TY - JOUR
T1 - Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK-STAT and MEK-ERK pathway activation
AU - Iwasaki, Takeshi
AU - Hayashi, Kazuhiko
AU - Matsushita, Michiko
AU - Nonaka, Daisuke
AU - Kohashi, Kenichi
AU - Kuwamoto, Satoshi
AU - Umekita, Yoshihisa
AU - Oda, Yoshinao
N1 - Funding Information:
This work was supported by the Fukuoka Foundation for Sound Health Cancer Research through funding to [T.I.] and grants from the Japan Society for the Promotion of Science (No. 26460433 [K.H.] : 17K08720 [K.H.] 26860238 [M.M.]; 17K15644 [M.M.] : 21K06885 [M.M.]) We thank the Research Initiative Center at Tottori University for technical assistance and the Research Support Center Graduate School of Medical Sciences at Kyushu University for providing equipment. We appreciate the English language review by Enago and thank Mr H. Sugihara and Dr K. Adachi at Tottori University and Mrs M. Nakamizo and Mrs M. Tomita at Kyushu University for technical assistance. We would also like to thank Dr I. Kinoshita and Dr H. Yamamoto at Kyushu University Hospital and Dr T. Iwasaki at Yamagishi Internal Medicine Clinic for helpful discussion. Part of this work was presented at the 110th USCAP annual meeting.
Funding Information:
This work was supported by the Fukuoka Foundation for Sound Health Cancer Research through funding to [T.I.] and grants from the Japan Society for the Promotion of Science (No. 26460433 [K.H.] : 17K08720 [K.H.] 26860238 [M.M.] ; 17K15644 [M.M.] : 21K06885 [M.M.])
Publisher Copyright:
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
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U2 - 10.1111/cas.15187
DO - 10.1111/cas.15187
M3 - Article
C2 - 34724284
AN - SCOPUS:85119676389
SN - 1347-9032
VL - 113
SP - 251
EP - 260
JO - Cancer Science
JF - Cancer Science
IS - 1
ER -
