Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas.
AffiliationDivision of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Tottori, Japan, 683-8503.
MetadataShow full item record
AbstractMerkel 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.
CitationComparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas. 2015, 46 (2):210-6 Hum Pathol
- Usefulness of significant morphologic characteristics in distinguishing between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative Merkel cell carcinomas.
- Authors: Iwasaki T, Matsushita M, Kuwamoto S, Kato M, Murakami I, Higaki-Mori H, Nakajima H, Sano S, Hayashi K
- Issue date: 2013 Sep
- Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator.
- Authors: Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS
- Issue date: 2011 Sep
- Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma.
- Authors: Sihto H, Kukko H, Koljonen V, Sankila R, Böhling T, Joensuu H
- Issue date: 2011 Jul 15
- Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis.
- Authors: Iwasaki T, Matsushita M, Nonaka D, Nagata K, Kato M, Kuwamoto S, Murakami I, Hayashi K
- Issue date: 2016 Feb
- A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma.
- Authors: Korkolopoulou P, Levidou G, Trigka EA, Prekete N, Karlou M, Thymara I, Sakellariou S, Fragkou P, Isaiadis D, Pavlopoulos P, Patsouris E, Saetta AA
- Issue date: 2012 Dec