HOME > Members > GCOE Organizing Members > Yoshinori Hasegawa MD, PhD


Yoshinori Hasegawa MD, PhDProfessor, Department of Respiratory Medicine, Nagoya University Graduate School of Medicine


Specialized field

Molecular biology of the pulmonary diseases and Lung cancer, Pharmacogenomics of cancer chemotherapy

Career Summary

1980
M.D., University of Tokushima
1980-1983
Resident, Social Insurance Chukyo Hospital
1983-1987
Postgraduate School, Nagoya University
1987-1989
Research Fellow, Dept. Microbiology and Immunology, UCLA
1989-1994
Clinical Fellow, 1st. Dept Internal Medicine, Nagoya University
1994-2002
Research Associate, 1st. Dept Internal Medicine, Nagoya University
2002-2007
Assistant Professor, Dept Respiratory Medicine, Nagoya University
2007-present
Professor of Medicine, Dept Respiratory Medicine, Nagoya

Research Theme

Common molecular target of tissue repair and cancer

Research Summary

Search for the common molecular targets of tissue repair and cancer

The phenotypic conversion of an epithelial cell to a mesenchymal cell or vice versa is described as an epithelial- mesenchymal transition (EMT) or a mesenchymal- epithelial transition (MET), which plays an important role for stems form its developmental importance and its involvement in several pathogenesis. The interest and research in EMT/MET are currently focus on the tissue inflammation/repair and tumor progression/invasion. We are searching the common molecular targets of tissue inflammation/repair and cancer pathogenesis in regard to EMT/MET associated molecules. We focused on the phosphatase and tensin homolog (PTEN), which is encoded by the PTEN gene, and mutations of its gene are a step in the development of many cancers. PTEN protein acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate, and it acts as part of an important signal pathway for cell growth, cell movement (migration) and adhesion. Because PTEN phosphatase activity, which involves dual-specific phosphatase activity against lipid and protein substrates, is negatively regulated by phosphorylation in its C-terminal tail, a recent study suggested that phosphorylation levels of PTEN (p-PTEN) are significantly higher in malignant leukemia cells than in normal B cells. Nevertheless, whether tumor microenvironment could modulate p-PTEN/PTEN ratio or not remains elusive and, if so, the exact role of phosphorylation of PTEN C-terminal tail in tumor growth and metastasis has not been fully evaluated. We confirmed the critical contribution of tumor microenvironment to increasing p-PTEN/PTEN ratio in lung cancers. By using human lung cancer cells with doxycycline (Dox)-dependent PTEN protein with four-alanine substitution of phosphorylation sites in its C-terminal tail, we demonstrated that compensatory induction of mutation of phosphorylation sites in the PTEN C-terminal tail completely inhibit malignant phenotypes in vitro and tumor growth in xenograft model in vivo. We believe compensatory modulation of PTEN expression and its phosphorylation sites would be a new therapeutic strategy for negatively regulating aberrant cell motility, proliferation, and phenotype alteration through EMT in lung cancers.

Principal Research Achievement

  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)
  44. Ando Y et al. UGT1AI*6 and UGT1A1*27 for individualized irinotecan chemotherapy. Curr Opin Mol Ther 9: 258-262 (2007)
  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)
  56. Uno Y et al. Characterization of six base pair deletion in the putative HNF1-binding site of human PXR promoter. J Hum Genet 48: 594-597 (2003)
  57. Sato M et al. The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14ARF, p16INK4a and RASSF1A in human lung cancer cell lines. Oncogene 21: 4822-4829 (2002)
  58. Ando Y et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60: 6921-6926 (2000)
  59. Ando Y et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 91: 1587-1588 (1999)
  60. Takada Y et al. 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis is mediated by tumor necrosis factor a in human monocytic U937 cells. J Biol Chem 274: 28286-28292 (1999)
  61. Ando Y et al. Prediction equation for glomerular filtration rate. Ann Intern Med 131: 629-630 (1999)
  62. Isobe K et al. Induction of antitumor immunity in mice by allo-major histocompatibility complex class I gene transfectant with strong antigen expression. J Natl Cancer Inst 81: 1823-1828 (1989)
  63. Hasegawa Y et al. Calcium-independent pathway of tumor necrosis factor-mediated lysis of target cells. J Immunol 142: 2670-2676 (1989)
  64. Ando K et al. Induction and characterization of minor histocompatibility antigens: specific primary cyotoxic T lymphocyte responses in vitro. J Immunol 140: 723-729 (1988)

Award

PAGE TOP