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Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors

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Cancer Communications 2023年第4期43卷 415-434页

作者： Hiroyuki Suzuki Hideki Iwamoto Takahiro Seki Toru Nakamura Atsutaka Masuda Takahiko Sakaue Toshimitsu Tanaka yasuko imamura Takashi Niizeki Masahito Nakano Shigeo Shimose Tomotake Shirono Yu Noda Naoki Kamachi Miwa Sakai Kazutoyo Morita Masamichi Nakayama Tomoharu Yoshizumi Ryoko Kuromatsu Hirohisa Yano Yihai Cao Hironori Koga Takuji Torimura Division of Gastroenterology Department of MedicineKurume University School of MedicineKurume CityFukuokaJapan Liver Cancer Research Division Research Center for Innovative Cancer TherapyKurume UniversityKurume CityFukuokaJapan Iwamoto Internal Medicine Clinic Kitakyushu CityFukuokaJapan Department of Microbiology Tumor and Cell biologyKarolinska InstitutetStockholmSweden Department of Surgery and Science Graduate School of Medical ScienceKyushu UniversityFukuoka CityFukuokaJapan Department of Pathology Kurume University School of MedicineKurume CityFukuokaJapan

Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not *** aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in ***:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC *** evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC *** on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were ***,in vivo genetic and pharmacological gain-and loss-of-function experiments were ***:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall ***,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor ***-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase ***,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib ***:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic *** TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 *** data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

关键词： hepatocellular carcinoma hypoxia IGFBP-1 lenvatinib molecular targeting resistance tyrosine kinase inhibitors

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Monitoring and mathematical modeling of mitochondrial ATP in myotubes at single-cell level reveals two distinct population with different kinetics

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Quantitative Biology 2020年第3期8卷 228-237页

作者： Naoki Matsuda Ken-ichi Hironaka Masashi Fujii Takumi Wada Katsuyuki Kunida Haruki Inoue Miki Eto Daisuke Hoshino Yasuro Furuichi yasuko Manabe Nobuharu LFujii Hiroyuki Noji Hiromi imamura Shinya Kuroda Department of Biological Sciences Graduate School of ScienceUniversity of TokyoTokyo 113-0033Japan Molecular Genetics Research Laboratory Graduate School of ScienceUniversity of TokyoTokyo 113-0033Japan Department of Mathematical and Life Sciences Graduate School of Integrated Sciences for LifeHiroshima UniversityHiroshima 739-8526Japan Laboratory of Computati onal Biology Graduate School of Biological SciencesNara Institute of Science and Tech no logyNara 630-0192Japan Department of Computational Biology and Medical Sciences Graduate School of Frontier SciencesUniversity of TokyoTokyo 113-0033Japan Department of Engineering Science Graduate School of Informatics and EngineeringUniversity of Electro-CommunicationsTokyo 182-8585Japan Department of Health Promotion Sciences Graduate School of Human Health SciencesTokyo Metropolitan UniversityTokyo 192-0397Japan Department of Applied Chemistry Graduate School of EngineeringUniversity of TokyoTokyo 113-8656Japan Department of Functional Biology Graduate School of BiostudiesKyoto UniversityKyoto 606-8501Japan CREST Japan Science and Technology CorporationTokyo 113-0033Japan

Backgrounds ATP is the major energy source for myotube contraction,and is quickly produced to compensate ATP consumption and to maintain sufficient ATP *** is consumed mainly in cytoplasm and produced in mitochondria during myotube *** understand the mechanism of ATP homeostasis during myotube contraction,it is essential to monitor mitochondrial ATP at single-cell level,and examine how ATP is produced and consumed in ***:We established C2C12 cell line stably expressing fluorescent probe of mitochondrial ATP,and induced differentiation into myotubes・We gave electric pulse stimulation to the differentiated myotubes,and measured mitochondrial *** constructed mathematical model of mitochondrial ATP at single-cell level,and analyzed kinetic parameters of ATP production and ***:We performed hierarchical clustering analysis of time course of mitochondrial ATP,which resulted in two *** 1 showed strong transient increase,whereas cluster 2 showed weak transient *** modeling at single-cell level revealed that the ATP production rate of cluster 1 was larger than that of cluster 2,and that both regulatory pathways of ATP production and consumption of cluster 1 were faster than those of cluster *** 1 showed larger mitochondrial mass than cluster 2,suggesting that cluster 1 shows the similar property of slow muscle fibers,and cluster 2 shows the similar property of fast muscle *** Cluster 1 showed the stronger mitochondrial ATP increase by larger ATP production rate,but not smaller *** 1 might reflect the larger oxidative capacity of slow muscle fiber.

关键词： mitocondrial ATP production ATP consumption single-cell analysis mathematical modeling

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