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KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

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.

SUBMITTER: Fujii T

PROVIDER: S-EPMC10778328 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Fujii Takashi T Nakano Yoshiko Y Hagita Daichi D Onishi Nobuyuki N Endo Arumu A Nakagawa Masaya M Yoshiura Toru T Otsuka Yohei Y Takeuchi Satoru S Suzuki Mario M Shimizu Yuzaburo Y Toyooka Terushige T Matsushita Yuko Y Hibiya Yuko Y Tomura Satoshi S Kondo Akihide A Wada Kojiro K Ichimura Koichi K Tomiyama Arata A

Cancers 20231219 1

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 a ...[more]

PMID: 38201436

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Project description:Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/β-catenin (wingless-int1/β-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of β-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/β-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

Dataset Information

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Publications

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

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