Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis.
Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis.
- 2012
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.
English
0027-8424
*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]
Washington Cancer Institute
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
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.
English
0027-8424
*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]
Washington Cancer Institute
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't