Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis.

MedStar author(s):
Citation: Proceedings of the National Academy of Sciences of the United States of America. 109(18):7067-72, 2012 May 1.PMID: 22511720Institution: Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Intracellular Signaling Peptides and Proteins/me [Metabolism] | *Melanoma, Experimental/me [Metabolism] | *Melanoma, Experimental/sc [Secondary] | *Melanoma/me [Metabolism] | *Nerve Tissue Proteins/me [Metabolism] | *Tumor Markers, Biological/me [Metabolism] | Animals | Base Sequence | Cell Line, Tumor | Female | Humans | Intracellular Signaling Peptides and Proteins/ai [Antagonists & Inhibitors] | Intracellular Signaling Peptides and Proteins/ge [Genetics] | Melanoma, Experimental/ge [Genetics] | Melanoma/ge [Genetics] | Melanoma/sc [Secondary] | Mice | Mice, Inbred C57BL | Mice, Nude | Nerve Tissue Proteins/ai [Antagonists & Inhibitors] | Nerve Tissue Proteins/ge [Genetics] | RNA, Small Interfering/ge [Genetics] | Signal Transduction | Tumor Markers, Biological/ge [Genetics]Year: 2012Local holdings: Available online from MWHC library: 1915 - presentISSN:
  • 0027-8424
Name of journal: Proceedings of the National Academy of Sciences of the United States of AmericaAbstract: Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma.All authors: Bezrookove V, Bienvenu G, Billings P, Climent J, Dar AA, De Semir D, Debs R, Federman S, Haqq C, Kashani-Sabet M, Leong SP, Meyer Tamguney TM, Miller JR 3rd, Nosrati M, Rangel J, Sagebiel RW, Thummala S, Tong S, Venna SFiscal year: FY2012Digital Object Identifier: Date added to catalog: 2013-09-17
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 22511720 Available 22511720

Available online from MWHC library: 1915 - present

Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma.

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