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Tumor Biology

Abstract 3419: NOS1 imparts a survival benefit to PAX-FKHR expressing alveolar rhabdomyosarcomas

Sheetal V. Bajaj, Violette Shahbazian, Michael J. Anderson and Timothy J. Triche
Sheetal V. Bajaj
1USC/Childrens Hospital Los Angeles, Los Angeles, CA.
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Violette Shahbazian
1USC/Childrens Hospital Los Angeles, Los Angeles, CA.
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Michael J. Anderson
1USC/Childrens Hospital Los Angeles, Los Angeles, CA.
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Timothy J. Triche
1USC/Childrens Hospital Los Angeles, Los Angeles, CA.
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DOI: 10.1158/1538-7445.AM10-3419 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Based on histology, two major forms are identified: embryonal and alveolar. Molecularly, these tumors are classified as translocation-positive alveolar RMS (ARMS, characterized by PAX3-FKHR or PAX7-FKHR chimeric fusions), translocation-negative alveolar RMS (nARMS), and embryonal RMS (ERMS). The PAX-FKHR oncogenes have been shown to be responsible, in part, for the aggressive clinical behavior and poor outcome of ARMS. It is thus important to identify biomarkers in this subgroup that can be used as potential therapeutic targets.

METHODS: Using Affymetrix Human Exon 1.0 ST (HuEx) microarrays, genome-wide expression profiles were generated on primary tumors from RMS patients accrued on COG treatment protocols. Data analysis was performed using institutional software (Genetrix) by standard classification methods. Expression of neuronal nitric oxide synthase (NOS1) was validated by qPCR, immunoblot and immunohistochemistry. A functional relationship, if any, to PAX-FKHR was determined by qPCR after siRNA-mediated knockdown of PAX-FKHR in ARMS cell lines and stable transduction of PAX-FKHR into an ERMS cell line. Further, shRNA targeting NOS1 using a lentiviral delivery system was used for functional NOS1 studies in ARMS cell lines.

RESULTS: Expression analysis revealed that NOS1 is highly expressed in ARMS with a PAX3 or PAX7 translocation. Little expression was found in nARMS, ERMS or normal muscle. This was confirmed by qPCR and immunoblotting in two independent groups of primary tumors and RMS cell lines. PAX-FKHR knockdown resulted in decreased expression of NOS1 and its corresponding protein in ARMS cell lines. PAX-FKHR expression in an ERMS cell line induced the expression of NOS1 and its corresponding protein where the native cell line showed no corresponding expression. Further, targeting NOS1 using shRNA in ARMS cell line caused decreased NOS1 expression leading to poor cell survival and cell death.

CONCLUSIONS: NOS1 is over-expressed in the more aggressive PAX3 or PAX7 ARMS when compared to translocation-negative RMS. Its expression appears to be regulated by PAX-FKHR, a tumor specific chimeric gene that has been implicated in regulating the malignant phenotype of ARMS. It seems to play an important role in the survival of these tumor cells. Taken together, these observations suggest that NOS1 is a downstream effecter of PAX-FKHR mediated oncogenesis and an essential factor for tumor cell survival that could be a therapeutic target, using suitable small molecule therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3419.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract 3419: NOS1 imparts a survival benefit to PAX-FKHR expressing alveolar rhabdomyosarcomas
Sheetal V. Bajaj, Violette Shahbazian, Michael J. Anderson and Timothy J. Triche
Cancer Res April 15 2010 (70) (8 Supplement) 3419; DOI: 10.1158/1538-7445.AM10-3419

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Abstract 3419: NOS1 imparts a survival benefit to PAX-FKHR expressing alveolar rhabdomyosarcomas
Sheetal V. Bajaj, Violette Shahbazian, Michael J. Anderson and Timothy J. Triche
Cancer Res April 15 2010 (70) (8 Supplement) 3419; DOI: 10.1158/1538-7445.AM10-3419
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Cancer Research Online ISSN: 1538-7445
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