Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
De Semir D,Nosrati M,Bezrookove V,Dar AA,Federman S,Bienvenu G,Venna S,Rangel J,Climent J,Meyer Tamgüney TM,Thummala S,Tong S,Leong SP,Haqq C,Billings P,Miller JR 3rd,Sagebiel RW,Debs R,Kashani-Sabet Mdoi
10.1073/pnas.1119949109subject
Has Abstractpub_date
2012-05-01 00:00:00pages
7067-72issue
18eissn
0027-8424issn
1091-6490pii
1119949109journal_volume
109pub_type
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