Akira Yamauchi

Publications (52)177.75 Total impact

• Article: Preoperative systemic therapy in locoregional management of early breast cancer: highlights from the Kyoto Breast Cancer Consensus Conference.

  Masakazu Toi, John R Benson, Eric P Winer, John F Forbes, Gunter von Minckwitz, Mehra Golshan, John F R Robertson, Hironobu Sasano, Bernard F Cole, Louis W C Chow, [......], Shotaro Kanao, Eun-Sook Lee, Shinzaburo Noguchi, Shinji Ohno, Ann H Partridge, Roman Rouzier, Mitsuhiro Tozaki, Tomoharu Sugie, Akira Yamauchi, Takashi Inamoto
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  ABSTRACT: Data reviewed at the Kyoto Breast Cancer Consensus Conference (KBCCC) showed that preoperative systemic therapy (PST) could optimize surgery through the utilization of information relating to pre- and post-PST tumor stage, therapeutic sensitivity, and treatment-induced changes in the biological characteristics of the tumor. As such, it was noted that the biological characteristics of the tumor, such as hormone receptors, human epidermal growth factor receptor-2, histological grade, cell proliferative activity, mainly defined by the Ki67 labeling index, and the tumor's multi-gene signature, should be considered in the planning of both systemic and local therapy. Furthermore, the timing of axillary sentinel lymph node diagnosis (i.e., before or after the PST) was also noted to be critical in that it may influence the likelihood of axillary preservation, even in node positive cases. In addition, axillary diagnosis with ultrasound and concomitant fine needle aspiration cytology or core needle biopsy (CNB) was reported to contribute to the construction of a treatment algorithm for patient-specific or individualized axillary surgery. Following PST, planning for breast surgery should therefore be based on tumor subtype, tumor volume and extent, therapeutic response to PST, and patient preference. Nomograms for predicting nodal status and drug sensitivity were also recognized as a tool to support decision-making in the selection of surgical treatment. Overall, review of data at the KBCCC showed that PST increases the likelihood of patients receiving localized surgery and individualized treatment regimens.
  Breast Cancer Research and Treatment 11/2012; · 4.43 Impact Factor
• Article: Clinical usefulness of human epidermal growth factor receptor-2 extracellular domain as a biomarker for monitoring cancer status and predicting the therapeutic efficacy in breast cancer.

  Keiichi Kontani, Noriyuki Kuroda, Shin-Ichiro Hashimoto, Chisa Murazawa, Shoko Norimura, Hiroaki Tanaka, Masahiro Ohtani, Naomi Fujiwara-Honjo, Yoshio Kushida, Manabu Date, Reiji Haba, Hitoshi Houchi, Akira Yamauchi, Hiroyasu Yokomise
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  ABSTRACT: We assessed the clinical usefulness of human epidermal growth factor receptor-2 extracellular domain (HER2ECD) as a biomarker for detecting cancer and monitoring disease status and for predicting the efficacy of anticancer treatment in breast cancer. Five-hundred and eighty serum samples from 252 patients with breast cancer were examined for the concentration of HER2ECD to compare with conventional tumor markers (CEA, CA15-3, NCC-ST439 and BCA225). Also, in 19 patients with HER2-overexpressed advanced or recurrent breast cancer who were treated with trastuzumab, clinical outcomes were evaluated retrospectively to determine whether their serum HER2ECD levels predict clinical responses. The proportion of patients with elevated HER2ECD levels was 15.1%, which was compatible with those with elevated conventional marker levels. In patients with HER2-overexpressed breast cancer, the positive rate of HER2ECD was significantly higher (24.1%) than those of conventional markers (7.4-12.9%), suggesting the usefulness of HER2ECD for detecting cancer in this population. HER2-overexpressed patients responding to trastuzumab (12 of 19 patients) showed significantly higher serum HER2ECD level (p = 0.033) and longer time to progression (TTP) (p = 0.039) and overall survival (OS) (p = 0.031) than did patients not responding (seven patients). Furthermore, higher response rates were observed in patients with elevated HER2ECD levels than in patients without elevated HER2ECD levels (91.3% vs. 14.3%, p = 0.032), whereas there was no difference in survival between the two groups. The results suggest that HER2ECD is a useful biomarker not only for detecting breast cancer recurrence but also for predicting tumor responses to trastuzumab.
  Cancer biology & therapy 10/2012; 14(1). · 2.64 Impact Factor
• Article: Galectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner.

  Souichi Oomizu, Tomohiro Arikawa, Toshiro Niki, Takeshi Kadowaki, Masaki Ueno, Nozomu Nishi, Akira Yamauchi, Mitsuomi Hirashima
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  ABSTRACT: Galectin-9 (Gal-9) ameliorates autoimmune reactions by suppressing Th17 cells while augmenting Foxp3(+) regulatory T cells (Tregs). However, the exact mechanism of Gal-9-mediated immune modulation has been elusive. In a MOG-induced experimental allergic encephalomyelitis model using Gal-9(-/-) mice, we observed exacerbated inflammation and an increase in IL-17-producing Th17 cells balanced by a decrease in Foxp3+ Tregs. During in vitro Th17 skewing using TGF-β1 and IL-6, exogenous Gal-9 suppressed Th17 cell development and expanded Foxp3(+) Tregs from naïve CD4 T cells in an IL-2-dependent manner. Although Gal-9 induced cell death in Tim3-expressing differentiated Th17 cells, Gal-9 suppressed Th17 development in a Tim-3-independent. Benzyl-α-GalNAc (an O-glycan biosynthesis inhibitor), but not swainsonine (a complex-type N-glycan biosynthesis inhibitor) abrogated Gal-9-mediated inhibition of Th17 development indicating that there is a linkage between Gal-9 and an unidentified glycoprotein(s) with O-linked β-galactosides that suppress Th17 development.
  Clinical Immunology 01/2012; 143(1):51-8. · 4.05 Impact Factor
• Article: Cell Surface Galectin-9 Expressing Th Cells Regulate Th17 and Foxp3(+) Treg Development by Galectin-9 Secretion.

  Souichi Oomizu, Tomohiro Arikawa, Toshiro Niki, Takeshi Kadowaki, Masaki Ueno, Nozomu Nishi, Akira Yamauchi, Toshio Hattori, Tsutomu Masaki, Mitsuomi Hirashima
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  ABSTRACT: Galectin-9 (Gal-9), a β-galactoside binding mammalian lectin, regulates immune responses by reducing pro-inflammatory IL-17-producing Th cells (Th17) and increasing anti-inflammatory Foxp3(+) regulatory T cells (Treg) in vitro and in vivo. These functions of Gal-9 are thought to be exerted by binding to receptor molecules on the cell surface. However, Gal-9 lacks a signal peptide for secretion and is predominantly located in the cytoplasm, which raises questions regarding how and which cells secrete Gal-9 in vivo. Since Gal-9 expression does not necessarily correlate with its secretion, Gal-9-secreting cells in vivo have been elusive. We report here that CD4 T cells expressing Gal-9 on the cell surface (Gal-9(+) Th cells) secrete Gal-9 upon T cell receptor (TCR) stimulation, but other CD4 T cells do not, although they express an equivalent amount of intracellular Gal-9. Gal-9(+) Th cells expressed interleukin (IL)-10 and transforming growth factor (TGF)-β but did not express Foxp3. In a co-culture experiment, Gal-9(+) Th cells regulated Th17/Treg development in a manner similar to that by exogenous Gal-9, during which the regulation by Gal-9(+) Th cells was shown to be sensitive to a Gal-9 antagonist but insensitive to IL-10 and TGF-β blockades. Further elucidation of Gal-9(+) Th cells in humans indicates a conserved role of these cells through evolution and implies the possible utility of these cells for diagnosis or treatment of immunological diseases.
  PLoS ONE 01/2012; 7(11):e48574. · 4.09 Impact Factor
• Source

  Available from: Masakazu Toi

  Article: Identifying gaps in the locoregional management of early breast cancer: highlights from the Kyoto Consensus Conference.

  Masakazu Toi, Eric P Winer, Takashi Inamoto, John R Benson, John F Forbes, Michihide Mitsumori, John F R Robertson, Hironobu Sasano, Gunter von Minckwitz, Akira Yamauchi, V Suzanne Klimberg
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  ABSTRACT: A consensus conference was held to investigate issues related to the local management of early breast cancer. Here, we highlight the major topics discussed at the conference and propose ideas for future studies. Regarding axillary management, we examined three major issues. First, we discussed whether the use of axillary reverse mapping could clarify the lymphatic system of breast and whether the ipsilateral arm might help avoid lymphedema. Second, the use of an indocyanine green fluorescent navigation system was discussed for intraoperative lymphatic mapping. These new issues should be examined further in practice. Finally, some agreement was reached on the importance of "four-node diagnosis" to aid in the diagnostic accuracy of sentinel nodes. Regarding breast treatment, there was general agreement that the clinical value of surgical margins in predicting local failure was dependent on the tumor's intrinsic biology and subtypes. For patients treated with preoperative chemotherapy, less extensive excision may be feasible in those who respond to systemic therapy in an acceptable manner. Most trials of preoperative chemotherapy lack outcome data on local recurrence. Therefore, there is a need for such data for overview analysis. We also agreed that radiation after mastectomy may be beneficial in node-positive cases where more than four nodes are involved. Throughout the discussions for both invasive and noninvasive disease, the investigation of nomograms was justified for major issues in the decision-making process, such as the presence or absence of microinvasion and the involvement of nonsentinel nodes in sentinel node-positive patients.
  Annals of Surgical Oncology 03/2011; 18(10):2885-92. · 4.17 Impact Factor
• Article: Galectin-9 ameliorates acute GVH disease through the induction of T-cell apoptosis.

  Kazuki Sakai, Eri Kawata, Eishi Ashihara, Yoko Nakagawa, Akira Yamauchi, Hisayuki Yao, Rina Nagao, Ruriko Tanaka, Asumi Yokota, Miki Takeuchi, Hideyo Hirai, Shinya Kimura, Mitsuomi Hirashima, Norio Yoshimura, Taira Maekawa
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  ABSTRACT: Galectins comprise a family of animal lectins that differ in their affinity for β-galactosides. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that was recently shown to function as a ligand for T-cell immunoglobin domain and mucin domain-3 (Tim-3) expressed on terminally differentiated CD4(+) Th1 cells. Gal-9 modulates immune reactions, including the induction of apoptosis in Th1 cells. In this study, we investigated the effects of Gal-9 in murine models of acute GVH disease (aGVHD). First, we demonstrated that recombinant human Gal-9 inhibit MLR in a dose-dependent manner, involving both Ca(2+) influx and apoptosis in T cells. Next, we revealed that recombinant human Gal-9 significantly inhibit the progression of aGVHD in murine BM transplantation models. In conclusion, Gal-9 ameliorates aGVHD, possibly by inducing T-cell apoptosis, suggesting that gal-9 may be an attractive candidate for the treatment of aGVHD.
  European Journal of Immunology 01/2011; 41(1):67-75. · 5.10 Impact Factor
• Article: Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells.

  Valerie Dardalhon, Ana C Anderson, Jozsef Karman, Lionel Apetoh, Rucha Chandwaskar, David H Lee, Melanie Cornejo, Nozomu Nishi, Akira Yamauchi, Francisco J Quintana, Raymond A Sobel, Mitsuomi Hirashima, Vijay K Kuchroo
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  ABSTRACT: IFN-gamma plays a central role in antitumor immunity. T cell Ig and mucin domain (Tim-3) is expressed on IFN-gamma-producing Th1 cells; on interaction with its ligand, galectin-9, Th1 immunity is terminated. In this study, we show that transgenic overexpression of Tim-3 on T cells results in an increase in CD11b(+)Ly-6G(+) cells and inhibition of immune responses. Molecular characterization of CD11b(+)Ly-6G(+) cells reveals a phenotype consistent with granulocytic myeloid-derived suppressor cells. Accordingly, we find that modulation of the Tim-3/galectin-9 (Gal-9) pathway impacts on tumor growth. Similarly, overexpression of Tim-3 ligand, Gal-9, results in an increase in CD11b(+)Ly-6G(+) cells and inhibition of immune responses. Loss of Tim-3 restores normal levels of CD11b(+)Ly-6G(+) cells and normal immune responses in Gal-9 transgenic mice. Our data uncover a novel mechanism by which the Tim-3/Gal-9 pathway regulates immune responses and identifies this pathway as a therapeutic target in diseases where myeloid-derived suppressor cells are disadvantageous.
  The Journal of Immunology 08/2010; 185(3):1383-92. · 5.79 Impact Factor
• Article: Targeting activating transcription factor 3 by Galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia.

  Junya Kuroda, Mio Yamamoto, Hisao Nagoshi, Tsutomu Kobayashi, Nana Sasaki, Yuji Shimura, Shigeo Horiike, Shinya Kimura, Akira Yamauchi, Mitsuomi Hirashima, Masafumi Taniwaki
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  ABSTRACT: Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for beta-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC(50)s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl(T315I), or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines. Collectively, hGal9 is a candidate agent that may overcome various kinds of resistance to treatment for CML and may suggest that ATF3 may be a new target molecule for the development of new treatment modalities that can overcome resistance to currently available chemotherapeutics.
  Molecular Cancer Research 07/2010; 8(7):994-1001. · 4.29 Impact Factor
• Article: Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway.

  Rena Tanikawa, Takahisa Tanikawa, Mitsuomi Hirashima, Akira Yamauchi, Yoshiya Tanaka
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  ABSTRACT: Galectin-9 is a beta-galactoside-binding lectin expressed in various tissues. It binds various glycoconjugates and modulates a variety of biological functions in various cell types. Although galectin-9 is expressed in bone, its function in human osteoblasts remains unclear. We demonstrate that galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway in the absence of bone morphogenetic proteins (BMPs). Galectin-9 increases alkaline phosphatase activities in human osteoblasts and induces the phosphorylation of Smad1/5/8 and translocation of Smad4 to the nucleus in the absence of BMPs. Galectin-9 also induces binding of Smad4 to the Id1 promoter and increases its activity. Anti-CD44 antibody inhibits Smad1/5/8 phosphorylation by galectin-9. Galectin-9 binds to CD44 and induces the formation of a CD44/BMP receptor complex. Because Smad1 is phosphorylated by BMP receptors, we propose that formation of the CD44/BMP receptor complex induced by galectin-9 may provide a trigger for the activation of Smads.
  Biochemical and Biophysical Research Communications 03/2010; 394(2):317-22. · 2.48 Impact Factor
• Article: Involvement of galectin-9 in lung eosinophilia in patients with eosinophilic pneumonia.

  Shigeki Katoh, Atsuya Nobumoto, Nobuhiro Matsumoto, Kiyoshi Matsumoto, Naomi Ehara, Toshiro Niki, Hiroyuki Inada, Nozomu Nishi, Akira Yamauchi, Kiyoyasu Fukushima, Mitsuomi Hirashima
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  ABSTRACT: Although we first found galectin-9 (Gal-9) as an eosinophil chemoattractant, its role in eosinophilic inflammation is still obscure. The purpose of the present study is to clarify the role of Gal-9 in human eosinophilic pulmonary inflammation in comparison with eotaxin (CCL11). We measured the levels of Gal-9 and eotaxin in the bronchoalveolar lavage fluid (BALF) of patients with acute and chronic eosinophilic pneumonia (AEP and CEP). Furthermore, the biological activities (chemotaxis and apoptosis) of Gal-9 were compared with those of eotaxin using interleukin-5-primed or -unprimed eosinophils. The levels of Gal-9 and eotaxin in the BALF from patients with AEP and those with CEP were higher than those found in the controls. Although there was little difference in Gal-9 level between patients with AEP and patients with CEP, the eotaxin level was significantly lower in patients with CEP. In patients with AEP, the eosinophil number correlated well with both the Gal-9 and eotaxin levels. However, in patients with CEP, the eosinophil number only correlated well with the Gal-9 level. Moreover, the Gal-9 level correlated with the eotaxin level in patients with AEP, but there was no significant correlation between those levels in patients with CEP. Anti-Gal-9 antibody treatment strongly reduces eosinophil chemotactic activity in the BALF of patients with AEP and in that of patients with CEP, whereas the anti-CCR3 (receptor for eotaxin) antibody strongly reduces this activity in the BALF of patients with AEP but not in that of patients with CEP. Furthermore, Gal-9 exhibited both chemotactic and proapoptotic activities for activated eosinophils, though eotaxin only exhibited chemotactic activity. The present results provide two possibilities: that Gal-9 is involved in pulmonary eosinophilia in patients with AEP and CEP, and that Gal-9 exhibits regulatory functions for activated eosinophils at the site of inflammation.
  International Archives of Allergy and Immunology 01/2010; 153(3):294-302. · 2.40 Impact Factor
• Article: Galectin-9 expands immunosuppressive macrophages to ameliorate T-cell-mediated lung inflammation.

  Tomohiro Arikawa, Naoki Saita, Souichi Oomizu, Masaki Ueno, Akihiro Matsukawa, Shigeki Katoh, Keisuke Kojima, Keiko Nagahara, Minoru Miyake, Akira Yamauchi, Hirotsugu Kohrogi, Mitsuomi Hirashima
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  ABSTRACT: Galectin-9 (Gal-9) plays pivotal roles in the modulation of innate and adaptive immunity to suppress T-cell-mediated autoimmune models. However, it remains unclear if Gal-9 plays a suppressive role for T-cell function in non-autoimmune disease models. We assessed the effects of Gal-9 on experimental hypersensitivity pneumonitis induced by Trichosporon asahii. When Gal-9 was given subcutaneously to C57BL/6 mice at the time of challenge with T. asahii, it significantly suppressed T. asahii-induced lung inflammation, as the levels of IL-1, IL-6, IFN-gamma, and IL-17 were significantly reduced in the BALF of Gal-9-treated mice. Moreover, co-culture of anti-CD3-stimulated CD4 T cells with BALF cells harvested from Gal-9-treated mice on day 1 resulted in diminished CD4 T-cell proliferation and decreased levels of IFN-gamma and IL-17. CD11b(+)Ly-6C(high)F4/80(+) BALF Mphi expanded by Gal-9 were responsible for the suppression. We further found in vitro that Gal-9, only in the presence of T. asahii, expands CD11b(+)Ly-6C(high)F4/80(+) cells from BM cells, and the cells suppress T-cell proliferation and IFN-gamma and IL-17 production. The present results indicate that Gal-9 expands immunosuppressive CD11b(+)Ly-6C(high) Mphi to ameliorate Th1/Th17 cell-mediated hypersensitivity pneumonitis.
  European Journal of Immunology 11/2009; 40(2):548-58. · 5.10 Impact Factor
• Article: Galectin-9 ameliorates immune complex-induced arthritis by regulating Fc gamma R expression on macrophages.

  Tomohiro Arikawa, Kota Watanabe, Masako Seki, Akihiro Matsukawa, Souichi Oomizu, Ken-mei Sakata, Atsuko Sakata, Masaki Ueno, Naoki Saita, Toshiro Niki, Akira Yamauchi, Mitsuomi Hirashima
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  ABSTRACT: Galectin-9 up-regulated Fc gamma RIIb expression of mouse peritoneal macrophages in vitro but down-regulated Fc gamma RIII expression. Galectin-9-treated macrophages stimulated with immune complexes (IC) produced less TNFalpha and IL-1 beta but more IL-10 than PBS-treated macrophages. Macrophage enhancing effects on IC-induced C5a and neutrophil chemotactic activity were also diminished for galectin-9-treated macrophages. In galectin-9-treated mice, the severity of IC-induced arthritis was reduced, as were pro-inflammatory cytokine levels in inflamed joints and serum C5a. Fc gamma RIIb expression of macrophages from galectin-9-treated mice was up-regulated, whereas Fc gamma RIII expression was down-regulated. Macrophages from galectin-9-treated mice produced less TNFalpha and IL-1 beta but more IL-10 than PBS-treated mice. Disease severity of galectin-9-transgenic mice was milder than wild-type mice, whereas that of galectin-9-deficient mice was exaggerated. Furthermore, macrophage Fc gamma RIIb expression in galectin-9-deficient mice was down-regulated, while Fc gamma RIII expression was up-regulated. These results suggest that galectin-9 suppresses IC-induced inflammation partly by regulating Fc gamma R expression on macrophages.
  Clinical Immunology 10/2009; 133(3):382-92. · 4.05 Impact Factor
• Article: Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance.

  Hitomi Imachi, Koji Murao, Hiroaki Dobashi, Mohammad M Bhuyan, Xueyuan Cao, Keiichi Kontani, Shoko Niki, Chisa Murazawa, Hiroo Nakajima, Norio Kohno, Hiroko Yamashita, Hirotaka Iwase, Shin-ichi Hayashi, Toshihiko Ishida, Akira Yamauchi
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  ABSTRACT: Multiple coactivator and corepressor complexes play an important role in endocrine processes and breast cancer; in particular, estrogen and estrogen receptor-alpha (ERalpha) promote the proliferation of breast cancer cells. Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1); it also serves as a critical link in the recruitment of nuclear receptor-mediated transcription. Here, we show that menin expressed in breast cancer cell line MCF-7 is colocalized with ERalpha and functions as a direct coactivator of ER-mediated transcription in breast cancer cells. In MCF-7 cells, coexpression of menin and estrogen-response element-luciferase induced the activity of the latter in a hormone-dependent manner. Cells knocked down for ERalpha exhibited impaired ERE-luciferase activity induced by menin. Mammalian two-hybrid assay and GST pull-down assays indicated that menin could interact with the AF-2 domain of ERalpha. These results indicate that menin is a direct activator of ERalpha function. Tamoxifen inhibited the binding of menin to AF-2 in mammalian two-hybrid assay, but in menin-overexpressing clones, tamoxifen suppressed ERE-luciferase activity only to the levels of nontreated wild-type MCF-7. In a clinical study with 65 ER-positive breast cancer samples-all of which had been treated with tamoxifen for 2-5 years as adjuvant therapies--menin-positive tumors had a worse outcome than menin-negative ones. These indicated that menin can function as a transcriptional regulator of ERalpha and is a possible predictive factor for tamoxifen resistance.
  Breast Cancer Research and Treatment 10/2009; 122(2):395-407. · 4.43 Impact Factor
• Article: Intracellular galectin-9 activates inflammatory cytokines in monocytes.

  Ai Matsuura, Junichi Tsukada, Takamitsu Mizobe, Takehiro Higashi, Fumihiko Mouri, Rena Tanikawa, Akira Yamauchi, Mitsuomi Hirashima, Yoshiya Tanaka
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  ABSTRACT: Whether galectin-9 plays a role in inflammatory responses remains elusive. The present study was designed to determine the role of intracellular galectin-9 in activation of inflammatory cytokine genes in human monocytes. Galectin-9 expression vector pBKCMV3-G9 was transiently co-transfected into THP-1 monocytic cells along with luciferase reporters carrying gene promoters of IL-1alpha (IL1A), IL-1beta (IL1B) and IFNgamma. Transient transfection studies showed that galectin-9 over-expression activated all three gene promoters, suggesting that intracellular galectin-9 induces inflammatory cytokine genes in monocytes. Galectin-9 over-expression also activated NF-IL6 (C/EBP beta) and AP-1, but not NF-kappaB. In contrast, extracellular galectin-9 is not involved in regulation of inflammatory cytokines. Immunoprecipitation/Western blotting, using anti-galectin-9 Ab and anti-NF-IL6 Ab, showed physical association of intracellular galectin-9 with NF-IL6. RT-PCR confirmed that galectin-9 over-expression increased IL-1alpha and IL-1beta mRNA levels in THP-1 cells. The interaction of galectin-9 with NF-IL6 was enhanced following LPS treatment in THP-1 cells. Intracellular galectin-9 synergized with LPS to activate NF-IL6. Nuclear translocation of galectin-9 was also observed in THP-1 cells treated with LPS. Our results indicate that galectin-9 is a LPS-responsive factor, and further demonstrate that intracellular galectin-9 transactivates inflammatory cytokine genes in monocytes through direct physical interaction with NF-IL6.
  Genes to Cells 05/2009; 14(4):511-21. · 2.68 Impact Factor
• Article: Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions.

  Keiko Nagahara, Tomohiro Arikawa, Souichi Oomizu, Keiichi Kontani, Atsuya Nobumoto, Hiroaki Tateno, Kota Watanabe, Toshiro Niki, Shigeki Katoh, Minoru Miyake, Syun-Ichiro Nagahata, Jun Hirabayashi, Vijay K Kuchroo, Akira Yamauchi, Mitsuomi Hirashima
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  ABSTRACT: A Tim-3 ligand, galectin-9 (Gal-9), modulates various functions of innate and adaptive immune responses. In this study, we demonstrate that Gal-9 prolongs the survival of Meth-A tumor-bearing mice in a dose- and time-dependent manner. Although Gal-9 did not prolong the survival of tumor-bearing nude mice, transfer of naive spleen cells restored a prolonged Gal-9-induced survival in nude mice, indicating possible involvement of T cell-mediated immune responses in Gal-9-mediated antitumor activity. Gal-9 administration increased the number of IFN-gamma-producing Tim-3(+) CD8(+) T cells with enhanced granzyme B and perforin expression, although it induced CD4(+) T cell apoptosis. It simultaneously increased the number of Tim-3(+)CD86(+) mature dendritic cells (DCs) in vivo and in vitro. Coculture of CD8(+) T cells with DCs from Gal-9-treated mice increased the number of IFN-gamma producing cells and IFN-gamma production. Depletion of Tim-3(+) DCs from DCs of Gal-9-treated tumor-bearing mice decreased the number of IFN-gamma-producing CD8(+) T cells. Such DC activity was significantly abrogated by Tim-3-Ig, suggesting that Gal-9 potentiates CD8(+) T cell-mediated antitumor immunity via Gal-9-Tim-3 interactions between DCs and CD8(+) T cells.
  The Journal of Immunology 01/2009; 181(11):7660-9. · 5.79 Impact Factor
• Article: Galectin-9 expression links to malignant potential of cervical squamous cell carcinoma.

  Meiyan Liang, Masaki Ueno, Souichi Oomizu, Tomohiro Arikawa, Rika Shinonaga, Shulan Zhang, Akira Yamauchi, Mitsuomi Hirashima
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  ABSTRACT: Galectin-9 (Gal-9) induces adhesion and aggregation of certain cell types and can be a prognostic factor in the patients with melanoma and breast cancer. We assessed the experiments to resolve whether Gal-9 expression in cervical neoplasm links to malignant potential of cervical squamous cell carcinoma (SCC) cells. Gal-9 expression was examined with immunohistochemical techniques in 23 normal cervical squamous epithelia, 17 cervical intraepithelial neoplasia (CIN), and 38 cervical SCC compared to E-cadherin. CIN was divided into low-grade and high-grade squamous intraepithelial lesions (8 LSIL and 9 HSIL), and SCC was into well-, moderately and poorly differentiated SCC (6 WSCC, 20 MSCC and 12 PSCC). Gal-9 and E-cadherin were evidently detected in normal epithelium and endocervical glands, but those in CIN and SCC were significantly faint. Moreover, both the Gal-9 and E-cadherin expressions in HSIL were significant lower than those in LSIL, suggesting their association with malignant transformation. Unexpectedly, Gal-9 and E-cadherin in WSCC were significantly high compared to those in HSIL. Furthermore, those in SCC were inversely correlated with the grade of differentiation (WSCC > MSCC > PSCC), implying the possible involvement of Gal-9 and E-cadherin in the differentiation of SCC. In contrast, they were not different among the FIGO stage. Gal-9 expression was well correlated with E-cadherin expression in CIN and SCC but not in normal cervical epithelia. The present results suggest that decreased Gal-9 expression is inversely associated with malignant potential or differentiation of cervical CIN and SCC as a differentiation biomarker.
  Journal of Cancer Research and Clinical Oncology 08/2008; 134(8):899-907. · 2.56 Impact Factor
• Article: Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices.

  Atsuya Nobumoto, Keiko Nagahara, Souichi Oomizu, Shigeki Katoh, Nozomu Nishi, Keisuke Takeshita, Toshiro Niki, Akira Tominaga, Akira Yamauchi, Mitsuomi Hirashima
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  ABSTRACT: We previously described an inverse correlation between galectin-9 (Gal-9) expression and metastasis in patients with malignant melanoma and breast cancer. This study verified the ability of Gal-9 to inhibit lung metastasis in experimental mouse models using highly metastatic B16F10 melanoma and Colon26 colon cancer cells. B16F10 cells transfected with a secreted form of Gal-9 lost their metastatic potential. Intravenous Gal-9 administration reduced the number of metastases of both B16F10 and Colon26 cells in the lung, indicating that secreted Gal-9 suppresses metastasis. Analysis of adhesive molecule expression revealed that B16F10 cells highly express CD44, integrin alpha1, alpha 4, alpha V, and beta1, and that Colon26 cells express CD44, integrin alpha2, alpha 5, alpha V, and beta1, suggesting that Gal-9 may inhibit the adhesion of tumor cells to vascular endothelium and the extracellular matrix (ECM) by binding to such adhesive molecules. Indeed, Gal-9 suppressed the binding of hyaluronic acid to CD44 on both B16F10 and Colon26 cells, and also suppressed the binding of vascular cell adhesion molecule-1 to very late antigen-4 on B16F10 cells. Furthermore, Gal-9 inhibited the binding of tumor cells to ECM components, resulting in the suppression of tumor cell migration. The present results suggest that Gal-9 suppresses both attachment and invasion of tumor cells by inhibiting the binding of adhesive molecules on tumor cells to ligands on vascular endothelium and ECM.
  Glycobiology 07/2008; 18(9):735-44. · 3.58 Impact Factor
• Article: Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis.

  Masako Seki, Souichi Oomizu, Ken-Mei Sakata, Atsuko Sakata, Tomohiro Arikawa, Kota Watanabe, Kanako Ito, Keisuke Takeshita, Toshiro Niki, Naoki Saita, Nozomu Nishi, Akira Yamauchi, Shigeki Katoh, Akihiro Matsukawa, Vijay Kuchroo, Mitsuomi Hirashima
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  ABSTRACT: The effects of galectin-9 on a mouse collagen-induced arthritis (CIA) model were assessed to clarify whether galectin-9 suppresses CIA by regulating T cell immune responses. Galectin-9 suppressed CIA in a dose-dependent manner, and such suppression was observed even when treatment was started on 7 days after the booster, indicating its preventive and therapeutic effects. Galectin-9 induced the decreased levels of pro-inflammatory cytokines, IL-17, IL-12, and IFNgamma in the joint. Galectin-9 induced the decreased number of CD4(+) TIM-3(+) T cells in peripheral blood. Galectin-9-deficient mice became susceptible to CIA may be by increased number of CD4(+) TIM-3(+) T cells and decreased number of Treg cells. We further found that galectin-9 induces differentiation of naive T cells to Treg cells, and it suppresses differentiation to Th17 cells in vitro. The present results suggested that galectin-9 ameliorates CIA by suppressing the generation of Th17, promoting the induction of regulatory T cells.
  Clinical Immunology 05/2008; 127(1):78-88. · 4.05 Impact Factor
• Article: Interaction of galectin-9 with lipid rafts induces osteoblast proliferation through the c-Src/ERK signaling pathway.

  Rena Tanikawa, Takahisa Tanikawa, Yosuke Okada, Kazuhisa Nakano, Mitsuomi Hirashima, Akira Yamauchi, Ryuji Hosokawa, Yoshiya Tanaka
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  ABSTRACT: Galectin-9 is a beta-galactoside-binding lectin expressed in various tissues, including bone. The role of galectin-9 in human osteoblasts, however, remains unclear. This study showed that galectin-9 interacts with lipid rafts and induces osteoblast proliferation through the c-Src/ERK signaling pathway. Galectin-9 is a beta-galactoside-binding lectin that modulates many biological functions by interacting with particular carbohydrates attached to proteins and lipids. However, the role of galectin-9 in bone metabolism and osteoblast proliferation remains unclear. This study investigated the effects of galectin-9 on osteoblast proliferation and its signaling mechanisms. The effect of galectin-9 on osteoblast proliferation was tested by measuring the conversion of tetrazolium salt WST-8 to formazan. Protein phosphorylation was assayed by western blotting and confocal microscopy was used to localize lipid rafts. Galectin-9-induced proliferation of the obtained osteoblasts in a dose-dependent manner, whereas galectin-1, -3, and -4 did not. Galectin-9-induced phosphorylation of c-Src and subsequent ERK1/ERK2 in the osteoblasts. The galectin-9-induced phosphorylation and proliferation were inhibited by PP2, a selective inhibitor of c-Src. Galectin-9-induced clustering of lipid rafts detected by cholera toxin B (CTB; binding the raft-resident ganglioside GM1) using confocal microscopy. Cross-linking of the GM1 ganglioside with CTB by anti-CTB antibody-induced phosphorylation of c-Src, whereas disruption of galectin-9-induced lipid rafts by beta-methylcyclodextrin reduced c-Src phosphorylation and proliferation of the cells. These results suggest that galectin-9, but not other galectins, induced proliferation of human osteoblasts through clustering lipid rafts on membrane and subsequent phosphorylation of the c-Src/ERK signaling pathway.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2008; 23(2):278-86. · 6.04 Impact Factor
• Article: Beneficial effect of galectin 9 on rheumatoid arthritis by induction of apoptosis of synovial fibroblasts.

  Masako Seki, Ken-mei Sakata, Souichi Oomizu, Tomohiro Arikawa, Atsuko Sakata, Masaki Ueno, Atsuya Nobumoto, Toshiro Niki, Naoki Saita, Kanako Ito, Shu-Yan Dai, Shigeki Katoh, Nozomu Nishi, Michishi Tsukano, Kouichiro Ishikawa, Akira Yamauchi, Vijay Kuchroo, Mitsuomi Hirashima
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  ABSTRACT: To compare the expression of galectin 9 (Gal-9) in synovial tissue (ST) from rheumatoid arthritis (RA) patients and osteoarthritis (OA) patients and to evaluate the effects of Gal-9 on fibroblast-like synoviocytes (FLS) in these patients. The expression of Gal-9 in ST and FLS was compared using immunohistochemical techniques. Apoptotic cells in RA and OA ST samples were detected by TUNEL assay. Apoptosis of FLS was analyzed by the sub-G(1) method in vitro. The in vivo suppressive effects of Gal-9 on collagen-induced arthritis (CIA) in a mouse model were also elucidated. The percentage of Gal-9-positive cells in ST samples and the amount of Gal-9 in synovial fluid samples were significantly higher in patients with RA than in patients with OA, suggesting the involvement of Gal-9 in the development of RA. Compared with the 2 wild-type Gal-9 forms, stable Gal-9, a mutant protein resistant to proteolysis, significantly induced apoptosis of FLS from RA patients. In contrast, other galectins, such as Gal-1, Gal-3, and Gal-8, did not induce apoptosis or suppress the proliferation of human RA FLS. Stable Gal-9 preferentially induced apoptosis and suppressed the proliferation of RA FLS in vitro. It also induced apoptosis of cells in RA ST implanted into SCID mice in vivo. In a mouse model of CIA, apoptotic cells were detected in the joints of stable Gal-9-treated mice, but not phosphate buffered saline-treated mice, and suppressed CIA characterized by pannus formation with inflammatory cell infiltration and bone/cartilage destruction. Gal-9-induced apoptosis of hyperproliferative RA FLS may play a critical role in the suppression of RA.
  Arthritis & Rheumatism 01/2008; 56(12):3968-76. · 7.87 Impact Factor