title: Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas.
abstract: Merkel cell polyomavirus (MCPyV) integrates monoclonally into the genomes of approximately 80% of Merkel cell carcinomas (MCCs), affecting their clinicopathological features. The molecular mechanisms underlying MCC development after MCPyV infection remain unclear. We investigated the association of MCPyV infection with activation of the Akt/mammalian target of rapamycin (mTOR)/4E-binding protein 1 (4E-BP1) signaling pathway in MCCs to elucidate the role of these signal transductions and to identify molecular targets for treatment. We analyzed the molecular and pathological characteristics of 41 MCPyV-positive and 27 MCPyV-negative MCCs. Expression of mTOR, TSC1, and TSC2 messenger RNA was significantly higher in MCPyV-negative MCCs, and Akt (T308) phosphorylation also was significantly higher (92% vs 66%; P = .019), whereas 4E-BP1 (S65 and T70) phosphorylation was common in both MCC types (92%-100%). The expression rates of most other tested signals were high (60%-100%) and not significantly correlated with MCPyV large T antigen expression. PIK3CA mutations were observed more frequently in MCPyV-positive MCCs (6/36 [17%] vs 2/20 [10%]). These results suggest that protein expression (activation) of most Akt/mTOR/4E-BP1 pathway signals was not significantly different in MCPyV-positive and MCPyV-negative MCCs, although these 2 types may differ in tumorigenesis, and MCPyV-negative MCCs showed significantly more frequent p-Akt (T308) activation. Therefore, certain Akt/mTOR/4E-BP1 pathway signals could be novel therapeutic targets for MCC regardless of MCPyV infection status.
authors.affiliation: Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503. Electronic address: iwasakit-path@umin.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503; Department of Pathobiological Science and Technology, School of Health Science, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503.
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Department of Histopathology, The Christie NHS Foundation Trust, Manchester, United Kingdom, M20 4BX.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nonaka
authors.affiliation: Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwamoto
authors.affiliation: Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503.
authors.forename: Masako
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Murakami
authors.affiliation: Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nagata
authors.affiliation: Department of Dermatology, School of Medicine, Kochi University Faculty of Medicine, Nankoku, Kochi, Japan, 783-8505.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Dermatology, School of Medicine, Kochi University Faculty of Medicine, Nankoku, Kochi, Japan, 783-8505.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
authors.affiliation: Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503. Electronic address: hayashik@med.tottori-u.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D008297:Male; D059965:Merkel cell polyomavirus / Q000302:isolation & purification*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D027601:Polyomavirus Infections / Q000821:virology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human
keywords: Akt/mTOR/4E-BP1 pathway; Merkel cell carcinoma; Merkel cell polyomavirus; PIK3CA; Squamous cell carcinoma