cancer formation. The growth and invasiveness of cervical cancer cells (SiHa and CaSki) were dose-dependently stimulated by IGF-1, whereas those of normal cervical epithelial cells were not. The immunoblot showed that IGF-1R proteins were abundant in cervical cancer cell lines. In contrast, IGF-1R protein was nearly undetectable in normal cervical epithelial cells. IGF-1-stimulated invasion and proliferation were abolished by functional-blocking monoclonal antibody against IGF-1R, whereas these cellular functions were unaffected by either IgG or monoclonal antibody to insulin receptor. Functional-blocking monoclonal antibody against integrins αvβ3, but not α2, α3, α4, α6, β1, β4 or α2β1, inhibited the IGF-1-stimulated invasion and proliferation in cervical cancer cells. αvβ3 integrin modulated IGF-1R phosphorylation by altering the rate of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) recruitment to the activated IGF-1R. The modulation of αvβ3 occupancy also affected the activation of IGF-1R downstream-signaling elements, including activation of Akt and extracellular signal-regulated protein kinases 1/2 (Erk1/2). The treatment of blocking antibody of αvβ3 integrin or IGF-1R significantly inhibited tumor growth and caused tumor regression in SCID mice model. Immunoblots of tumor tissues confirmed that the phosphorylation of IGF-1R and downstream targets of Akt and Erk1/2 were remarkably decreased in SCID mice treated with blocking antibodies of αvβ3 or IGF-1R. Thus, these data suggest that the signal interaction between IGF-1R and αvβ3 integrin plays an important role in promoting the development and progression of cervical cancer.

Keywords: EGF, epidermal growth factor; Erk1/2, extracellular signal-regulated protein kinases 1/2; IGF-1R, insulin-like growth factor 1 receptor; IRS, insulin receptor substrate; KSFM, keratinocyte serum-free medium; MAP, mitogen-activated protein; PI3K, phosphatidylinositol-3 kinase; SHP-2, Src homology 2-containing phosphotyrosine phosphatase

Journal Article.  5838 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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