KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Cancers - 16(2023), 1 vom: 19. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fujii, Takashi [VerfasserIn] |
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| Links: |
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| Themen: |
Glioma |
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| Anmerkungen: |
Date Revised 14.01.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/cancers16010009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366920146 |
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| 100 | 1 | |a Fujii, Takashi |e verfasserin |4 aut | |
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| 520 | |a 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 | ||
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| 650 | 4 | |a KLC1-ROS1 fusion | |
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| 700 | 1 | |a Nakano, Yoshiko |e verfasserin |4 aut | |
| 700 | 1 | |a Hagita, Daichi |e verfasserin |4 aut | |
| 700 | 1 | |a Onishi, Nobuyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Endo, Arumu |e verfasserin |4 aut | |
| 700 | 1 | |a Nakagawa, Masaya |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshiura, Toru |e verfasserin |4 aut | |
| 700 | 1 | |a Otsuka, Yohei |e verfasserin |4 aut | |
| 700 | 1 | |a Takeuchi, Satoru |e verfasserin |4 aut | |
| 700 | 1 | |a Suzuki, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Shimizu, Yuzaburo |e verfasserin |4 aut | |
| 700 | 1 | |a Toyooka, Terushige |e verfasserin |4 aut | |
| 700 | 1 | |a Matsushita, Yuko |e verfasserin |4 aut | |
| 700 | 1 | |a Hibiya, Yuko |e verfasserin |4 aut | |
| 700 | 1 | |a Tomura, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Kondo, Akihide |e verfasserin |4 aut | |
| 700 | 1 | |a Wada, Kojiro |e verfasserin |4 aut | |
| 700 | 1 | |a Ichimura, Koichi |e verfasserin |4 aut | |
| 700 | 1 | |a Tomiyama, Arata |e verfasserin |4 aut | |
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