title: Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis.
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.
authors.affiliation: Auerback Melanoma Research Laboratory and Melanoma Center, University of California, San Francisco, CA 94115, USA.
authors.forename: David
authors.initials: D
authors.lastname: De Semir
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nosrati
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.forename: Scot
authors.initials: S
authors.lastname: Federman
authors.forename: Geraldine
authors.initials: G
authors.lastname: Bienvenu
authors.forename: Suraj
authors.initials: S
authors.lastname: Venna
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel
authors.forename: Joan
authors.initials: J
authors.lastname: Climent
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Meyer Tamgüney
authors.forename: Suresh
authors.initials: S
authors.lastname: Thummala
authors.forename: Schuyler
authors.initials: S
authors.lastname: Tong
authors.forename: Stanley P L
authors.initials: SP
authors.lastname: Leong
authors.forename: Chris
authors.initials: C
authors.lastname: Haqq
authors.forename: Paul
authors.initials: P
authors.lastname: Billings
authors.forename: James R
authors.initials: JR
authors.lastname: Miller
authors.forename: Richard W
authors.initials: RW
authors.lastname: Sagebiel
authors.forename: Robert
authors.initials: R
authors.lastname: Debs
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashani-Sabet
mesh_terms: D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C418612:PHIP protein, human; C420744:Phip protein, mouse; D034741:RNA, Small Interfering