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金沢大学がん進展制御研究所　腫瘍分子生物学研究分野 高橋智聡研究

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  1. Taniguchi K, Sugihara K, Miura T, Hoshi D, Kohno S, Takahashi C, Hirata E and Kiyokawa E. Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells. Cancer Sci., 2024 (accepted)
  2. Yu H, Kohno S, Voon DC, Hussein NH, Zhang Y, Nakayama J, Takegami Y and Takahashi C. RECK/GPR124-driven WNT signaling in pancreatic and gastric cancer cells. Cancer Sci., 2024 (accepted)
  3. Kayahashi K, Hasan M, Khatun A, Kohno S, Terakawa J, Horike S, Toyoda N, Matsuoka A, Iizuka T, Obata T, Ono M, Mizumoto Y, Takahashi C, Fujiwara H and Daikoku T. Androgen-responsive FOXP4 is a target for endometrial carcinoma. Commun Biol., 7(1):740, 2024.
  4. Maruzen S, Munesue S, Okazaki M, Takada S, Nakanuma S, Makino I, Gong L, Kohno S, Takahashi C, Tajima H, Yamamoto Y and Yagi S. Inhibitory Effects of Metformin for Pancreatic Neuroendocrine Neoplasms: Experimental Study on Mitochondrial Function. Onco, 2024(accepted)
  5. Gong L, Voon DC, Nakayama J, Takahashi C and Kohno S. RB1 loss induces quiescent state through downregulation of RAS signaling in mammary epithelial cells. Cancer Sci., 115(5):1576-1586, 2024.
  6. Momtazkari S, Choudhury AD, Yong ZWE, Le DT, Canh NH, Harada K, Hori T, Osato M, Takahashi C, Koh CP, and Voon DC. Differential requirement for IL-2 and IL-23 in the differentiation and effector functions of Th17/ILC3-like cells in a human T cell line. J.Leukoc. Biol., 115(6):1108-1117, 2024.
  7. Fujita H, Arai S, Arakawa H, Hamamoto K, Kato T, Arai T, Nitta N, Hotta K, Hosokawa N, Ohbayashi T, Takahashi C, Inokuma Y, Tamai I, Yano S, Kunishima M, Watanabe Y. Drug–drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers. Bioorg Med Chem., Mar 15:102:117674, 2024.
  8. Ma M, Wu M, Gu S, Yang J, Wang C, Zhang Y, Cheng S, Xu S, Zhang M, Wu Y, Zhao Y, Tian X, Takahashi C, Sheng J, and Wang Y. Inactivation of CSGALNACT2 Promotes Ovarian Cancer Migration and Invasion Through the MAPK/ERK Signaling Pathway. Cell Oncol., 2023. (accepted)
  9. Okada N, Ueki C, Shimazaki M, Tsujimoto G, Kohno S, Muranaka H, Yoshikawa K and Takahashi C.NFYA promotes the malignant behavior of triple-negative breast cancer through the regulation of lipid metabolism.Commun Biol.,6(1):596, 2023.
  10. Noguchi M, Kohno S, Pellattiero A, Machida Y, Shibata K, Shintani N, Kohno T, Gotoh N, Takahashi C, Hirao A, Kasahara A, and Scorrano L. Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinoma resistant cell. Cell Death & Disease., 14(4):241, 2023.
  11. Noyes C, Kitajima S, Li F, Suita Y, Miriyala S, Isaac S, Ahsan N, Knelson E, Vajdi A, Tani T, Thai TC, Xu D, Murai J, Tapinos N, Takahashi C, Barbie DA and Yajima M. The germline factor DDX4 contributes to the chemoresistance of small cell lung cancer cells. Commun. Biol., 6(1):65., 2023.
  12. Inaba Y, Hashiuchi E, WatanabeH, Kimura K, Oshima Y, Tsuchiya K, Murai S, Takahashi C, Matsumoto M, Kitajima S, Yamamoto Y, Honda M, Asahara S, Ravnskjaer K, Horike S, Kaneko S, Kasuga M, Nakano H, Harada K, and Inoue H. The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nat. Commun.,14(1):167, 2023.
  13. Okahashi N, Shima T, Kondo Y, Araki C, Tsuji S, Sawai A, Uehara H, Kohno S, Shimizu H, Takahashi C and Matsuda F. Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells. bioRxiv 2023.
  14. Loc PT, Hui Peng H, Ueno M, KohnoS, Kasada A, Hosomichi K, Sato T, Kurayoshi K, Kobayashi M, Tadokoro Y, Kasahara A, Shoulkamy MI, Xiao B, Worley PF, Takahashi C, Tajima A, and Hirao A. RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia. BBRC 621:74-79, 2022.
  15. Oo SM, Oo HK, Takayama H, Ishii KA, Takeshita Y, Goto H, Nakano Y, Kohno S, Takahashi C, Nakamura H, Saito Y, Matsushita M, Okamatsu-Ogura Y, Saito M and Takamura T. Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat. Cell Reports38(13): 2022 Mar 29, 110566
  16. Murata T, Hashimoto K, Kohno S, Takahashi C, Yamaguchi M, Ito C, Itoigawa M, Kojima R, Hikita K, Kaneda N. Chemical inducer of regucalcin attenuates lipopolysaccharide-induced inflammatory responses in pancreatic MIN6 ß-cells and RAW264.7 macrophages. FEBS Open Bio 12:175-191, 2022. doi:10.1002/2211-5463.13321
  17. Sheng J, Kohno S, Okada N, Okahashi N, Teranishi K, Matsuda F, Shimizu S, Linn P, Nagatani N, Yamamura M, Harada K, Horike S, Inoue H, Yano S, Kumar S, Kitajima S, Ajioka I and Takahashi C. Treatment of retinoblastoma 1-intact hepatocellular carcinoma with cyclin-dependent kinase 4/6 inhibitor combination therapy. Hepatology, 74(4):1971-1993, 2021.
  18. Gutiérrez J, Gonzalez D, Escalona-Rivano R, Takahashi C and Brandan E. Reduced RECK levels accelerate skeletal muscle differentiation, improve muscle regeneration and decrease fibrosis. FASEB J.May;35(5):e21503,2021.
  19. Nakamura M, Li Y, Choi BR, Matas-Rico E, Troncoso J, Takahashi C and Sockanathan S. GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of amyloid precursor protein. Sci. Transl. Med., 17;13(585):eabe6178, 2021.
  20. Nomura N, Ito C, Ooshio T, Tadokoro Y, Kohno S, Ueno M, Kobayashi M, Kasahara A, Takase Y, Kurayoshi K, Si S, Takahashi C, Komatsu M, Yanagawa T, Hirao A. Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner. Sci. Rep.,Jan 18;11(1):1666, 2021.
  21. Hu HT, Sasakura N, Matsubara D, Furusawa N, Mukai M, Kitamura N, Obayashi T, Nishimura T, Oono-Yakura K, Funato Y, Okamura Y, Tarao K, Nakano Y, Murakami Y, Kinoshita K, Takahashi C, Miki H, Gonda K, Scita G, Hanawa-Suetsugu K and Suetsugu S. Involvement of I-BAR protein IRSp53 in tumor cell growth via extracellular microvesicle secretion. bioRxiv 2020.
  22. Murata T, Yamaguchi M, Kohno S, Takahashi C, Watanabe R, Hatori K, Hikita K and Kaneda N.Regucalcin enhances adipocyte differentiation and attenuates inflammation in 3T3-L1 cells. FEBS Open Bio., 10(10):1967-1984, 2020.
  23. Seliverstov RY, Zaraiskiy MI, Tyurin RV, Naryshkin AG, Valerko VG, Semiglazov VV, Takahashi C. MicroRNA in monitoring of the evolution of glial cerebral tumors. Siberian Journal of Oncology, 19:47-53, 2020.
  24. Kohno S*, Linn P*, Nagatani N, Watanabe Y, Kumar S, Soga T and Takahashi C. Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion. Oncogene, 39: 5690-5707, 2020. *;equally contributed.
  25. Kulathunga N, Kohno S, Linn P, Nishimoto Y, Horike S, Zaraiskii M, Kumar S, Muranaka H and Takahashi C. Peripubertal High Fat Diet Promotes c-Myc Stabilization in Mammary Gland Epithelium. Cancer Sci., 111(7): 2336-2348, 2020.
  26. Thumkeo D, Katsura Y, Nishimura Y,Kanchanawong P,Tohyama K, Ishizaki T, Kitajima S, Takahashi C,Hirata T,Watanabe N,Krummel MF and Narumiya S.mDia1/3-dependent actin polymerization spatiotemporally controls LAT phosphorylation by Zap70 at the immune synapse. Science Advances 2020 Jan 1;6(1):e2432.
  27. Li F*, Kitajima S*, Kohno S, Yoshida A, Tange S, Sasaki S, Okada N, Nishimoto Y, Muranaka H, Nagatani N, Suzuki M, Masuda S, Thai TC, Nishiuchi T, Tanaka T, Barbie DA, Mukaida N and Takahashi C. RB inactivation induces a protumoral microenvironment via enhanced CCL2 secretion. Cancer Research, 79:3903-3915, 2019. doi: 10.1158/0008-5472.CAN-18-3604. * equal contribution.
    【Link 1】 【Link 2】 【Link 3】
  28. Nishimura T, NakataA, Xiaoxi C, Nishi K, Meguro-Horike M, Sasaki S,Kita K, Horike S,Saitoh K, Kato K, Kaori I, Murayama T, Kohno S, Takahashi C, Mukaida N, Yano S, Soga T, Tojo A and Gotoh N. Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2. Oncogene, 38:2464-2481, 2019.
  29. Kitajima S, Asahina H, Chen T, Guo S, Laura GQ, Cavanaugh JD, Merlino AA, Tange S, Terai H, Kim JW, Wang X, Zhou S, Xu N, Wang S, Zhu Z, Thai TC, Takahashi C, Wang Y, Neve R, Stinson S, Tamayo P, Watanabe H, Kirschmeier PT, K Wong KK, and Barbie DA. Overcoming resistance to dual innate immune and MEK inhibition downstream of KRAS. Cancer Cell 34:439-452, 2018.
  30. Zhao J, Okamoto Y, Asano Y, Ishimaru K, Aki S, Yoshioka K, Takuwa N, Wada T, Inagaki Y, Takahashi C, Nishiuchi T, Takuwa Y. Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages. PLoS One, 13(5):e0197604, 2018.
  31. Sasaki S, Baba T, Muranaka H, TanabeY, Takahashi C, Matsugo S and Mukaida N. Involvement of prokineticin 2-expressing neutrophil infiltration in 5-fluorouracil-induced aggravation of breast cancer metastasis to lung. Mol Cancer Ther, 17:1515-1525, 2018.
  32. Murata T, Yamaguchi Y, Kohno S, Takahashi C, Kakimoto M, Sugimura Y, Kamihara M, Hikita K and Kaneda N. Regucalcin confers resistance to amyloid-β toxicity in neuronally differentiated PC12 cells. FEBS openbio, 8:349-360, 2018.
  33. Muranaka H, Hayashi A, Minami K, Kitajima S, Kohno S, Nishimoto Y, Nagatani N, Suzuki M, Kulathunga N, Sasaki N, Okada N, Matsuzaka T, Shimano H, Tada H and Takahashi C. A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling. Oncogenesis 26;6 (6):e350, 2017.
  34. Kitajima S, Yoshida A, Kohno S, Li F, Suzuki S, Nagatani N, Nishimoto Y, Sasaki N, Muranaka H, Wan Y, Thai T C, Okahashi N, Matsuda F, Shimizu H, Nishiuchi T, Suzuki Y, Tominaga K, Gotoh N, Suzuki M, Ewen M E, Barbie D A, Hirose O, Tanaka T and Takahashi C.The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity. Oncogene 36:5145-5157, 2017.
  35. Nagata N, Xu L, Kohno S, Ushida Y, Aoki Y, Umeda R, Fuke N, Zhuge F, Ni Y, Nagashimada M, Takahashi C, Suganuma H, Kaneko S and Ota T. Glucoraphanin ameliorates obesity and insulin resistance through adipose tissue browning and reduction of metabolic endotoxemia in mice. Diabetes 66:1222-1236, 2017.
  36. Yoshida A, Kitajima S, Li F, Chaoyang C, Yujiro T, Kohno S, Wan Y, Hayashi N, Muranaka H, Nishimoto Y, Nagatani N, Nishiuchi T, Thai T C, Suzuki S, Nakao S, Tanaka T, Hirose O, Barbie D A and Takahashi C. MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6. Oncotarget 8:13872-13885, 2017.
  37. Hegazy AM, Yamada D, Kobayashi M, Kohno S, Ueno M, Ali MA, Ohta K, Tadokoro Y, Ino Y, Todo T, Soga T, Takahashi C and Hirao A. Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance. J Bio Chem, 291:21496-21509, 2016.
  38. Kitajima S, Li F, Takahashi C. Primary Culture of Mouse Thyroid Calcitonin-producing Cell (C cell) Tumors. Bio-Protocol, 5, 2015. (http://bio-protocol.org/e1681)
  39. Salah M, Nishimoto Y, Kohno S, Kondoh A, Kitajima S, Muranaka H, Nishiuchi T, Ibrahim A, Yoshida A and Takahashi C. An in vitro system to characterize prostate cancer progression identified signaling required for self-renewal. Mol Carcinog, 55:1974-1989, 2016.
  40. Gutiérrez J, Droppelmann CA, Contreras O, Takahashi C, Brandan E. RECK-mediated β1-integrin regulation by TGF-β1 is critical for wound contraction in mice. PLoS One,10(8):e0135005, 2015.
  41. Okahashi N, Kohno S, Kitajima S, Matsuda F, Takahashi C, Shimizu H.Metabolic characterization of cultured mammalian cells by mass balance analysis, tracer labeling experiments and computer-aided simulations.　J Biosci Bioeng, 120:725-731, 2015.
  42. Kitajima S*, Kohno S*, Kondoh A, Sasaki N. Nishimoto Y, Li F, Mohammed SA, Muranaka H, Nagatani N, Suzuki M, Kido Y and Takahashi C. Undifferentiated state induced by Rb-p53 double inactivation in mouse thyroid neuroendocrine cells and embryonic fibroblasts. Stem Cells, 33: 1657-1669, 2015. *; equally contributed.
  43. Rajabi HN, Takahashi C and Ewen ME. Retinoblastoma protein and MyoD function together to effect the repression of Fra-1 and in turn Cyclin D1 during terminal cell cycle arrest associated with myogenesis. J Biol Chem 289: 23417-23427, 2014.
  44. Ali MA, Naka K, Yoshida A, Fuse K, Kasada A, Hoshii T, Tadokoro Y, Ueno M, Ohta K, Kobayashi M, Takahashi C, Hirao A. Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients. Biochem Biophys Res Commun, 450: 837-843, 2014.
  45. Siddesha JM, Valente AJ, Sakamuri SS, Yoshida T, Gardner JD, Somanna N, Takahashi C, Noda M, Chandrasekar B. Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK. J Mol Cell Cardiol 65: 9-18, 2013. 
  46. Hayashi N, Kobayashi M, Shamma A, Morimura Y, Takahashi C, Yamamoto KI. Regulatory interaction between NBS1 and DNMT1 responding to DNA damage. J Biochem, 154: 429-435, 2013.
  47. Shamma A, Suzuki M, Hayashi, N, Kobayashi M, Sasaki N, Nishiuchi T, Doki Y, Okamoto T, Kohno S, Muranaka H, Kitajima S, Yamamoto K, Takahashi C. ATM mediates pRB function to control DNMT1 protein stability and DNA methylation. Mol Cell Biol, 33: 3113-3124, 2013.
  48. Taura M, Suico M A, Koyama K, Komatsu K, Miyakita R, Matsumoto C, Kudo E, Kariya R, Goto H, Kitajima S, Takahashi C, Shuto T, Nakao M, Okada S, and Kai H. Rb/E2F1 regulates the innate immune receptor Toll-like receptor 3 in epithelial cells. Mol Cell Biol,32: 1581-1590, 2012.
  49. Kitajima S, Miki T, Takegami Y, Kido Y, Noda M, Hara E, Shamma A, and Takahashi C. Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling. Oncogene,30: 737-750, 2011.
  50. Chandana E P, Maeda Y, Ueda A, Kiyonari H, Oshima N, Yamamoto M, Kondo S, Oh J, Takahashi R, Yoshida Y, Kawashima S, Alexander D B, Kitayama H, Takahashi C, Tabata Y, Matsuzaki T, and Noda M. Involvement of the Reck tumor suppressor protein in maternal and embryonic vascular remodeling in mice. BMC Dev Biol,10: 84-96, 2010.
  51. Loayza-Puch F, Yoshida Y, Matsuzaki T, Takahashi C, Kitayama H, and Noda M. Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs. Oncogene,29: 2638-2648, 2010.
  52. Miki T, Shamma A, Kitajima S, Takegami Y, Noda M, Nakashima Y, Watanabe K, and Takahashi C. The β1-integrin-dependent function of RECK in physiologic and tumor angiogenesis. Mol Cancer Res,8: 665-676, 2010.
  53. Omura A, Matsuzaki T, Mio K, Ogura T, Yamamoto M, Fujita A, Okawa K, Kitayama H, Takahashi C, Sato C, and Noda M. RECK forms cowbell-shaped dimers and inhibits matrix metalloproteinase-catalyzed cleavage of fibronectin. J Biol Chem,284: 3461-3469, 2009.
  54. Shamma A, Takegami Y, Miki T, Kitajima S, Noda M, Obara T, Okamoto T, and Takahashi C. Rb Regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer Cell,15: 255-269, 2009.
  55. Kawashima S, Imamura Y, Chandana E P, Noda T, Takahashi R, Adachi E, Takahashi C, and Noda M. Localization of the membrane-anchored MMP-regulator RECK at the neuromuscular junctions. J Neurochem,104: 376-385, 2008.
  56. Fotiadou P P, Takahashi C, Rajabi H N, and Ewen M E. Wild-type NRas and KRas perform distinct functions during transformation. Mol Cell Biol,27: 6742-6755, 2007.
  57. Miki T, Takegami Y, Okawa K, Muraguchi T, Noda M, and Takahashi C. The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) interacts with membrane type 1 matrix metalloproteinase and CD13/aminopeptidase N and modulates their endocytic pathways. J Biol Chem,282: 12341-12352, 2007.
  58. Muraguchi T, Takegami Y, Ohtsuka T, Kitajima S, Chandana E P, Omura A, Miki T, Takahashi R, Matsumoto N, Ludwig A, Noda M, and Takahashi C. RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci,10: 838-845, 2007.
  59. Nakaji K, Ihara M, Takahashi C, Itohara S, Noda M, Takahashi R, and Tomimoto H. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke,37: 2816-2823, 2006.
  60. Takahashi C, Contreras B, Iwanaga T, Takegami Y, Bakker A, Bronson R T, Noda M, Loda M, Hunt J L, and Ewen M E. Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor. Nat Genet,38: 118-123, 2006.
  61. Echizenya M, Kondo S, Takahashi R, Oh J, Kawashima S, Kitayama H, Takahashi C, and Noda M. The membrane-anchored MMP-regulator RECK is a target of myogenic regulatory factors. Oncogene,24: 5850-5857, 2005.
  62. Ihara M, Kinoshita A, Yamada S, Tanaka H, Tanigaki A, Kitano A, Goto M, Okubo K, Nishiyama H, Ogawa O, Takahashi C, Itohara S, Nishimune Y, Noda M, and Kinoshita M. Cortical organization by the septin cytoskeleton is essential for structural and mechanical integrity of mammalian spermatozoa. Dev Cell,8: 343-352, 2005.
  63. Takenaka K, Ishikawa S, Yanagihara K, Miyahara R, Hasegawa S, Otake Y, Morioka Y, Takahashi C, Noda M, Ito H, Wada H, and Tanaka F. Prognostic significance of reversion-inducing cysteine-rich protein with Kazal motifs expression in resected pathologic stage IIIA N2 non-small-cell lung cancer. Ann Surg Oncol,12: 817-824, 2005.
  64. Oh J, Seo D W, Diaz T, Wei B, Ward Y, Ray J M, Morioka Y, Shi S, Kitayama H, Takahashi C, Noda M, and Stetler-Stevenson W G. Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. Cancer Res,64: 9062-9069, 2004.
  65. Oh J, Takahashi R, Adachi E, Kondo S, Kuratomi S, Noma A, Alexander D B, Motoda H, Okada A, Seiki M, Itoh T, Itohara S, Takahashi C, and Noda M. Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice. Oncogene,23: 5041-5048, 2004.
  66. Takahashi C, Contreras B, Bronson R T, Loda M, and Ewen M E. Genetic interaction between Rb and K-ras in the control of differentiation and tumor suppression. Mol Cell Biol,24: 10406-10415, 2004.
  67. Takenaka K, Ishikawa S, Kawano Y, Yanagihara K, Miyahara R, Otake Y, Morioka Y, Takahashi C, Noda M, Wada H, and Tanaka F. Expression of a novel matrix metalloproteinase regulator, RECK, and its clinical significance in resected non-small cell lung cancer. Eur J Cancer,40: 1617-1623, 2004.
  68. Takeuchi T, Hisanaga M, Nagao M, Ikeda N, Fujii H, Koyama F, Mukogawa T, Matsumoto H, Kondo S, Takahashi C, Noda M, and Nakajima Y. The membrane-anchored matrix metalloproteinase (MMP) regulator RECK in combination with MMP-9 serves as an informative prognostic indicator for colorectal cancer. Clin Cancer Res,10: 5572-5579, 2004.
  69. Arai T, Kasper J S, Skaar J R, Ali S H, Takahashi C, and DeCaprio J A. Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Proc Natl Acad Sci U S A,100: 9855-9860, 2003.
  70. Takahashi C, Bronson R T, Socolovsky M, Contreras B, Lee K Y, Jacks T, Noda M, Kucherlapati R, and Ewen M E. Rb and N-ras function together to control differentiation in the mouse. Mol Cell Biol,23: 5256-5268, 2003.
  71. Furumoto K, Arii S, Mori A, Furuyama H, Gorrin Rivas M J, Nakao T, Isobe N, Murata T, Takahashi C, Noda M, and Imamura M. RECK gene expression in hepatocellular carcinoma: correlation with invasion-related clinicopathological factors and its clinical significance. Reverse-inducing--cysteine-rich protein with Kazal motifs. Hepatology,33: 189-195, 2001.
  72. Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara R M, Nishimura S, Imamura Y, Kitayama H, Alexander D B, Ide C, Horan T P, Arakawa T, Yoshida H, Nishikawa S, Itoh Y, Seiki M, Itohara S, Takahashi C, and Noda M. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell,107: 789-800, 2001.
  73. Izumi H, Takahashi C, Oh J, and Noda M. Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogenes. FEBS Lett,481: 31-36, 2000.
  74. Sasahara R M, Takahashi C, and Noda M. Involvement of the Sp1 site in ras-mediated downregulation of the RECK metastasis suppressor gene. Biochem Biophys Res Commun,264: 668-675, 1999.
  75. Ishida-Takahashi A, Otani H, Takahashi C, Washizuka T, Tsuji K, Noda M, Horie M, and Sasayama S. Cystic fibrosis transmembrane conductance regulator mediates sulphonylurea block of the inwardly rectifying K+ channel Kir6.1. J Physiol,508: 23-30, 1998.
  76. Takahashi C, Sheng Z, Horan T P, Kitayama H, Maki M, Hitomi K, Kitaura Y, Takai S, Sasahara R M, Horimoto A, Ikawa Y, Ratzkin B J, Arakawa T, and Noda M. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci U S A,95: 13221-13226, 1998.
  77. Takahashi C, Akiyama N, Matsuzaki T, Takai S, Kitayama H, and Noda M. Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene. Oncogene,12: 2137-2146, 1996.
  78. Takahashi C, Kumagai S, Tsubata R, Sorachi K, Ozaki S, Imura H, and Nakao K. Portal hypertension associated with anticardiolipin antibodies in a case of systemic lupus erythematosus. Lupus,4: 232-235, 1995.
  79. Adachi Y, Copeland T D, Takahashi C, Nosaka T, Ahmed A, Oroszlan S, and Hatanaka M. Phosphorylation of the Rex protein of human T-cell leukemia virus type I. J Biol Chem,267: 21977-21981, 1992.
  80. Adachi Y, Ishida-Takahashi A, Takahashi C, Takano E, Murachi T, and Hatanaka M. Phosphorylation and subcellular distribution of calpastatin in human hematopoietic system cells. J Biol Chem,266: 3968-3972, 1991.
  81. Tanaka A, Takahashi C, Yamaoka S, Nosaka T, Maki M, and Hatanaka M. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A,87: 1071-1075, 1990.

欧文総説

  1. Jindan Sheng. Treatment of RB1-intact hepatocellular carcinoma with CDK4/6 inhibitor combination therapy. 金沢大学十全医学会雑誌, 131: 3, 98- 103, 2022.
  2. Takahashi C and Kato J. Targeting Abnormal Cell Cycle in Cancer: A Preface to the Special Issue. Onco 2:34-35 , 2022.
  3. Linn P, Kohno S, Sheng J, Kulathunga N, Yu H, Zhang Z, Voon D, Watanabe Y and Takahashi C. Targeting RB1 loss in cancers. Cancers, 13: 3737, 2021.
  4. Takahashi C and Kato J. Synthetic inhibitors of CDK4/6 activities and tumor suppression: a preface to the special issue. Onco, 1(1):1-2, 2021.
  5. Kitajima S, Li F, Takahashi C. Tumor Milieu Controlled by RB Tumor Suppressor. Int J Mol Sci., 2020 Apr1;21(7).
  6. Kitajima S and Takahashi C. The intersection of RB tumor suppressor function, stem cells, metabolism and inflammation. Cancer Science 108(9): 1726-1731, 2017.
  7. Kohno S, Kitajima S, Sasaki N and Takahashi C. RB tumor suppressor functions shared by stem cell and cancer cell strategies. World J Stem Cells, 8: 170-184, 2016.
  8. Hayashi N. and Takahashi C. Pleiotropic functions of RB protein in tumour suppression. Archives in Cancer Res, 2015. (on line)
  9. Takahashi C, Sasaki N, and Kitajima S. Twists in views on RB functions in cellular signaling, metabolism and stem cells. Cancer Sci, 103: 1182-1188, 2012.
  10. Noda M, Takahashi C, Matsuzaki T, and Kitayama H. What we learn from transformation suppressor genes: lessons from RECK. Future Oncol,6: 1105-1116, 2010.
  11. Noda M, and Takahashi C. Recklessness as a hallmark of aggressive cancer. Cancer Sci,98: 1659-1665, 2007.
  12. Takahashi C, and Ewen M E. Genetic interaction between Rb and N-ras: differentiation control and metastasis. Cancer Res,66: 9345-9348, 2006.
  13. Noda M, Oh J, Takahashi R, Kondo S, Kitayama H, and Takahashi C. RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling. Cancer Metastasis Rev,22: 167-175, 2003.
  14. Sasahara R M, Brochado S M, Takahashi C, Oh J, Maria-Engler S S, Granjeiro J M, Noda M, and Sogayar M C. Transcriptional control of the RECK metastasis/angiogenesis suppressor gene. Cancer Detect Prev,26: 435-443, 2002.
  15. Sasahara R M, Takahashi C, Sogayar M C, and Noda M. Oncogene-mediated downregulation of RECK, a novel transformation suppressor gene. Braz J Med Biol Res,32: 891-895, 1999.
  16. Takahashi C, Akiyama N, Kitayama H, Takai S, and Noda M. Possible involvement of MSX-2 homeoprotein in v-ras-induced transformation. Leukemia,11 Suppl 3: 340-343, 1997.

和文総説

  1. 李鳳凱. がん抑制遺伝子RB1の不活性化はCCL2を介してがんを促進する微小環境を構築する. 金沢大学十全医学会雑誌, 129: 2, 37- 39, 2020.
  2. 村中勇人. リピドミクス・プロファイリングによるがん抑制遺伝子産物pRbの脂質代謝制御における役割の探索. 金沢大学十全医学会雑誌 , 127(2): 47-48, 2018.
  3. 北嶋俊輔, 河野晋, 髙橋智聡. RBとp53の二重不活性化により、マウス甲状腺C細胞および線維芽細胞は高度な未分化性を獲得する. BioMedサーカス.com 最新研究情報「執筆者自身による研究論文レビュー 第35回」 2015.
  4. Takahashi C, Takegami Y, and Shamma A. Genetic and biochemical interactions of Rb and ras. Seikagaku,81: 873-883, 2009.
  5. Takahashi C, Muraguchi T, Takegami Y, and Miki T. Regulation of Notch signaling and its polarity mediated by ectodomain shedding of DSL ligands. Tanpakushitsu Kakusan Koso,54: 1742-1746, 2009.
  6. Takahashi C, Junseo O, and Noda M. The membrane-anchored metalloproteinase inhibitor RECK. Tanpakushitsu Kakusan Koso,47: 1889-1895, 2002.

和文著書

  1. 高橋智聡, 河野晋. 『がん細胞社会における細胞間相互作用Which intercellular interaction should be targeted in cancer therapy?』別冊・医学のあゆみp67-71, 2021「細胞競合による生体制御とがん」井垣達吏編
  2. 高橋智聡, 河野晋. 『がん細胞社会における細胞間相互作用Which intercellular interaction should be targeted in cancer therapy?』医学のあゆみVol.274No.5p469-473, 2020「細胞競合による生体制御とがん」井垣達吏編
  3. 高橋智聡, 河野晋. 『RB1によるがん幹細胞の制御Control of undifferentiated behavior of cancer cells by RB1』医学のあゆみVol.273 No.5 p410-414, 2020「治療標的としてのがん幹細胞」伊藤貴浩編
  4. 河野晋、村中勇人、北嶋俊輔、佐々木信成、鈴木美砂、髙橋智聡. 実験医学増刊 号「RBとがんの代謝」Vol.35 No.10 p21-25, 2017曽我朋義編, 羊土社刊
  5. 河野晋、北嶋俊輔、佐々木信成、髙橋智聡. 生化学 『代謝変化とエピジェテックス制御』「RBがん抑制遺伝子産物による細胞未分化性制御」88巻3号 p335-341, 2016.
  6. 西本裕希、髙橋智聡. 生体の科学 特集『細胞の社会学―細胞間で繰り広げられる協調と競争』「13．がん細胞社会のなかの多様性・多層性」Vol.67 No. 2 p151-154, 2016 藤田恭之編,松田道行監修 医学書院刊
  7. 髙橋智聡. 家族性腫瘍学 ― 家族性腫瘍の最新研究動向 ― II. 各論 原因遺伝子 RB1. 日本臨牀, 73巻: p336-341, 2015.
  8. 高橋 智聡. 実験医学　私のメンター ～受け継がれる研究の心～「Mark E. Ewen―若きPIの苦悩」Vol.32 No.19 p3116-3120, 2014 鈴木拓, 今井浩三編　羊土社刊
  9. 高橋 智聡. 実験医学　News and Hot Paper Digest「ニッチ細胞の遺伝子変異が発がんを誘導する？骨芽細胞の場合」Vol.32 No.9 p1379-1380,2014 藤井宣晴編　羊土社刊
  10. 高橋 智聡. 実験医学　News and Hot Paper Digest「セリンはピルビン酸キナーゼM2の天然リガンドである」Vol.31 No.3, 412-413頁, 2013 小笹徹編　羊土社刊
  11. 高橋智聡: “第5節 細胞周期制御遺伝子3(Rb)”, 「疾患モデルの作製と利用　がん」中村 卓郎編集, 200-214頁, エル・アイ・シー, 2012.
  12. 北嶋俊輔、高橋智聡: “インビトロがん幹細胞モデル”, 実験医学 増刊 「がん幹細胞-ステムネス、ニッチ、標的治療への理解」須田年生編集, Vol.29-No.20, 203-209頁, 羊土社, 2011.
  13. 高橋智聡: “Rasシグナル制御と発癌”, 実験医学 増刊「秒進分歩する癌研究と分子標的治療」原英二、平尾敦、矢野聖二、佐谷秀行編集, Vol.29-No.2, 20-25頁, 羊土社, 2011.
  14. 北嶋俊輔、石川智夫、木戸敬治、高橋智聡: “その他腫瘍モデル”,「完全版マウス・ラット疾患モデル活用ハンドブック」秋山徹、奥山隆平、河府和義編集, 163- 180頁, 羊土社, 2010.
  15. 高橋智聡、野田亮: “MMPと膜結合型MMP制御因子RECK”, 実験医学 増刊「タンパク質修飾・分解の新機能に迫る」田中啓二、 西道隆臣編集, 131-136頁, 羊土社, 2004.
  16. 高橋智聡: “マトリックスメタロプロテアーゼ制御因子RECKと血管リモデリング”, 実験医学 増刊「血管研究の最先端と治療への展開」渋谷正史、江頭健輔、室原豊明編集, 78-83頁, 羊土社, 2004.
  17. 高橋智聡、野田亮: “癌化のアルゴリズム” 「癌化のシグナル伝達機構」 秋山徹、豊島久眞男編集, 15-25頁, 中外医学社, 1994.

特許

  • 発明の名称：ＲＢ１陽性癌の治療用医薬組成物及びキット
    出願番号　：特願2020-180429
    出願日　　：2020年10月28日
  • 発明の名称：抗癌剤及びその使用
    出願番号　：特願2019-228526
    出願日　　：2019年12月18日
    登録日　　：2024年6月25日
  • 発明の名称：癌細胞を正常復帰させる機能を有する遺伝子
    出願番号　：特願平08-229731
    出願日　　：1996年 8月30日

代表的な論文

Rasがん遺伝子による細胞形態変化の誘導に拮抗する遺伝子を探すという目的で機能的クローニングを行った。RECK遺伝子は、様々ながん遺伝子による発現制御を受け、その強制発現は、がん細胞の浸潤転移を抑制した。この遺伝子産物には、細胞外マトリクスを分解するMMP-9というプロテアーゼの作用を拮抗的に阻害する活性があることがわかった。RECKは、がん化シグナルと細胞外マトリクスのリモデリングをつなぐ分子と想像された。
RECK遺伝子を完全に欠損させたマウスは、胚発生の途中で死んでしまうことがわかった。また、血管発生の異常が顕著であった。RECKタンパク質には、MMP-2という別のプロテアーゼの活性を阻害する働きのあることもわかった。
線虫におけるRbがん抑制遺伝子とRasシグナルの遺伝学的関係をヒントに、マウスにおけるRbとN-rasの遺伝学的関係を問うた論文。Rb欠損は胎性致死で、細胞周期、細胞死、最終分化の異常を伴う。N-rasの同時欠損は、最終分化のみをレスキューし、胎性致死性の出現を数日間遅らせた。RbとRasの間に双方抑制的な遺伝学的関係があることに気づいた。
Rbと同時にK-rasを片アレル欠損したマウスを解析した。この論文では、胚発生だけでなく、Rbへテロ型欠損マウスに生じる脳下垂体腫瘍におけるK-rasプロトがん遺伝子の影響を検討した。K-rasを片アレル欠損することにより、脳下垂体腫瘍の悪性度が抑制され、マウスの寿命が延長した。胚発生におけるRbとrasの関係が、腫瘍でも成立すること、そして、野生型のras遺伝子にも、がんを進展させる働きのあることを証明した。
ところが、Rbをヘテロ型欠損したマウスに発生する甲状腺カルシトニン産生細胞（C細胞）由来の腫瘍は、N-rasを同時欠損することによって、高度に悪性化した。N-rasをヘテロ型欠損させても、残った正常アレルが、腫瘍の悪性進展の過程で欠失する現象も見られた。細胞と、その細胞の遺伝学的背景によっては、rasプロトがん遺伝子が、がん抑制遺伝子のように振る舞うということを示した。この理由は、2009年の論文において明らかにした。
RECKは、GPIアンカータンパク質であり、細胞膜の脂質ラフトというマイクロドメインに分布する。この論文では、マススペクトル法等を用いて、MT1-MMPとCD13/APNという２種類のプロテアーゼが、RECKと直接に結合することによって、脂質ラフトに移動することを示した。この結果、RECKが存在すると、この二つのタンパク質のエンドサイトーシス経路が変更され、タンパク質寿命を短縮することが示された。
RECKを完全欠損したマウスの中枢神経系では、神経前駆細胞の早熟分化が起こることを突き止めた。これを突破口として、RECKが、ADAM10という細胞膜のプロテアーゼの活性を抑制すること、そして、その働きに依存して、RECKが、神経前駆細胞の自己複製を司るNotchシグナルを制御することを見いだした。
N-rasを同時欠損すると、Rbをヘテロ型欠損するマウスに発生するC細胞腫瘍がなぜ悪性化するのか。Rbのみを欠くマウスのC細胞腫瘍には、DNA損傷応答と細胞老化の痕跡が見えた。しかし、N-rasを同時欠損すると、その痕跡は生じない。Rbがないと、N-RasはRbがあるときよりも活性が上昇し、DNA損傷応答と細胞老化を誘導、これが、腫瘍の悪性進展に拮抗していた。これは、Rbと同時に、細胞老化を司る遺伝子を欠損させるとC細胞腫瘍が高度に悪性化することによって証明された。では、なぜ、Rbがないと、N-Rasは活性が亢進するのか。Rbを導入しても細胞周期が変化しない細胞や導入条件を検討し、マイクロアレー法を用いて、Rbの転写ターゲット遺伝子をしぼり直した。そこには、タンパク質イソプレニル化を制御する酵素をコードする遺伝子が多数含まれていた。イソプレニル化はN-Rasの成熟の第一段階である。実際に、Rbを欠くと、de novoにつくられたN-Rasタンパク質の膜輸送が亢進することを観察した。RbがどのようにしてRasの活性を制御するのか、まだ完全ではないが、一定の答えを出した。また、この研究によって、Rb機能とタンパク質の脂質修飾そして脂質合成系がつながった。
RECK遺伝子の機能を更に探索した。これまで、がん浸潤・転移、胚発生、血管新生、神経幹細胞機能、エンドサイトーシス等のコンテクストにおいて本遺伝子の機能を探索してきた。本論文では、RECK遺伝子の欠損が、細胞の増殖に与える影響を正確に検討した。RECK欠損細胞は、野生型細胞に較べて不死化しやすい。しかし、急激なノックダウンは、細胞老化を誘導したのである。この一見逆説的な現象をヒントに、RECKがEGFRシグナルに拮抗することを見いだした。
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