Merkel Cell Polyomavirus Infection Associated with Akt/Mammalian Target of Rapamycin/4E-BP1 Signaling Pathway Activation in the Pathogenesis of Merkel Cell Carcinoma
Takeshi Iwasaki, Michiko Matsushita, Daisuke Nonaka, Hideki Nakajima, Satoshi Kuwamoto, Ichiro Murakami, Shigetoshi Sano, Osamu Yamamoto, Kazuhiko Hayashi. Tottori University, Yonago, Tottori, Japan; Christie Hospital, NHS Foundation Trust, Manchester, United Kingdom; Kochi Universify, Nankoku, Kouchi, Japan
Background: Merkel cell polyomavirus (MCPyV) monoclonally integrates into genomes of approximately 80% human Merkel cell carcinomas (MCCs) and undergoes mutation. It affects clinicopathological features of MCCs, and MCPyV-large T antigen (MCPyV-LT) plays a pivotal role in pathogenesis by inhibiting cell cycle-regulating function of the retinoblastoma protein. However, the molecular mechanisms involved in MCC development after MCPyV infection are unclear. We investigated the association of MCPyV infection with the activation of AKT/mammalian target of rapamycin (mTOR)/4E-BP1 signaling pathway in MCC to elucidate the role of signal transduction MCC molecular pathogenesis and to discover molecular targets for MCC treatment.
Design: We analyzed molecular pathological characteristics of 39 MCPyV-positive and 26 MCPyV-negative MCCs detected using real-time polymerase chain reaction. PIK3CA mutations (exons 9 and 20), mRNA expression of Akt/mTOR/4EBP1 signaling pathway, and clinical data were compared between MCPyV-positive and -negative MCCs, and immunohistochemical expression of MCPyV-LT and phosphorylation status of Akt/mTOR/4EBP1 signals including Akt and 4E-BP1 were studied.
Results: Heat-map analysis of mRNA expression of the signals in the Akt/mTOR/4E-BP1 signaling pathway revealed differences in patterns between MCPyV-positive and MCPyV-negative MCCs. MCPyV-negative MCCs showed significantly higher expression of some signals including mTOR than MCPyV-positive MCCs (p < 0.05). PIK3CA mutations were found in 6/25 and 0/23 MCPyV-positive and -negative MCCs, respectively. Akt/mTOR/4E-BP1 signaling pathway activation was very common in MCCs, as evidenced by the phosphorylation pattern and very low proportion of MCCs with negative staining with antibodies (2/61).This pattern was significantly different in MCPyV-positive and -negative MCCs (p = 0.04) but was not associated with differences in prognosis. No significant correlation was observed between MCPyV-LT expression and most signals in Akt/mTOR/4E-BP1 signaling pathway.
Conclusions: These results suggest that MCPyV-positive and -negative MCCs may have different tumorigenic pathways and Akt/mTOR/4E-BP1 signaling pathway signals may be novel targets for targeted therapy in MCC treatment.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 60, Wednesday Morning