KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway
Author:
Fujii Takashi123ORCID, Nakano Yoshiko4, Hagita Daichi123, Onishi Nobuyuki5, Endo Arumu2, Nakagawa Masaya2, Yoshiura Toru2ORCID, Otsuka Yohei2, Takeuchi Satoru2, Suzuki Mario3, Shimizu Yuzaburo3, Toyooka Terushige2, Matsushita Yuko13, Hibiya Yuko13, Tomura Satoshi6, Kondo Akihide3ORCID, Wada Kojiro2, Ichimura Koichi13ORCID, Tomiyama Arata123ORCID
Affiliation:
1. Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan 2. Department of Neurosurgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan 3. Department of Neurosurgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan 4. Department of Pediatrics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 5. Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan 6. Division of Traumatology, Research Institute, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan
Abstract
Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.
Subject
Cancer Research,Oncology
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