HARASHIMA Nanae

写真a

Title

Professor

Researcher Number(JSPS Kakenhi)

60345311
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Current Affiliation Organization 【 display / non-display 】

  • Duty   University of the Ryukyus   Faculty of Medicine   Health Sciences   Professor  

  • Concurrently   University of the Ryukyus   Graduate School of Health Sciences   Division of Health Sciences   Professor  

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University 【 display / non-display 】

  • 1997.04
    -
    2001.03

    Kurume University   Graduate School, Division of Medicine   Graduated

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Graduate School 【 display / non-display 】

  • 1995.04
    -
    1997.03

    University of the Ryukyus  Graduate School, Division of Health Care  Master's Course  Completed

  • 1997.04
    -
    2001.03

    Kurume University  Graduate School, Division of Medicine  Doctor's Course  Completed

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External Career 【 display / non-display 】

  • 2002.02
    -
    2005.07

     

  • 2005.07
    -
    2007.03

     

  • 2007.04
    -
    2017.03

    Shimane University Faculty of Medicine, School of Medicine  

  • 2007.04
    -
    2017.03

     

  • 2017.04
    　
    　

    University of the Ryukyus  

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Research Interests 【 display / non-display 】

  • 腫瘍免疫学

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Research Areas 【 display / non-display 】

  • Life Science / Tumor biology

  • Life Science / Pathological biochemistry

  • Life Science / Tumor diagnostics and therapeutics

  • Life Science / Tumor biology

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Published Papers 【 display / non-display 】

  • Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.

    Tanino R, Tsubata Y, Harashima N, Harada M, Isobe T

    Oncotarget ( Oncotarget )  9 ( 24 ) 16807 - 16821   2018.03 [ Peer Review Accepted ]

    Type of publication: Research paper (scientific journal)

    　View Summary

    Pemetrexed (PEM) improves the overall survival of patients with advanced nonsmall cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 (SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosinekinase- inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

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  • HIF-1 alpha-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+patients with RCC

    Minami Takafumi, Sugimoto Koichi, Shimizu Nobutaka, De Velasco Marco, Nozawa Masahiro, Yoshimura Kazuhiro, Harashima Nanae, Harada Mamoru, Uemura Hirotsugu

    CANCER SCIENCE ( WILEY )  109   331 - 331   2018.01 [ Peer Review Accepted ]

    Type of publication: Research paper (other science council materials etc.)

  • Pemetrexed-Resistant Non-Small Cell Lung Cancer Cell Lines Have Novel Drug-Resistant Mechanisms

    Tanino, R; Tsubata, Y; Harashima, N; Harada, M; Isobe, T

    JOURNAL OF THORACIC ONCOLOGY   12 ( 11 ) S1949 - S1949   2017.11 [ Peer Review Accepted ]

    Type of publication: Research paper (scientific journal)

  • Contrasting effects of cyclophosphamide on anti-CTL-associated protein 4 blockade therapy in two mouse tumor models

    Yuichi Iida, Nanae Harashima, Takanobu Motoshima, Yoshihiro Komohara, Masatoshi Eto, Mamoru Harada

    CANCER SCIENCE ( WILEY )  108 ( 10 ) 1974 - 1984   2017.10 [ Peer Review Accepted ]

    Type of publication: Research paper (scientific journal)

    　View Summary

    Immune checkpoint blockade is a promising anticancer therapy, but must be used in combination with other anticancer therapies to increase its therapeutic efficacy. Cyclophosphamide (CP) is a chemotherapeutic drug that shows immune-modulating effects. In this study, we examined the effect of CP on anti-CTL-associated protein 4 (CTLA-4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after i.p. injection of CP (100 mg/kg) followed by anti-CTLA-4 antibody. However, administration in the reverse order increased apoptosis in tumor-specific CD8(+) T cells. In the RENCA renal carcinoma model, the antitumor effect of combination therapy was marginal and the tumor-bearing state reduced body weight with an increased serum level of interleukin-6. Interestingly, although CP monotherapy increased myeloid-derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti-CTLA-4 therapy increased MDSCs only in RENCA-bearing mice. Additionally, the serum levels of chemokine ligand 2 and C-X-C motif chemokine 10 were increased by the combination therapy only in RENCA-bearing mice and in vivo depletion of Gr-1(+) cells augmented the antitumor effect to some degree. These results reveal a contrasting effect of CP on anti-CTLA-4 therapy between the two mouse tumor models. Cyclophosphamide augments the antitumor effect of anti-CTLA-4 therapy in CT26-bearing hosts, whereas CP after anti-CTLA-4 therapy attenuates this effect through induction of apoptosis in tumor-reactive T cells. Alternatively, CP-induced MDSCs can be increased by anti-CTLA-4 therapy only in RENCA-bearing hosts with an elevated level of interleukin-6.

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  • HIF-2α dictates the susceptibility of pancreatic cancer cells to TRAIL by regulating survivin expression.

    Harashima N, Takenaga K, Akimoto M, Harada M

    Oncotarget ( IMPACT JOURNALS LLC )  8 ( 26 ) 42887 - 42900   2017.06 [ Peer Review Accepted ]

    Type of publication: Research paper (scientific journal)

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    Cancer cells develop resistance to therapy by adapting to hypoxic microenvironments, and hypoxia-inducible factors (HIFs) play crucial roles in this process. We investigated the roles of HIF-1 alpha and HIF-2 alpha in cancer cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) using human pancreatic cancer cell lines. siRNA-mediated knockdown of HIF-2 alpha, but not HIF-1 alpha, increased susceptibility of two pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL in vitro under normoxic and hypoxic conditions. The enhanced sensitivity to TRAIL was also observed in vivo. This in vitro increased TRAIL sensitivity was observed in other three pancreatic cancer cell lines. An array assay of apoptosis-related proteins showed that knockdown of HIF-2 alpha decreased survivin expression. Additionally, survivin promoter activity was decreased in HIF-2 alpha knockdown Panc-1 cells and HIF-2 alpha bound to the hypoxia-responsive element in the survivin promoter region. Conversely, forced expression of the survivin gene in HIF-2 alpha shRNA-expressing Panc-1 cells increased resistance to TRAIL. In a xenograft mouse model, the survivin suppressant YM155 sensitized Panc-1 cells to TRAIL. Collectively, our results indicate that HIF-2 alpha dictates the susceptibility of human pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL by regulating survivin expression transcriptionally, and that survivin could be a promising target to augment the therapeutic efficacy of death receptor-targeting anti-cancer therapy.

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Other Papers 【 display / non-display 】

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Presentations 【 display / non-display 】

  • Positive conversion of Tax specific CTL response in ATL patients after hematopoietic stem cell transplantation.

    Harashima N. N., Shimizu Y., Takamori A., Kurihara K., Utsunomiya A., Tanosak i R., Masuda M., Okamura J., and Kannagi M.

    AIDS Res. Hum. Retroviruses  2007.05  -  2007.05 

  • Positive conversion of Tax specific CTL response in ATL patients after hematopoietic stem cell transplantation.

    Harashima N. N, Shimizu Y, Takamori A, Kurihara K, Utsunomiya A, Tanosak i R, Masuda M, Okamura J, Kannagi M

    AIDS Res. Hum. Retroviruses  2007.05  -  2007.05 

  • Major target epitopes recognized by Tax specific CTL activated in ATL patients after hematopoietic stem cell transplantation.

    Harashima N. N., Kurihara K., Shimizu Y., Utsunomiya A., Tanosaki R., Masuda M., Miyazaki Y., Okamura J., and Kannagi M.

    AIDS Res. Hum. Retroviruses  2005  -  2005 

  • Major target epitopes recognized by Tax specific CTL activated in ATL patients after hematopoietic stem cell transplantation.

    Harashima N. N, Kurihara K, Shimizu Y, Utsunomiya A, Tanosaki R, Masuda M, Miyazaki Y, Okamura J, Kannagi M

    AIDS Res. Hum. Retroviruses  2005  -  2005 

  • Reactivation of stromg HTLV-I-specific CTL response in ATL patients following Non-myeloablative hematopoietic stem cell transplantation.

    AIDS Res. Hum. Retroviruses  1900.01  -  1900.01 

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Industrial Property 【 display / non-display 】

  • PEPTIDE HAVING HTLV-1-SPECIFIC CTL-INDUCING ACTIVITY

    Industrial Property No PCT/JP2004/005414  (2004.04.15)

    Patent No European Patent No. 1616950  (2008.06.25)

    HARASHIMA Nanae, KANNAGI Mari

  • COMPOSITIONS AND METHODS FOR PREVENTION OR TREATMENT OF NEOPLASTIC DISEASE IN A MAMMALIAN SUBJECT

    Industrial Property No US 14/549,296  (2014.12.08)

    Childs RW., Takahashi Y., Kajigaya S., Harashima N.

  • COMPOSITIONS AND METHODS FOR PREVENTION OR TREATMENT OF NEOPLASTIC DISEASE IN A MAMMALIAN SUBJECT.

    Industrial Property No US 14/549,296  (2014.12.08)

    Childs RW, Takahashi Y, Kajigaya S, Harashima N

  • PCT/JP2004/005414

    Industrial Property No PCT/JP2004/005414  (2004.04)

  • PEPTIDE HAVING HTLV-1-SPECIFIC CTL-INDUCING ACTIVITY

    Industrial Property No no_data  (1900.01.01)

    Unexpectedly No no_data  (1900.01.01)

    Patent No 特許1616950  (2008.06.25)

    HARASHIMA Nanae, KANNAGI Mari

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Grant-in-Aid for Scientific Research 【 display / non-display 】

  • Grant-in-Aid for Scientific Research(C)

    Project Year: 2013.04  -  2016.03 

    Direct: 4,100,000 (YEN) 

  • Grant-in-Aid for Young Scientists(B)

    Project Year: 2011.04  -  2013.03 

    Direct: 3,400,000 (YEN) 

  • Grant-in-Aid for Young Scientists(B)

    Project Year: 2008.04  -  2010.03 

    Direct: 3,300,000 (YEN) 

  • Anti-viral immuno therapeutic approaches for adult T-cell leukemia

    Grant-in-Aid for Scientific Research on Priority Areas

    Project Year: 2005  -  2009 

    Investigator(s): KANNAGI Mari, HARASHIMA Nanae 

    Direct: 48,500,000 (YEN)  Overheads: 48,500,000 (YEN) 

    　View Summary

    Our previous studies suggested that immunological approaches to activate HTLV-I-specific T-cell response potentially induce prophylactic and therapeutic effects on ATL. In order to verify this notion and apply for bedside, we indicated that vaccination reduced proviral load in a rat model, and that a subpopulation of HTLV-I-carriers showed weak HTLV-I-specific T-cell response and elevated proviral load. Moreover, we discovered an innate immune-mediated mechanism suppressing HTLV-I expression in vivo.

  • Grant-in-Aid for Scientific Research on Priority Areas

    Project Year: 2003  -  2003 

    Direct: 3,600,000 (YEN)  Overheads: 3,600,000 (YEN) 

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SDGs 【 display / non-display 】

  • 天然植物由来生理活性物質を応用したがん治療抵抗性克服

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