title: Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma.
abstract: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an important oncogene contributing to cancer progression partially by regulating cMYC and AKT. We examined CIP2A expression in cutaneous melanomas, its association with clinicopathological parameters and mapped molecular mechanisms regulated by CIP2A in vitro. CIP2A expression was analyzed by immunohistochemistry in 17 nevi, 132 primary melanomas and 49 metastases. Effects of siRNA-mediated down-regulation on proliferation, apoptosis and signaling pathways were assessed in melanoma cell lines. In superficial spreading melanomas (SSM), high nuclear CIP2A expression was associated with poor overall survival (OS) (P = 0.0018). Surprisingly, high cytoplasmic expression was related to improved relapse-free (P = 0.031) and OS (P = 0.014) in nodular melanomas (NM). In vitro experiments revealed that CIP2A can regulate proliferation and/or apoptosis partially through the PI3K/AKT pathway but also independently. In summary, CIP2A could represent a potential therapeutic target in SSM. However, in NM cytoplasmic CIP2A is associated with improved prognosis indicating that CIP2A has distinct, complex functions dependent on the molecular context and histological subtype. As seen in other cancer types, CIP2A can influence cMYC and AKT, but our data also suggest that in melanoma it has additional targets which need to be identified.
authors: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
authors: Vivi Ann
authors: VA
authors: Flørenes
authors: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
authors: Elisabeth
authors: E
authors: Emilsen
authors: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
authors: Hiep Phuc
authors: HP
authors: Dong
authors: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
authors: Mette
authors: M
authors: Førsund
authors: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
authors: Ruth
authors: R
authors: Holm
authors: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
authors: Ana
authors: A
authors: Slipicevic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D001324:Autoantigens / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D015331:Cohort Studies; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009506:Nevus / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D001324:Autoantigens; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; C500266:CIP2A protein, human
keywords: Apoptosis; CIP2A; melanoma; survival; therapy