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長谷川 好規 Yoshinori Hasegawa名古屋大学大学院医学系研究科呼吸器内科学・教授・医学博士


専門分野

呼吸器疾患の分子病態解析と遺伝子多型解析に基づく悪性腫瘍の治療法開発・薬理遺伝学

略歴

1980年
徳島大学医学部医学科卒業
1980年-1983年
社会保険中京病院・臨床研修医
1983年-1987年
名古屋大学大学院・医学研究科
1987年-1989年
米国カリフォルニア大学医学部ロサンゼルス校研究員
1989年-1994年
名古屋大学研究生・医学部附属病院第一内科
1994年-2002年
名古屋大学助手・医学部附属病院第一内科
2002年-2007年
名古屋大学講師・医学部附属病院呼吸器内科
2007年-present
名古屋大学教授・大学院医学系研究科病態内科学講座 呼吸器内科学

研究課題名

組織修復と腫瘍化のメカニズムに関する共通標的分子の探索

これまでの成果と今後の展望

A. 研究目的
上皮細胞が間葉系細胞に変化する現象は、Epithelial-Mesenchymal Transition (EMT) として、またその逆の現象は、 Mesenchyma-Epithelial Transition (MET)として知られており、初期胚発生における原腸陥入や器官形成過程に重要な役割を果たすことが報告されている。近年、がんの浸潤能と転移能の獲得にEMTが関与することが報告されEMT現象に関与する分子の同定が始まった。一方、炎症過程、そして組織修復・リモデリングの各過程においてEMTを含めた細胞の形質転換に伴う細胞の遊走が明らかになり、細胞がEMTにより細胞起源固有の生物学的特性、特に細胞間接着に作用する接着因子を喪失させ、細胞骨格構造の変化に伴う線維芽細胞様形態の獲得および線維芽細胞が有する生物学的特性の獲得により、細胞可動性・遊走性を向上させることがわかってきた。我々は、これまで肺の炎症と線維化メカニズムにおける流血中骨髄由来細胞やCre-loxP systemを用いた上皮間葉系細胞転換(EMT)の役割について研究を展開してきている。また、癌細胞自体においても、EMTと癌細胞の遊走性や腫瘍原性に関する複数のEMT制御因子(ZEB1、Twist、EpCAM)の役割について研究を進めてきた。本研究では、固形癌、特に肺組織環境下における肺癌の増殖における間葉系細胞の増殖制御と癌細胞の細胞浸潤・転移制御を目的とし、EMT・MET分子を基軸に標的分子を探索し、固形癌治療戦略の可能性を研究することを目的とした。

B. 研究成果
EMTを誘導する複数の刺激を包括的に制御する治療戦略として、PTEN C末端リン酸化部位リン酸化に着目した。はじめに、TGFβにより誘導されるEMT表現型獲得におけるPTEN C末端リン酸化部位の役割を検討した。その結果、線維化病変から過剰産生および活性が誘導されると考えられているTGFβは、その刺激により、肺上皮細胞に対して有意なPTEN発現抑制とPTEN C末端リン酸化亢進をもたらすことを明らかにした。これによってp-PTEN/PTEN ratio亢進が誘導され、結果としてPTENの制御下にあるTGFβ誘導シグナル伝達系の活性化亢進がおこる状態になることを示した。PTEN C末端リン酸化部位に人工的に遺伝子変異を作成し、リン酸化阻害PTEN(PTEN4A)はTGFβ誘導細胞遊走およびEMT表現型獲得を完全に抑制した。一方、PTEN-Wildの遺伝子導入による制御効果は限定的であった。また、TGFβ刺激のない正常状態においてPTEN4A導入は細胞増殖に影響を与えないが、TGFβ刺激が存在する病的状態において有意に細胞増殖抑制を示すことを確認した。これらの結果は、PTEN C末端リン酸化部位のリン酸化制御がPTEN シグナル経路の制御に極めて有用な標的となることを示唆する。また、炎症性線維化病変の制御においても、低酸素環境がEMTを誘導し、線維化におよぼす影響を明らかにした。本研究から、癌とそれを取り巻く線維化をはじめとする炎症性病変の両軸に対する分子標的としてのPTENの役割を明らかにした。

主要研究業績

  1. Sato M, Shames DS, Hasegawa Y: Emerging evidence of Epithelial-to-Mesenchymal Transition in lung carcinogenesis. Respirology, in press (2012)
  2. Sashio T, Kume H, Takeda N, Asano T, Tsuji S, Kondo M, Hasegawa Y, Shimokata K: Possible Involvement of Sphingosine-1-Phosphate/G(i)/RhoA Pathways in Adherence of Eosinophils to Pulmonary Endothelium. Allergol Int, in press (2012)
  3. Horio M, Sato M, Takeyama Y, Elshazley M, Yamashita R, Hase T, Yoshida K, Usami N, Yokoi K, Sekido Y, Kondo M, Toyokuni S, Gazdar AF, Minna JD, Hasegawa Y: Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells. Ann Surg Oncol, in press (2012)
  4. Ogawa S, Horio Y, Yatabe Y, Fukui T, Ito S, Hasegawa Y, Mitsudomi T, Hida T: Patterns of recurrence and outcome in patients with surgically resected small cell lung cancer. Int J Clin Oncol, in press (2012)
  5. Deguchi D, Feuerstein M, Kitasaka T, Suenaga Y, Ide I, Murase H, Imaizumi K, Hasegawa Y, Mori K: Real-time marker-free patient registration for electromagnetic navigated bronchoscopy: a phantom study. Int J Comput Assist Radiol Surg, in press (2012)
  6. Nakashima H, Hashimoto N, Aoyama D, Kohnoh T, Sakamoto K, Kusunose M, Imaizumi K, Takeyama Y, Sato M, Kawabe T, Hasegawa Y: Involvement of the transcription factor twist in phenotype alteration through epithelial-mesenchymal transition in lung cancer cells. Mol Carcinog, in press (2012)
  7. Hayashi Y, Matsushima M, Nakamura T, Shibasaki M, Hashimoto N, Imaizumi K, Shimokata K, Hasegawa Y, Kawabe T: Quercetin protects against pulmonary oxidant stress via heme oxygenase-1 induction in lung epithelial cells. Biochem Biophys Res Commun, 417, 169-174 (2012)
  8. Sakamoto K, Taniguchi H, Kondoh Y, Wakai K, Kimura T, Kataoka K, Hashimoto N, Nishiyama O, Hasegawa Y: Acute exacerbation of IPF following diagnostic bronchoalveolar lavage procedures. Respir Med, 106, 436-442 (2012)
  9. Aso H, Ito S, Mori A, Morioka M, Suganuma N, Kondo M, Imaizumi K, Hasegawa Y: Prostaglandin E2 enhances interleukin-8 production via EP4 receptor in human pulmonary microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol, 302, L266-273 (2012)
  10. Morioka M, Parameswaran H, Naruse K, Kondo M, Sokabe M, Hasegawa Y, Suki B, Ito S: Microtubule dynamics regulate cyclic stretch-induced cell alignment in human airway smooth muscle cells. PLoS One, 6, e26384 (2011)
  11. Maeda M, Hasegawa H, Hyodo T, Ito S, Asano E, Yuang H, Funasaka K, Shimokata K, Hasegawa Y, Hamaguchi M, Senga T: ARHGAP18, a GTPase-activating protein for RhoA, controls cell shape, spreading, and motility. Mol Biol Cell, 22, 3840-3852 (2011)
  12. Tachi T, Hase T, Okamoto Y, Kaji N, Arima T, Matsumoto H, Kondo M, Tokeshi M, Hasegawa Y, Baba Y: A clinical trial for therapeutic drug monitoring using microchip-based fluorescence polarization immunoassay. Anal Bioanal Chem, 401, 2301-2305 (2011)
  13. Saito S, Nakayama T, Hashimoto N, Miyata Y, Egashira K, Nakao N, Nishiwaki S, Hasegawa M, Hasegawa Y, Naoe T: Mesenchymal stem cells stably transduced with a dominant-negative inhibitor of CCL2 greatly attenuate bleomycin-induced lung damage. Am J Pathol, 179, 1088-1094 (2011)
  14. Hase T, Sato M, Yoshida K, Girard L, Takeyama Y, Horio M, Elshazley M, Oguri T, Sekido Y, Shames DS, Gazdar AF, Minna JD, Kondo M, Hasegawa Y: Pivotal role of epithelial cell adhesion molecule in the survival of lung cancer cells. Cancer Sci, 102, 1493-1500 (2011)
  15. Hibino Y, Morise M, Ito Y, Mizutani T, Matsuno T, Ito S, Hashimoto N, Sato M, Kondo M, Imaizumi K, Hasegawa Y: Capsaicinoids regulate airway anion transporters through Rho kinase- and cyclic AMP-dependent mechanisms. Am J Respir Cell Mol Biol, 45, 684-691 (2011)
  16. Mori A, Ito S, Morioka M, Aso H, Kondo M, Sokabe M, Hasegawa Y: Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca(2+) concentrations in human airway smooth muscle cells. Eur J Pharmacol, 659, 72-78 (2011)
  17. Kotani H, Kishi R, Mouri A, Sashio T, Shindo J, Shiraki A, Hiramatsu T, Iwata S, Taniguchi H, Nishiyama O, Iwata M, Suzuki R, Gonda H, Niwa T, Kondo M, Hasegawa Y, Kume H, Noda Y: Influence of leukotriene pathway polymorphisms on clinical responses to montelukast in Japanese patients with asthma. J Clin Pharm Ther, 37, 112-116 (2011)
  18. Nishiyama O, Taniguchi H, Kondoh Y, Takada K, Baba K, Saito H, Sugino Y, Yamamoto M, Ogasawara T, Kondo M, Imaizumi K, Hasegawa Y, Suzuki R, Shimokata K: Phase II study of S-1 monotherapy as a first-line treatment for elderly patients with advanced nonsmall-cell lung cancer: the Central Japan Lung Study Group trial 0404. Anticancer Drugs, 22, 811-816 (2011)
  19. Nakamura T, Matsushima M, Hayashi Y, Shibasaki M, Imaizumi K, Hashimoto N, Shimokata K, Hasegawa Y, Kawabe T: Attenuation of TGF-ss-Stimulated Collagen Production in Fibroblasts by Quercetin-Induced HO-1. Am J Respir Cell Mol Biol, 44, 614-620 (2011)
  20. Kameda H, Tokuda H, Sakai F, Johkoh T, Mori S, Yoshida Y, Takayanagi N, Taki H, Hasegawa Y, Hatta K, Yamanaka H, Dohi M, Hashimoto S, Yamada H, Kawai S, Takeuchi T, Tateda K, Goto H: Clinical and radiological features of acute-onset diffuse interstitial lung diseases in patients with rheumatoid arthritis receiving treatment with biological agents: importance of pneumocystis pneumonia in Japan revealed by a multicenter study. Intern Med, 50, 305-313 (2011)
  21. Aso H, Kondoh Y, Taniguchi H, Kimura T, Nishiyama O, Kato K, Kataoka K, Hasegawa Y: Noninvasive ventilation in patients with acute exacerbation of pulmonary tuberculosis sequelae. Intern Med, 49, 2077-2083 (2010)
  22. Oguri T, Shimokata T, Inada M, Ito I, Ando Y, Sasaki Y, Hasegawa Y: Pharmacokinetic analysis of carboplatin in patients with cancer who are undergoing hemodialysis. Cancer Chemoth Pharm, 66, 813-817 (2010)
  23. Shimokata T, Ando Y, Yasuda Y, Hamada A, Kawada K, Saito H, Matsuo S, Kondo M.Imaizumi, K, Hasegawa Y: Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with cancer. Cancer Sci, 101, 2601-2605 (2010)
  24. Usami N, Yokoi K, Hasegawa Y, Taniguchi H, Shindo J, Yamamoto M, Suzuki R, Imaizumi K, Kondo M, Shimokata K: Central Japan Lung Study Group. Phase II study of carboplatin and gemcitabine as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer: a report from the Central Japan Lung Study Group, CJLSG 0503 trial. Int J Clin Oncol, 15, 583-587 (2010)
  25. Morise M, Ito Y, Mastuno T, Hibino Y, Mizutani T, Ito S, Hashimoto N, Kondo M, Imaizumi K, Hasegawa Y: Heterogous regulation of anion transporters by menthol in human airway epithelial cells. Eur J Pharmacol, 635, 204-211 (2010)
  26. Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y: Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Resp Cell Mol Biol, 43, 161-172 (2010)
  27. Ito S, Suki B, Kume H, Numaguchi Y, Ishii M, Iwaki M, Kondo M, Naruse K, Hasegawa Y, Sokabe M: Actin cytoskeleton regulates stretch-activated Ca2+ influx in human pulmonary microvascular endothelial cells. Am J Resp Cell Mol Biol, 43, 26-34 (2010)
  28. Asano T, Kume H, Taki F, Ito S, Hasegawa Y: Thalidomide attenuates airway hyperresponsiveness and eosinophilic inflammation in a murine model of allergic asthma. Biol Pharm Bull, 33, 1028-1032 (2010)
  29. Takeyama Y, Sato M, Horio M, Hase T, Yoshida K, Yokoyama T, Nakashima H, Hashimoto N, Sekido Y, Gazdar AF, Minna JD, Kondo M, Hasegawa Y. Knockdown of ZEB1, a master epithelial-to-mesenchymal transition (EMT) gene, suppresses anchorage-independent cell growth of lung cancer cells. Cancer Lett, 296, 216-224 (2010)
  30. Ichikawa M, Suzuki R, Kataoka K, Noda Y, Shindoh J, Matsumoto S, Tanikawa Y, Suzuki K, Baba K, Shindo Y, Kondo M, Imaizumi K, Kume H, Hasegawa Y, Takagi K, Taniguchi H. Second-line weekly paclitaxel in resistant or relapsed non-small cell lung cancer treated with docetaxel and carboplatin: A multi-center phase II study. Lung Cancer, 69, 319-322 (2010)
  31. Iwano S, Imaizumi K, Okada T, Hasegawa Y, Naganawa S. Virtual bronchoscopy-guided transbronchial biopsy for aiding the diagnosis of peripheral lung cancer. Eur J Radiol, in press (2010)
  32. Ito S, Suki B, Kume H, Numaguchi Y, Ishii M, Iwaki M, Kondo M, Naruse K, Hasegawa Y, Sokabe M. Actin cytoskeleton regulates stretch-activated Ca2+ influx in human pulmonary microvascular endothelial cells. Am J Respir Cell Mol Biol, in press (2010)
  33. Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol, in press(2010)
  34. Morise M, Ito Y, Matsuno T, Hibino Y, Mizutani T, Ito S, Hashimoto N, Kondo M, Imaizumi K, Hasegawa Y. Heterologous regulation of anion transporters by menthol in human airway epithelial cells. Eur J Pharmacol, 635, 204-11 (2010)
  35. Goto Y, Shinjo K, Kondo Y, Shen L, Toyota M, Suzuki H, Gao W, An B, Fujii M, Murakami H, Osada H, Taniguchi T, Usami N, Kondo M, Hasegawa Y, Shimokata K, Matsuo K, Hida T, Fujimoto N, Kishimoto T, Issa JP, Sekido Y. Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma. Cancer Res, 69, 9073-82 (2009)
  36. Takagi Y, Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Hashimoto I, Hayashi Y, Kawabe T, Shimokata K, Hasegawa Y. Erythromycin-induced CXCR4 expression on microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol, 297, L420-31 (2009)
  37. Shindo Y, Sato S, Maruyama E, Ohashi T, Ogawa M, Hashimoto N, Imaizumi K, Sato T, Hasegawa Y. Health-care-associated pneumonia among hospitalized patients in a Japanese community hospital. Chest, 135, 633-640 (2009)
  38. Shibasaki M, Hashimoto K, Okamoto M, Hayashi Y, Imaizumi K, Hashimoto N, Ozaki N, Yokoi T, Takagi K, Hasegawa Y, Shimokata K, Kawabe T. Up-regulation of surfactant protein production in a mouse model of secondary pulmonary alveolar proteinosis. Am J Respir Cell Mol Biol, 40, 536-542 (2009)
  39. Iwata S, Ito S, Iwaki M, Kondo M, Sashio T, Takeda N, Sokabe M, Hasegawa Y, Kume H. Regulation of endothelin-1-induced interleukin-6 production by Ca(2+) influx in human airway smooth muscle cells. Eur J Pharmacol, 605, 15-22 (2009)
  40. Sekigawa T, Tajima A, Hasegawa T, Hasegawa Y, Inoue H, Sano Y, Matsune S, Kurono Y, Inoue I. Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma. Clin Exp Allergy, 39, 972-981 (2009)
  41. Suzuki R, Yamamoto M, Saka H, Taniguchi H, Shindoh J, Tanikawa Y, Nomura F, Gonda H, Imaizumi K, Hasegawa Y, Shimokata K. A phase study of carboplatin and paclitacel with meloxicam. Lung Cancer, 63, 72-76 (2009)
  42. Iwaki M, Ito S, Morioka M, Iwata S, Numaguchi Y, Ishii M, Kondo M, Kume H, Naruse K, Sokabe M, Hasegawa Y. Mechanical stretch enhances IL-8 production in pulmonary microvascular endothelial cells. Biochem Biophys Res Commun, 389, 531-6 (2009)
  43. Ito S, Kume H, Naruse K, Kondo M, Takeda N, Iwata S, Hasegawa Y, Sokabe M. A Novel Ca2+ influx pathway activated by mechanical strech in human airway smooth muscle cells. Am J Respir Cell Mol Biol, 38, 407-413 (2008)
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  45. Mori K et al. Bronchoscope tracking without fiducial markers using ultra-tiny electromagnetic tracking system and its evaluation in different environments. Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv. 10: 644-651 (2007)
  46. Okamoto M et al. Macrophage-derived chemokine in malignant and tuberculous pleurisy. Respirology 12: 581?584 (2007)
  47. Hasegawa Y et al. Screening for adverse reactions to irinotecan treatment using the lnvader UGT1A1 molecular assay. Expert Rev Mol Diagn 6: 527-533 (2006)
  48. Yokoyama T et al. EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci 97: 753-759 (2006)
  49. Kitagawa C et al. Genetic polymorphisms in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 15: 35-41 (2005)
  50. Ando Y et al. Clinical pharmacogenetics of irinotecan. Drug Metab Rev 37: 565-574 (2005)
  51. Ito G et al. Krupple-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells. Cancer Res 64: 3838-3843 (2004)
  52. Hasegawa Y et al. Rapid Detection of UGT1A1 Gene Polymorphisms by Newly Developed Invader Assay. Clin Chem 50: 1479-1480 (2004)
  53. Jinnai N et al. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin induced asthma: a candidate gene approach. Hum Mol Genet 13: 3203-3217 (2004)
  54. Hashimoto N et al. CD40 plays a crucial role in lipopolysaccharide-induced acute lung injury. Am J Respir Cell Mol Biol 30: 808-815 (2004)
  55. Usami N et al. b-catenin inhibits cell growth of a malignant mesothelioma cell line, NCI-H28,with a 3p21.3 homozygous deletion. Oncogene 22: 5978-5986 (2003)
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