Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK-STAT and MEK-ERK pathway activation

Takeshi Iwasaki, Kazuhiko Hayashi, Michiko Matsushita, Daisuke Nonaka, Kenichi Kohashi, Satoshi Kuwamoto, Yoshihisa Umekita, Yoshinao Oda

Research output: Contribution to journalArticlepeer-review

Abstract

Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK-ERK and JAK-STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV-positive and 20 MCPyV-negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK-ERK and JAK-STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P =.038) and pERK1/2 (P =.019) was significantly higher in MCPyV-negative than in MCPyV-positive MCCs. Male gender (hazard ratio [HR] 2.882, P =.039), older age (HR 1.137, P <.001), negative MCPyV status (HR 0.324, P =.013), and advanced cancer stage (HR 2.672, P =.041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV-negative MCC cell lines than in an MCPyV-positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV-negative than in MCPyV-positive cell lines. These results suggest that activation of the JAK2 and MEK-ERK pathways was more prevalent in MCPyV-negative than in MCPyV-positive MCC and the JAK inhibitor ruxolitinib inhibited MEK-ERK pathway activation. Consequently, the JAK-STAT and MEK-ERK signaling pathways may be potential targets for MCPyV-negative MCC treatment.

Original languageEnglish
Pages (from-to)251-260
Number of pages10
JournalCancer Science
Volume113
Issue number1
DOIs
Publication statusPublished - Jan 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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