1. Merkel cell polyomavirus-negative Merkel cell carcinoma is associated with JAK-STAT and MEK-ERK pathway activation
- Author
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Kenichi Kohashi, Yoshihisa Umekita, Satoshi Kuwamoto, Yoshinao Oda, Takeshi Iwasaki, Kazuhiko Hayashi, Michiko Matsushita, and Daisuke Nonaka
- Subjects
MAPK/ERK pathway ,Male ,Cancer Research ,Ruxolitinib ,Skin Neoplasms ,MAP Kinase Signaling System ,Merkel cell polyomavirus ,Biology ,MEK‐ERK pathway ,Merkel cell carcinoma ,Clinical Research ,Cell Line, Tumor ,Nitriles ,medicine ,Humans ,Phosphorylation ,STAT3 ,Aged ,Cell Proliferation ,Janus Kinases ,Aged, 80 and over ,Sex Characteristics ,Cell growth ,JAK‐STAT pathway ,Age Factors ,JAK-STAT signaling pathway ,food and beverages ,General Medicine ,Original Articles ,Middle Aged ,medicine.disease ,biology.organism_classification ,Prognosis ,Carcinoma, Merkel Cell ,Gene Expression Regulation, Neoplastic ,STAT Transcription Factors ,medicine.anatomical_structure ,Pyrimidines ,Oncology ,Cancer research ,biology.protein ,Pyrazoles ,Female ,Original Article ,Merkel cell ,medicine.drug - 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, This study investigates the relationship between Merkel cell polyomavirus (MCPyV) status and activation of the MEK‐ERK and JAK‐STAT signaling pathways in Merkel cell carcinoma (MCC). We observed that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC, leading us to conclude that MCC tumorigenic pathways differ depending on MCPyV status. MEK‐ERK pathway activation was inhibited by a JAK inhibitor in vitro in MCPyV‐negative MCC. Thus, JAK‐STAT and MEK‐ERK pathway inhibition may present a promising new treatment strategy for patients with advanced MCC.
- Published
- 2021