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The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

Oncogene volume 26, pages 1995–2005 (2007)Cite this article

Abstract

Kaposi sarcoma (KS), a multifocal neoplasm of the skin that can spread to visceral organs, is the most prevalent malignant tumor in acquired immuno deficiency syndrome (AIDS) patients. KS-associated herpesvirus (KSHV or HHV8) is considered the primary etiological factor of this malignancy, as well as of primary effusion lymphoma and multicentric Castleman's disease. KS lesions are characterized by proliferating spindle cells of endothelial cell (EC) origin. The action of the insulin-like growth factor (IGF) system has been implicated in many malignancies, and recent data have demonstrated that the IGF-I receptor (IGF-IR) is required for in vitro growth of the KS-derived KSIMM cell line. To examine whether the IGF pathway is also involved in KSHV-mediated transformation of ECs, we examined the expression and function of the IGF system in KSHV-infected, immortalized dermal microvascular EC (E-DMVEC). The expression of the insulin receptor (IR) was strongly induced in latently infected E-DMVEC, whereas the expression levels of the IGF-IR remained unchanged. Gene knockdown of IR, but not IGF-IR, prevented the characteristic focus formation seen in KSHV-infected E-DMVEC. Similarly, treatment with the IR-specific small-molecule inhibitor HNMPA-(AM3) inhibited postconfluent growth. These data suggest a role for the IR, but not the IGF-IR, in KSHV-induced transformation of vascular ECs.

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Acknowledgements

This work was supported by Grants PS1-RR00163 and RO1-CA099906 (AVM and KF). Initial support for this project was from Virogenomics, Inc., a company that may have a commercial interest in the results of this research. A potential conflict of interest by KF and AVM has been reviewed and managed by the OHSU Conflict of Interest in Research Committee. PPR was supported by the Molecular Hematology Training Grant T32 HL007781-13 and a Tartar Trust fellowship. This work was also partially supported by an award from the American Heart Association to PPR.

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Authors and Affiliations

  1. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA

    P P Rose, V R DeFilippis, A V Moses & K Früh

  2. Pediatrics, Oregon Health and Science University, Portland, OR, USA

    J M Carroll & C T Roberts Jr

  3. University of Washington School of Medicine, Seattle, WA, USA

    P A Carroll & M Lagunoff

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  1. P P Rose
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  2. J M Carroll
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  3. P A Carroll
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  4. V R DeFilippis
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  5. M Lagunoff
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  6. A V Moses
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  7. C T Roberts Jr
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  8. K Früh
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Correspondence to K Früh.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Rose, P., Carroll, J., Carroll, P. et al. The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma. Oncogene 26, 1995–2005 (2007). https://doi.org/10.1038/sj.onc.1210006

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