詳細

樋口　智紀 （ヒグチ　トモノリ）

  • 医学科　助教
Last Updated :2024/04/19

研究者情報

学位

  • 博士（医学）（和歌山県立医科大学）

ホームページURL

科研費研究者番号

  • 00448771

J-Global ID

研究キーワード

  • 造血器腫瘍   皮膚リンパ腫   腫瘍学   ウイルス学   細菌学   病理学   免疫学   ケモカイン   分子生物学   

研究分野

  • ライフサイエンス / 血液、腫瘍内科学
  • ライフサイエンス / 皮膚科学
  • ライフサイエンス / 腫瘍生物学
  • ライフサイエンス / ウイルス学
  • ライフサイエンス / 免疫学
  • ライフサイエンス / 実験病理学
  • ライフサイエンス / 分子生物学

所属学協会

  • 日本分子生物学会   日本癌学会   日本病理学会   

研究活動情報

論文

  • Yumiko Hashida; Kimiko Nakajima; Tomonori Higuchi; Kozo Nakai; Masanori Daibata
    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 165 105523 - 105523 2023年08月 
    BACKGROUND: European studies suggest an association between cutavirus (CuV) and cutaneous T-cell lymphoma (CTCL); however, the worldwide prevalence of CuV in patients with CTCL and its prognostic impact remain unknown. METHODS: We investigated the prevalence and viral loads of CuV DNA using biopsy specimens from the lesional skins of 141 Japanese patients with cutaneous malignancies, including 55 patients with various types of CTCL. RESULTS: CuV DNA was detected significantly more frequently in biopsies from patients with mycosis fungoides (MF) (38% [13/34]; the most common subtype of CTCL) than in those from patients with other cutaneous malignancies (6% [6/107]; P<0.001). The viral-load range in patients with CuV DNA-positive MF was 23-3922 copies/103 cells and 8-65 copies/μg of DNA. A phylogenetic analysis using the partial sequences of the CuV viral capsid protein 1 (VP1)/VP2 genes revealed that the CuV sequences identified here were clustered in a Japanese-specific clade distinct from that comprising CuV sequences from European patients with MF. Kaplan-Meier curves and a log-rank test showed that CuV positivity was associated with a shorter disease-specific survival in patients with MF (P = 0.031), whereas no significant difference in overall survival was observed (P = 0.275). No significant correlation was observed between CuV DNA load and survival in patients with CuV-positive MF. CONCLUSIONS: Our results suggest that CuV is associated with MF in a subset of Japanese patients. Large-scale prospective studies are warranted to clarify the role of CuV status, especially regarding the viral genotype, on adverse outcomes in patients with CuV-positive MF.
  • Kenji Yorita; Tatsuya Fujii; Toshitaka Nagao; Ichiro Murakami; Yumiko Hashida; Tomonori Higuchi; Masanori Daibata; Makoto Toi; Yoshiyuki Ayada; Takuro Igawa
    Radiology case reports 18 5 1933 - 1938 2023年05月 
    A case of an asymptomatic 19-year-old woman with Kimura disease presenting with a nodule in the right parotid gland is presented. She had a medical history of atopic dermatitis and noticed a mass on her right-side neck. Cervical lymphadenopathy was clinically diagnosed. The initial management plan was to observe the lesion, which had enlarged from 1 cm to 2 cm in diameter 6 months later. An excisional biopsy was performed, and the pathology confirmed an eosinophil-containing inflammatory parotid gland lesion with many squamous nests and cysts, mimicking a parotid gland tumor. High serum immunoglobulin E levels, peripheral blood eosinophilia, and pathological and genetic diagnoses confirmed Kimura disease. The lesion tested negative for human polyomavirus 6. No recurrence was observed 15 months after the biopsy. The prognosis of Kimura disease without human polyomavirus 6 infection may be favorable; however, further validation of this hypothesis is required as only 5 or 6 cases of Kimura disease have been evaluated for this viral infection. Proliferative squamous metaplasia occurring in parotid gland lesions of Kimura disease is rare and may complicate the diagnostic imaging and pathological diagnosis.
  • Yumiko Hashida; Tomonori Higuchi; Masanori Daibata
    Virology journal 20 1 69 - 69 2023年04月 
    BACKGROUND: Cutavirus (CuV) is the newest human parvovirus and is currently receiving increasing attention because of its possible association with cutaneous T-cell lymphoma. Despite the pathogenetic potential of CuV, it has been detected in normal skin; however, little is known about the prevalence, infection levels, and genetic variations of this virus in the skin of the general population. METHODS: We investigated the CuV DNA prevalence and viral loads concerning age, sampling location, and gender using 678 skin swabs collected from the normal-appearing skins of 339 Japanese participants aged 2-99 years. Phylogenetic analyses were also conducted based on the near-full-length CuV sequences identified in this study. RESULTS: Both the CuV DNA prevalence and viral loads were significantly higher in the skin of elderly persons aged ≥60 years compared with those of persons aged < 60 years. CuV DNA tended to persist in the skin of elderly individuals. No significant difference in viral loads was observed between the skin of the upper arm and the skin of the forehead in CuV DNA-positive specimens. Significantly higher viral loads were evident in men vs. women, although no gender-associated differences in viral prevalence were noted. Phylogenetic analyses demonstrated the existence of Japanese-specific viruses that were genetically distinct from viruses prevalent in other areas, especially Europe. CONCLUSIONS: This large study suggests that high levels of CuV DNA are prevalent on the skin of elderly adults. Our findings also indicated the prevalence of geographically related CuV genotypes. A follow-up study of this cohort should provide helpful information on whether CuV may become pathogenic.
  • Naoya Kitamura; Yumiko Hashida; Tomonori Higuchi; Seiji Ohno; Shinya Sento; Eri Sasabe; Ichiro Murakami; Tetsuya Yamamoto; Masanori Daibata
    Odontology 111 4 971 - 981 2023年03月 
    Abstract Oral microbiome studies have mainly focussed on bacteria, with the relationship between viruses and oral cancers remaining poorly understood. Oral cancers can develop even in the absence of any history of daily smoking or drinking. Oral cancer patients frequently have multiple primary cancers in the oral cavity and other organs, such as the upper gastrointestinal tract. Merkel cell polyomavirus (MCPyV) is a novel oncovirus identified from a subtype of skin cancer in 2008. In this study, we investigated the potential involvement of MCPyV in the pathogenesis of oral squamous cell carcinoma (OSCC). Participants comprised 115 Japanese patients with OSCC (single primary: 109 tumours in 109 patients; multiple primaries: 16 tumours in 6 patients) treated in our department between 2014 and 2017. DNA was extracted from formalin-fixed paraffin-embedded specimens of primary lesions. MCPyV DNA copy counts were analysed by quantitative real-time polymerase chain reaction. Twenty-four of the 115 patients (20.9%) were positive for MCPyV DNA. No association was found between presence or absence of MCPyV DNA and clinical characteristics other than number of primary lesions. The MCPyV DNA-positive rate was significantly higher for multiple primary OSCCs (62.5%, 10/16 tumours) than for single primary OSCCs (16.5%, 18/109 tumours; P < 0.001). Furthermore, MCPyV DNA load was significantly higher for patients with multiple primaries (P < 0.05). MCPyV was observed more frequently and DNA load was significantly higher with multiple primary OSCCs than with single primary OSCC. MCPyV may play some role as an oncovirus for multiple primary OSCCs.
  • Tomonori Higuchi; Yumiko Hashida; Kazuhiko Matsuo; Kosuke Kitahata; Takako Ujihara; Ichiro Murakami; Takashi Nakayama; Masanori Daibata
    Cancer science 114 6 2622 - 2633 2023年03月 
    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) develops in the setting of long-standing inflammation. This type of lymphoma may have specific expression profiles of chemokines involved in the pathogenesis of DLBCL-CI. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and represents a valuable model for the study of this disease category. Using a panel of PAL cell lines, we found that PAL cells expressed and secreted C-X-C motif chemokine ligands 9 and 10 (CXCL9 and CXCL10), the ligands of CXCR3, in contrast to EBV-negative DLBCL cell lines, which did not. Culture supernatants from PAL cell lines attracted CXCR3-expressing CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells from human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CXCR3-positive cytotoxic lymphocytes that expressed interferon-γ. The expression of CXCL9 and CXCL10 was detected in PAL tumor biopsy samples from patients, and CXCR3-positive lymphocytes were abundant in the tissue samples. Collectively, these findings suggest that CXCL9 and CXCL10 are produced by PAL cells and can elicit cytotoxic responses via CXCR3. This chemokine system is also likely to contribute to tissue necrosis, which is a signature histological feature of DLBCL-CI. Further studies are warranted to determine whether the CXCL9-CXCL10/CXCR3 axis exerts antitumor effects in DLBCL-CI.
  • Fumiya Ogasawara; Tomonori Higuchi; Tomohiro Nishimori; Yumiko Hashida; Kensuke Kojima; Masanori Daibata
    Journal of cellular and molecular medicine (IF: 5.299) 26 22 5580 - 5589 2022年11月 [査読有り]
     
    Primary human herpesvirus 8 (HHV8)-unrelated effusion large B-cell lymphoma (ELBCL) is recognized as a new clinical entity, but its pathogenesis and therapeutic strategies remain largely unknown. We have generated two mouse models with profuse lymphomatous effusions that resemble HHV8-unrelated ELBCL occurring in humans, by grafting the cell lines designated as Pell-1 and Pell-2. Using these in vivo models, we evaluated the potential role of vascular endothelial growth factor (VEGF) in the pathogenesis of HHV8-unrelated ELBCL. Both Pell-1 and Pell-2 cells consistently produced very high levels of VEGF in mice, in contrast to in vitro findings of relatively low VEGF production in culture medium by HHV8-unrelated ELBCL cells, especially Pell-1 cells. Conversely, returning Pell-1 cells grown in mice to culture medium markedly suppressed VEGF production to the original in vitro level. These findings suggest that the tumour microenvironment plays a role in the steady production of VEGF. We also found that the interaction between HHV8-unrelated ELBCL cells and peritoneal mesothelial cells increased the production of VEGF in vitro. Finally, we found that bevacizumab significantly suppressed effusion formation and lymphoma cell growth in both mouse models. These results suggest that bevacizumab is a rational approach to the treatment of HHV8-unrelated ELBCL.
  • Ichiro Murakami; Yumiko Hashida; Tomonori Higuchi; Masanori Daibata
    [Rinsho ketsueki] The Japanese journal of clinical hematology 63 5 383 - 392 2022年 
    Histiocytosis is classified based on proliferating histiocyte-like cells. Langerhans cell histiocytosis (LCH) has several subtypes with various outcomes, from spontaneous to fatal regression, and these subtypes had been managed as different diseases. However, these different names of disease were unified to one disease named histiocytosis X since they are pathologically identical. Presently, LCH has been used as a unified name because proliferating cells have the characteristics of Langerhans cells. Since then, clonality and BRAF mutations have been reported, and their neoplastic characteristics has become clear; however, explaining its various subtypes is difficult with only the neoplastic character. Various relationships/correlations are also known between inflammatory factors and LCH subtypes. We have pointed out that the Merkel cell polyomavirus may be involved in LCH development and LCH is a disease with both neoplastic and reactive characters, that is, "a disease in which abnormal Langerhans-like cells with neoplastic character overreact to some triggers."
  • Yumiko Hashida; Tomonori Higuchi; Shuichi Matsumoto; Mitsuko Iguchi; Ichiro Murakami; Masamitsu Hyodo; Masanori Daibata
    Cancer Science (IF: 6.518) 112 10 4404 - 4417 2021年10月 [査読有り]
     
    Human papillomavirus (HPV) infection in patients with oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant for better prognosis. However, there remain HPV-positive patients who have poor outcomes. The stratification strategy for detecting high-risk patients among those with HPV-positive OPSCC has not been well delineated, especially for Asian patients. We undertook a retrospective cohort study on the survival rate of 89 Japanese patients diagnosed with primary OPSCC. The tumors were concurrently analyzed for the presence of HPV E6 DNA/mRNA, viral DNA load, p16 expression, viral physical status, and viral variant lineage. Human papillomavirus 16 viral DNA was found in 45 (51%) OPSCCs. Human papillomavirus 16 DNA-positive OPSCCs with higher viral load (classified as HPV16 DNA-medium/high OPSCCs) showed significantly favorable overall survival and progression-free survival compared with HPV16 DNA-positive OPSCCs with lower viral load (<10 copies/cell; HPV16 DNA-low OPSCCs) and HPV16 DNA-negative OPSCCs. E6 mRNA expression was observed in all HPV16 DNA-medium/high OPSCCs but not in HPV16 DNA-low OPSCCs. Notably, p16-positive and HPV16 DNA-negative/low OPSCCs showed significantly worse survival than p16-positive and HPV16 DNA-medium/high OPSCCs and resembled HPV-unrelated OPSCCs with regard to survival and risk factor profile. Although not significant, a trend toward shorter survival was observed for HPV16-integrated OPSCCs. Phylogenetic analysis revealed two major types of HPV16 variants termed Asian (A4) and European (A1/A2/A3) variants, but no difference in survival between these variants was observed. Altogether, these findings suggest that HPV viral load is a potentially informative factor for more accurate risk stratification of patients with OPSCC.
  • Yumiko Hashida; Tomonori Higuchi; Saeko Nakajima; Kimiko Nakajima; Takako Ujihara; Kenji Kabashima; Shigetoshi Sano; Masanori Daibata
    Journal of infectious diseases (IF: 7.759) 223 10 1724 - 1732 2021年05月 [査読有り]
     
    BACKGROUND: Human polyomaviruses (HPyVs) have been associated with several cutaneous inflammatory conditions. More investigation is needed to identify further presentations of cutaneous pathology associated with HPyVs. Our aim was to investigate the possible association of skin-tropic HPyVs with folliculitis, particularly eosinophilic pustular folliculitis (EPF). METHODS: This study included 55 Japanese patients, comprising 13 patients with EPF and 42 patients with suppurative folliculitis. HPyV DNAs were detected by quantitative polymerase chain reaction. Expression of viral antigen and geographically related viral genotypes were also assessed. RESULTS: Human polyomavirus 6 (HPyV6) DNA was found in 9 of 13 (69%) patients with EPF, a rate significantly higher than that found in suppurative folliculitis (1/42; 2%). Of the 7 HPyV6 DNA-positive EPF specimens analyzed, 4 were positive for HPyV6 small tumor antigen. All the HPyV6 strains detected in this study were of the Asian/Japanese genotype. CONCLUSIONS: The predominant detection of HPyV6 DNA and the expression of viral antigen suggest a possible association between HPyV6 infection and EPF in a subset of patients. Worldwide studies are warranted to determine whether Asian/Japanese genotype HPyV6 is associated preferentially with the incidence and pathogenesis of this eosinophil-related skin disease that has an ethnic predilection for the East Asian population.
  • Yumiko Hashida; Tomonori Higuchi; Kimiko Nakajima; Takako Ujihara; Ichiro Murakami; Mikiya Fujieda; Shigetoshi Sano; Masanori Daibata
    Journal of Investigative Dermatology (IF: 7.590) 140 8 1650 - 1653.e4 2020年08月 [査読有り]
  • Higuchi T; Matsuo K; Hashida Y; Kitahata K; Ujihara T; Taniguchi A; Yoshie O; Nakayama T; Daibata M
    Cancer Letters (IF: 9.756) 453 184 - 192 2019年07月 [査読有り]
     
    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas associated with chronic inflammation (DLBCL-CI) develop in patients with chronic inflammation but without any predisposing immunodeficiency. Given the expression of the EBV latent genes, DLBCL-CI should have mechanisms for evasion of host antitumor immunity. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and may provide a valuable model for the study of immune evasion by DLBCL-CI. This study demonstrates that PAL cell lines express and secrete CCL17 and/or CCL22 chemokines, the ligands of C-C motif chemokine receptor 4 (CCR4), in contrast to EBV-negative DLBCL cell lines. Accordingly, culture supernatants of PAL cell lines efficiently attracted CCR4-positive regulatory T (Treg) cells in human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CCR4-expressing Treg cells. Furthermore, this study confirmed that CCR4-expressing Treg cells were abundantly present in primary PAL tissues. Collectively, these findings provide new insight into the mechanisms of immune evasion by PAL, and further studies are warranted on whether such mechanisms eventually lead to the development of DLBCL-CI.
  • Hashida Y; Higuchi T; Tanaka M; Shibata Y; Nakajima K; Sano S; Daibata M
    Journal of Infectious Diseases (IF: 7.759) 219 10 1564 - 1573 2019年04月 [査読有り]
     
    BACKGROUND:
    Human skin microorganisms have been associated with various skin diseases. However, most studies have focused on bacterial communities, and little is known about normally resident skin viruses such as the Polyomaviridae and their association with cutaneous disorders.

    METHODS:
    We investigated the infection levels of Merkel cell polyomavirus (MCPyV), human polyomavirus 6 (HPyV6), and human polyomavirus 7 (HPyV7), using triplet skin swabs collected from lesional and nonlesional skins of 86 Japanese patients with inflammatory skin diseases and mycosis fungoides, and from 149 healthy control individuals.

    RESULTS:
    This age-matched case-control study provides the first analyses of the loads of polyomaviruses in association with various skin diseases. The viral loads were significantly higher for HPyV6/HPyV7 and lower for MCPyV in patients with psoriasis. The viral load variation was observed not only at lesion sites, but also at clinically unaffected skin sites in most of the patients. The viral strains tested were all of the Asian/Japanese genotype.

    CONCLUSIONS:
    Our findings suggest a covariation in the infection levels of cutaneous polyomaviruses in certain inflammatory skin conditions. Worldwide prospective longitudinal studies are warranted to understand the influence of such alterations on the pathogenesis of inflammatory skin disorders.
  • Kikuchi H; Higuchi T; Hashida Y; Taniguchi A; Kamioka M; Taguchi T; Yokoyama A; Murakami I; Fujieda M; Daibata M
    Oncotarget (IF: 5.168) 9 71 33482 - 33499 2018年09月 [査読有り]
     
    "Double-hit" lymphoma (DHL) is a high-grade B-cell lymphoma that harbors concurrent MYC and BCL2 or BCL6 rearrangements. Because cases of MYC/BCL6 DHL are uncommon, most reported conclusions have been based on cases of MYC/BCL2 DHL. Lack of experimental MYC/BCL6 DHL models continues to hinder the pathophysiologic and therapeutic investigations of this disorder. We herein describe a novel MYC/BCL6 DHL cell line, designated DH-My6, carrying both the MYC-IGH and BCL6-IGH fusion genes. Interruptions of MYC and BCL6 expressions using short interfering RNAs and chemical inhibitors led to significant attenuation of DH-My6 cell growth. Greater antitumor effects were found when the cells were treated with a combination of MYC and BCL6 inhibitors. Moreover, the PLK1 inhibitor volasertib and the HDAC inhibitor vorinostat synergized strongly when combined with the bromodomain inhibitor JQ1. DH-My6 is a new well-validated MYC/BCL6 DHL cell line that will provide a useful model for studies of the pathogenesis and therapeutics for the less common DHL tumor type. The rationale for approaches targeting both MYC and BCL6, and in combination with PLK1 or HDAC inhibitors for superior suppression of the aggressive MYC/BCL6 DHL warrants further in vivo testing in a preclinical model.
  • Murakami I; Wada N; Nakashima J; Iguchi M; Toi M; Hashida Y; Higuchi T; Daibata M; Matsushita M; Iwasaki T; Kuwamoto S; Horie Y; Nagata K; Hayashi K; Oka T; Yoshino T; Imamura T; Morimoto A; Imashuku S; Gogusev J; Jaubert F
    Cell Communication and Signaling (IF: 5.908) 16 1 49 - 49 2018年08月 [査読有り]
     
    BACKGROUND:
    The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual's reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.

    METHODS:
    We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups' data.

    RESULTS:
    We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS/MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH.

    CONCLUSION:
    We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.
  • Yumiko Hashida; Tomonori Higuchi; Kiyohiko Matsui; Yuka Shibata; Kimiko Nakajima; Shigetoshi Sano; Masanori Daibata
    Journal of infectious diseases (IF: 7.759) 217 10 1601 - 1611 2018年04月 [査読有り]
     
    Background: Merkel cell polyomavirus (MCPyV) is a ubiquitous cutaneous virus that causes Merkel cell carcinoma, which develops preferentially in white populations from Europe and North America. However, the genomic variations of MCPyV among ethnic groups have not been well delineated, and even less is known regarding alterations in the noncoding control region (NCCR) in the general population. Methods: MCPyV strains recovered from skin swab specimens from 250 healthy participants with distinct ethnicities and geographic origins were subjected to sequencing analysis of the NCCR. Results: A 25-base pair tandem repeat caused by a 25-base pair insertion within the NCCR was found predominantly in Japanese and East Asian individuals. Based on the presence of 2 other insertions and a deletion, the NCCR could be classified further into 5 genotypes. This tandem repeat was also found exclusively in the NCCR from Japanese patients with Merkel cell carcinoma, while other genotypes were detected in white patients from Europe and North America. Conclusions: Our results suggest that the MCPyV NCCR varies according to ethnicity and that assessing the short NCCR sequence provides a rapid and simple means for identification of the Japanese and East Asian variant genotype. It remains to be established whether these NCCR variations are associated differentially with the pathogenesis of MCPyV-driven Merkel cell carcinoma between regions with varying endemicity.
  • Yumiko Hashida; Tomonori Higuchi; Shigenobu Matsuzaki; Kimiko Nakajima; Shigetoshi Sano; Masanori Daibata
    Journal of Infectious Diseases (IF: 7.759) 217 3 483 - 493 2018年01月 [査読有り]
     
    Background. Despite the pathogenetic potential of human polyomavirus 6 (HPyV6) and human polyomavirus 7 (HPyV7), they have been found in the normal skin of healthy individuals. However, little is known about the prevalence, infection levels, and geographical variations of these polyomaviruses in the skin. Methods. Using skin swabs from 470 participants aged 2-98 years, we estimated the prevalence of copy numbers of HPyV6 and HPyV7 with respect to age and ethnicity. Phylogenetic analyses were conducted based on viral sequences obtained from Asian and white populations. Results. This study provides the first analyses of the age-specific prevalence and levels of HPyV6 and HPyV7 infections in normal skin. Comparisons of age groups revealed that the prevalence and viral loads were significantly higher in elderly persons. Phylogenetic analyses demonstrated the existence of Asian/Japanese-specific strains genetically distinct from strains prevalent in the skin of the white population studied. Conclusions. This large study suggests that HPyV6 and HPyV7 infections in the skin are highly prevalent in elderly adults. Further research is warranted to understand whether persistent infection with high viral loads in the skin could be a risk factor for the development of HPyV6-A nd HPyV7-associated skin disorders.
  • Tomonori Higuchi; Yumiko Hashida; Ayuko Taniguchi; Mikio Kamioka; Masanori Daibata
    Scientific Reports (IF: 4.966) 7 1 11026  2017年09月 [査読有り]
     
    The genetic events that lead to aggressive transformation of cases of splenic marginal zone lymphoma (SMZL) after the chronic clinical stage have not been well understood. We aimed to find candidate genes associated with aggressive features of SMZL. We have successfully established two SMZL cell lines, designated SL-15 and SL-22, derived from the same patient's tumor clone in chronic and aggressive phases, respectively. Microarray analysis identified cell cycle-associated genes-specifically PLK1-as the most significantly upregulated in primary aggressive SMZL cells compared with cells from chronic phase. EPHA4 and MS4A1 (CD20) were found to be downregulated dramatically. These gene expression patterns were reproduced in both cell lines. Genetic knockdown of PLK1 resulted in inhibition of cell proliferation and induction of apoptosis in SL-22 cells, which expressed higher levels of PLK1 than SL-15 cells. SL-22 cells needed higher concentrations of chemical PLK1 inhibitors to achieve greater effects. In addition, we found homozygous deletion of the MS4A1 gene as a newly identified molecular mechanism of CD20-negative conversion. Our findings are expected to stimulate further studies on whether PLK1 could be a potential therapeutic target for this tumor. Furthermore, cases with CD20-negatively converted lymphomas should be screened for the genomic loss of MS4A1.
  • 新規発がん遺伝子SOX4による成人T細胞白血病/リンパ腫(ATLL)の新たな発がん機構の解明
    小森 悠平; 樋口 智紀; 松尾 一彦; 義江 修; 中山 隆志
    日本薬学会年会要旨集 136年会 3 198 - 198 (公社)日本薬学会 2016年03月
  • Masataka Taguchi; Yoshitaka Imaizumi; Daisuke Sasaki; Tomonori Higuchi; Kazuto Tsuruda; Hiroo Hasegawa; Jun Taguchi; Yasushi Sawayama; Daisuke Imanishi; Tomoko Hata; Katsunori Yanagihara; Osamu Yoshie; Yasushi Miyazaki
    Annals of Hematology (IF: 4.030) 94 4 693 - 695 2015年04月 [査読有り]
  • 成人ヒトT細胞白血病/リンパ腫(ATLL)発がんにおけるSOX4の役割の解明
    小森 悠平; 樋口 智紀; 松尾 一彦; 義江 修; 中山 隆志
    日本薬学会年会要旨集 135年会 4 60 - 60 (公社)日本薬学会 2015年03月
  • Kazunori Masahata; Eiji Umemoto; Hisako Kayama; Manato Kotani; Shota Nakamura; Takashi Kurakawa; Junichi Kikuta; Kazuyoshi Gotoh; Daisuke Motooka; Shintaro Sato; Tomonori Higuchi; Yoshihiro Baba; Tomohiro Kurosaki; Makoto Kinoshita; Yosuke Shimada; Taishi Kimura; Ryu Okumura; Akira Takeda; Masaru Tajima; Osamu Yoshie; Masahiro Fukuzawa; Hiroshi Kiyono; Sidonia Fagarasan; Tetsuya Iida; Masaru Ishii; Kiyoshi Takeda
    Nature Communications (IF: 17.694) 5 3704  2014年04月 [査読有り]
     
    Gut-associated lymphoid tissues are responsible for the generation of IgA-secreting cells. However, the function of the caecal patch, a lymphoid tissue in the appendix, remains unknown. Here we analyse the role of the caecal patch using germ-free mice colonized with intestinal bacteria after appendectomy. Appendectomized mice show delayed accumulation of IgA(+) cells in the large intestine, but not the small intestine, after colonization. Decreased colonic IgA(+) cells correlate with altered faecal microbiota composition. Experiments using photoconvertible Kaede-expressing mice or adoptive transfer show that the caecal patch IgA(+) cells migrate to the large and small intestines, whereas Peyer's patch cells are preferentially recruited to the small intestine. IgA(+) cells in the caecal patch express higher levels of CCR10. Dendritic cells in the caecal patch, but not Peyer's patches, induce CCR10 on cocultured B cells. Thus, the caecal patch is a major site for generation of IgA-secreting cells that migrate to the large intestine.
  • Tomonori Higuchi; Takashi Nakayama; Tokuzo Arao; Kazuto Nishio; Osamu Yoshie
    Blood (IF: 25.476) 121 18 3640 - 3649 2013年05月 [査読有り]
     
    Previously, we have shown that an AP-1 family member, FRA-2, is constitutively expressed in adult T-cell leukemia/lymphoma (ATL) and, together with JUND, upregulates CCR4 and promotes ATL cell growth. Among the identified potential target genes of FRA-2/JUND was SOX4. Here, we examine the expression and function of SOX4 in ATL. SOX4 was indeed consistently expressed in primary ATL cells. FRA-2/JUND efficiently activated the SOX4 promoter via an AP-1 site. Knockdown of SOX4 expression by small interfering RNA (siRNA) strongly suppressed cell growth of ATL cell lines. Microarray analyses revealed that SOX4 knockdown reduced the expression of genes such as germinal center kinase related (GCKR), NAK-associated protein 1 (NAP1), and histone deacetylase 8 (HDAC8). We confirmed consistent expression of GCKR, NAP1, and HDAC8 in primary ATL cells. We also showed direct activation of the HDAC8 promoter by SOX4. Furthermore, siRNA knockdown of GCKR, NAP1, and HDAC8 each significantly suppressed cell growth of ATL cell lines. Taken together, we have revealed an important oncogenic cascade involving FRA-2/JUND and SOX4 in ATL, which leads to the expression of genes such as GCKR, NAP1, and HDAC8.
  • Takashi Nakayama; Tomonori Higuchi; Naoki Oiso; Akira Kawada; Osamu Yoshie
    Anticancer Research (IF: 2.435) 32 4 1367 - 1373 2012年04月 [査読有り]
     
    Adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphomas (CTCLs) are known to frequently express CC chemokine receptor 4 (CCR4). Previously, we investigated the transcriptional control of CCR4 expression in ATLL and have found that an activating protein 1 (AP1) family member, FBJ murine osteosarcoma viral oncogene homolog (FOS)-related antigen 2 (FRA2), is consistently expressed at high levels in ATLL and, together with v-JUN avian sarcoma virus 17 oncogene homolog D (JUND), up-regulates the expression of CCR4 as well as that of several proto-oncogenes such as v-MYB myeloblastosis viral oncogene homolog (MYB), murine double minute 2 homolog (MDM2), and B-cell lymphoma 6 (BCL6). Here, we examined the expression of these genes in clinical samples of CTCLs. We detected the transcripts of FRA2, JUND, CCR4, MYB, MDM2, and BCL6 at high levels in CTCL skin lesions. Except for BCL6, we confirmed protein expression of FRA2, JUND, CCR4, MYB, and MDM2 in CTCL skin lesions. Furthermore, siRNA-mediated knockdown of FRA2 or JUND suppressed cell growth and the expression of CCR4, MYB, MDM2, and BCL6 in CTCL cell lines. Our results, thus, demonstrate the presence of a common oncogenic cascade initiated by FRA2/JUND in CCR4-expressing mature T-cell malignancies such as ATLL and CTCLs.
  • Takashi Nakayama; Yoshiko Watanabe; Naoki Oiso; Tomonori Higuchi; Akiko Shigeta; Nobuyuki Mizuguchi; Fuminori Katou; Kenji Hashimoto; Akira Kawada; Osamu Yoshie
    Journal of Immunology (IF: 5.426) 185 11 6472 - 6479 2010年12月 [査読有り]
     
    Eotaxin-3/CCL26 is a functional ligand for CCR3 and abundantly produced by IL-4-/IL-13-stimulated vascular endothelial cells. CCL26 also functions as a natural antagonist for CCR1, CCR2, and CCR5. In this study, we report that CCL26 is yet a functional ligand for CX3CR1, the receptor for fractalkine/CX3CL1, which is expressed by CD16(+) NK cells, cytotoxic effector CD8(+) T cells, and CD14(low)CD16(high) monocytes. Albeit at relatively high concentrations, CCL26 induced calcium flux and chemotaxis in mouse L1.2 cells expressing human CX3CR1 but not mouse CX3CR1 and competed with CX3CL1 for binding to CX3CR1. In chemotaxis assays using human PBMCs, CCL26 attracted not only eosinophils but also CD16(+) NK cells, CD45RA(+)CD27(-)CD8(+) T cells, and CD14(low)CD16(high) monocytes. Intraperitoneal injection of CCL26 into mice rapidly recruited mouse eosinophils and intravenously transferred human CD16(+) NK cells into the peritoneal cavity. IL-4-stimulated HUVECs produced CCL26 and efficiently induced adhesion of cells expressing CX3CR1. Real-time PCR showed that skin lesions of psoriasis consistently contained CX3CL1 mRNA but not CCL26 mRNA, whereas those of atopic dermatitis contained CCL26 mRNA in all samples but CX3CL1 mRNA in only about half of the samples. Nevertheless, the skin lesions from both diseases consistently contained CX3CR1 mRNA at high levels. Thus, CCL26 may be partly responsible for the recruitment of cells expressing CX3CR1 in atopic dermatitis particularly when the expression of CX3CL1 is low. Collectively, CCL26 is another agonist for CX3CR1 and may play a dual role in allergic diseases by attracting eosinophils via CCR3 and killer lymphocytes and resident monocytes via CX3CR1. The Journal of Immunology, 2010, 185: 6472-6479.
  • Keiji Shimada; Mitsutoshi Nakamura; Eiwa Ishida; Tomonori Higuchi; Hiroshi Yamamoto; Kazutake Tsujikawa; Noboru Konishi
    Cancer Science (IF: 6.518) 99 1 39 - 45 2008年01月 [査読有り]
     
    A novel gene, prostate cancer antigen (PCA)-1, was recently reported to be expressed in the prostate; however, its biological roles remain unclear. Knockdown of the PCA-1 gene by small interfering RNA transfection induced apoptosis through reducing the expression of the anti-apoptotic molecule Bcl-xl and cytoplasmic release of cytochrome c in the androgen-independent prostate cancer cell line PC3. Moreover, in vitro matrigel and in vivo chorioallantoic membrane assays showed that silencing of PCA-1 significantly downregulated discoidin receptor (DDR)-1 expression, resulting in suppression of cancer-cell invasion. Transfection with PCA-1 increased the levels of both Bcl-xl and DDR1, which made the cells more invasive through the upregulation of matrix metalloproteinase 9 in DU145. Interestingly, long-term culture using androgen-free medium increased the level of PCA-1 and the related expression of Bcl-xl and DDR-1 in the androgen-sensitive cancer cell line LNCaP, suggesting that PCA-1 signaling is associated with androgen independence. Immunohistochemical analysis in a series of 169 prostate carcinomas showed that PCA-1 and DDR1 were strongly expressed in prostate cancer cells, including preneoplastic lesions, but there was little or no expression in normal epithelium. Moreover, the expression of PCA-1 and DDR-1 was associated with a hormone-independent state of prostate cancer. Taken together, we propose that PCA-1-DDR-1 signaling is a new important axis involved in malignant potential prostate cancer associated with hormone-refractory status.
  • Tomonori Higuchi; Mitsutoshi Nakamura; Keiji Shimada; Eiwa Ishida; Kazuya Hirao; Noboru Konishi
    Prostate (IF: 4.012) 68 1 105 - 113 2008年01月 [査読有り]
     
    OBJECTIVES. Recent studies in selected human tumors have demonstrated reduced expression of HRK with hypermethylation. Because no similar study has been performed specifically in prostatic lesions, we examined whether the methylation status of HRK is altered in prostate cancers. METHODS. We chose to analyze the hypermethylation status of HRK, the expression of HRK protein and mRNA with 12q13.1 loss of heterozygosity (LOH) and with p53 mutation, and lesion apoptotic indices as determined by transferase-mediated digoxigenin-tagged 16-desoxyuridine-triphosphate nick end-labeling (TUNEL) assays in 53 prostate cancers. RESULTS. Twenty of the 53 prostate cancers (38%) demonstrated hypermethylation in either the promoter or in exon 1 and, more significantly, the loss of HRK expression observed in 14 cancers by immunohistochemistry (IHC) was associated with promoter methylation. In addition, high apoptotic indices in tumors were related to positive HRK expression. Prostate cancers demonstrating HRK methylation also showed methylation of multiple other genes, such as p14(ARF), p16(INK4a), O-6-MGMT, and GTS-P, but, with the exception of one case, p53 mutations were not detected. When compared to tumors having a Gleason score (GS) of 5-6, a significant difference in the apoptotic indices was found among prostate cancers of GS 7 (P < 0.001) or GS 8-9 (P = 0.007). We also detected a close correlation between the loss of HRK expression and decreased apoptosis in GS 5-6 and GS 7 tumors (P = 0.008, P < 0.001, respectively). CONCLUSIONS. HRK appears to be inactivated principally by promoter hypermethylation in prostate cancers. We further suggest that the decreased expression of HRK may play an important role in tumor progression by modulating apoptotic cell death.
  • Keiji Shimada; Mitsutoshi Nakamura; Eiwa Ishida; Tomonori Higuchi; Motoyoshi Tanaka; Lchiro Ota; Noboru Konishi
    American Journal of Pathology (IF: 5.770) 171 3 1003 - 1012 2007年09月 [査読有り]
     
    We here examined whether c-Jun NH2 terminal kinase (JNK) might be involved in the progression of urothelial carcinomas. In vitro and in vivo invasion assays using Matrigel and chick embryo chorioallantoic membrane approaches showed constitutive activation of JNK to significantly increase two processes, invasion and angiogenesis, in the human urothelial carcinoma cell line kU-7, this being suppressed by a JNK inhibitor, SP600125, or cell-permeable peptides. In addition, we found that mitogen-activated protein kinase phosphatase (MK.P)-1 functions as an endogenous inhibitor of JNK-mediated signals in urothelial carcinoma cells: chorioallantoic membrane assays showed UMUC14 cells with low MKP-1 expression to be more invasive and have pronounced angiogenesis compared to UMUC6 cells with high MKP-1. Furthermore, knockdown of the MKP-1 gene by siRNA transfection enhanced JNK activation in UMUC6 cells to the UMUC14 level. Immunohistochemically, JNK was found to be highly phosphorylated in high-grade and invasive carcinomas ( >= pT2) as well as carcinoma in situ but not in low-grade and noninvasive phenotypes (pTa, pT1). In contrast, MKP-1 was much more expressed in low-grade/noninvasive cancers than with the high-grade/invasive phenotype, reversely correlating with phosphorylated JNK. Taken together, JNK activation and decreased expression of MKP-1 may play important roles in progression of urothelial carcinoma.
  • Mitsutoshi Nakamura; Keiji Shimada; Eiwa Ishida; Tomonori Higuchi; Hiroyuki Nakase; Toshisuke Sakaki; Noboru Konishi
    Neuro-Oncology (IF: 13.029) 9 2 113 - 123 2007年04月 [査読有り]
     
    Astrocytomas are the most common pediatric brain tumors, accounting for 7%-8% of all childhood cancers. Relatively few studies have been performed on their molecular properties; therefore, classification of pediatric astrocytic tumors into genetic subtypes similar to that of adult tumors remains to be defined. Here, we report an extensive characterization of 44 pediatric astrocytomas -16 diffuse astrocytomas (WHO grade II), 10 anaplastic astrocytomas (WHO grade III), and 18 glioblastomas (WHO grade IV)-in terms of genetic alterations frequently observed in adult astrocytomas. Some form of p53 mutation was found in three diffuse astrocytomas, in three anaplastic astrocytomas, and in six glioblastomas examined; PTEN mutations were detected only in two glioblastomas. EGFR amplification was detected in only one anaplastic astrocytoma and two glioblastomas, but no amplification was observed for the PDGFR-gene. Loss of heterozygosity (LOH) on 1p/19q and 10p/10q was less common in pediatric astrocytic tumors than in those seen in adults, but the frequency of LOH on 22q was comparable, occurring in 44% of diffuse astrocytomas, 40% of anaplastic astrocytomas, and 61% of glioblastomas. Interestingly, a higher frequency of p53 mutations and LOH on 19q and 22q in tumors from children six or more years of age at diagnosis was found, compared with those from younger children. Our results suggest some differences in children compared to adults in the genetic pathways leading to the formation of de novo astrocytic tumors. In addition, this study suggests potentially distinct developmental pathways in younger versus older children.
  • Eiwa Ishida; Mitsutoshi Nakamura; Keiji Shimada; Tomonori Higuchi; Keisuke Takatsu; Katsunari Yane; Noboru Konishi
    Pathobiology (IF: 3.916) 74 6 344 - 352 2007年 [査読有り]
     
    Objective: The aim of this study was hypermethylation of multiple genes for papillary thyroid carcinomas ( PTCs). Methods: We examined 39 lesions using methylation- specific PCR to assess hypermethylation in genes, including p16(INK4a), p14(ARF), RB1, p27(Kip1) and 0(6)-MGMT. Homozygous deletions of p16(INK4a) and p14(ARF) were investigated by differential PCR, all with reference to clinicopathological factors. Results: We found methylation of p16(INK4a) in 35.9% (14/39); p14(ARF) in 2.6% (1/39); RB1 in 23.1% (9/39); p27(Kip1) in 15.4% (6/39), and 0(6)-MGMT in 15.4% (6/39). Hypermethylation of at least one of these genes was apparent in 66.7% (26/39). Homozygous deletions of p14(ARF) and p16(INK4a) were detected in 7.7 (3/39) and 2.6% (/39), respectively. In cases with p16(INK4a) alterations, tumors were significantly increased. A history of chronic thyroid disease and lymphocytic infiltration was significantly associated with p14(ARF) alterations, without regional lymph node metastases. Conclusions: Our data suggest that alterations in p16(INK4a), mainly hypermethylation, may be linked to tumor growth but not tumor development, while alterations in p14(ARF) may contribute to the induction of chronic inflammation-related PTCs. Copyright (c) 2007 S. Karger AG, Basel.
  • M. Nakamura; S. Morimoto; A. Ishii; T. Higuchi; T. Ogihara; K. Kakudo
    Cellular and Molecular Biology (IF: 1.206) 52 3 15 - 18 2006年 [査読有り]
     
    Bone mineral density and the serum concentration of osteocalcin are influenced by multiple genetic factors, including hormone and genes. Our aim was to evaluate the correlation between the dinucleotide (cytosine (C)-adenine (A)) repeat polymorphism at the calcitonin locus and bone mineral density and serum osteocalcin levels. Sixty-six healthy Japanese women over 50 years of age were included in this study. The bone mineral density of the second to fourth lumbar vertebrae was measured using dual-energy X-ray absorptiometry and serum osteocalcin was measured using an immunoradiometric assay. We isolated DNA from peripheral leukocytes and genotyped the cytosine-adenine repeats at the calcitonin locus using the polymerase chain reaction. We found that bone mineral density was not correlated with the number of cytosine-adenine repeats. However, the circulating osteocalcin level was significantly different among the different cytosine-adenine repeat groups. The osteocalcin level of the 10/17 (C-A) heterozygote group was significantly lower than those of the other groups (p < 0.01). The 10/17 (C-A) and 17/17 (C-A) genotypes are common in the Japanese population, and the osteocalcin levels of the 10/17 heterozygotes were significantly lower than those of the 17/17 homozygote (p < 0.05). Our findings suggest that the cytosine-adenine repeat at the calcitonin gene locus may be one of the genetic factors that regulate serum osteocalcin levels in Japanese women.
  • Hiroshi Miyamoto; Wataru Nakai; Naoto Yajima; Akemi Fujibayashi; Tomonori Higuchi; Koki Sato; Aizo Matsushiro
    DNA Research (IF: 4.477) 6 4 235 - 240 1999年 [査読有り]
     
    In enterohemorrhagic Escherichia coli, Shiga toxin is produced by lysogenic prophages. We have isolated the prophage VT2-Sa that is responsible for production of Shiga toxin type 2 protein, and determined the complete nucleotide sequence of this phage DNA. The entire DNA sequence consisted of 60,942 bp, exhibiting marked similarity to the 933W phage genome. However, several differences were observed in the immunity and replication regions, where cI, cI, cIII, N, cro, O, and P genes were present: Predicted amino acid sequences of N, cI, cro, O and P in the VT2-Sa genome did not show significant similarity to the counterparts of the 933W genome however its ci showed higher similarity to λ. Furthermore, O and P closely resembled those of phage HK022. These observations suggest that the various degrees of homology observed in the immunity and replication regions of VT2-Sa could have resulted from frequent recombination events among the lambdoid pliages, and that these regions play a key role as a functional unit for phage propagation in competition with other lambdoid phages.

書籍

  • 臨床免疫・アレルギー科 サイトカインのすべて（完全改訂版）
    樋口 智紀; 中山 隆志 (担当:共著範囲:)2012年05月

講演・口頭発表等

  • ヒトヘルペスウイルス8型陰性原発性滲出性リンパ腫細胞由来の異種移植モデルにおけるビラブレシブの抗腫瘍活性
    樋口智紀; 西森大洋; 橋田裕美子; 大畑雅典
    第81回日本癌学会学術総会 2022年09月 ポスター発表
  • HHV8陰性原発性滲出性リンパ腫細胞由来の異種移植モデルの樹立とその解析
    西森大洋; 樋口智紀; 橋田裕美子; 大畑雅典
    第80回日本癌学会学術総会 2021年10月 ポスター発表
  • ヒトヘルペスウイルス8型感染を認めない原発性滲出液リンパ腫様リンパ腫に由来する新規細胞株の樹立
    西森大洋; 樋口智紀; 橋田裕美子; 谷口亜裕子; 小島研介; 大畑雅典
    第79回日本癌学会学術集会 2020年10月 口頭発表（一般）
  • EBV陽性膿胸関連リンパ腫はケモカインCCL17およびCCL22を発現し，CCR4陽性制御性T細胞を誘引する  [通常講演]
    樋口 智紀; 橋田 裕美子; 西森 大洋; 大畑 雅典
    第67回日本ウイルス学会学術集会 2019年10月 ポスター発表 東京 日本ウイルス学会
  • EBV陽性膿胸関連リンパ腫はCCR4陽性制御性T細胞の誘引に寄与するケモカインCCL17およびCCL22を発現する  [通常講演]
    樋口 智紀; 橋田 裕美子; 氏原 隆子; 谷口 亜裕子; 中山 隆志; 大畑 雅典
    第78回 日本癌学会学術総会 2019年09月 口頭発表（一般） 京都 日本癌学会
  • MYCおよびBCL6遺伝子転座を有する高悪性度B細胞リンパ腫細胞株におけるMYC/PLK1阻害による細胞増殖抑制効果  [通常講演]
    樋口 智紀; 菊地 広朗; 橋田 裕美子; 田口 尚弘; 上岡 樹生; 谷口 亜裕子; 村上 一郎; 大畑 雅典
    第77回 日本癌学会学術総会 2018年09月 ポスター発表 大阪 日本癌学会
  • 進行性脾辺縁帯リンパ腫でPLK1 は過剰発現し，細胞の増殖および生存を高める  [通常講演]
    樋口 智紀; 橋田 裕美子; 上岡 樹生; 谷口 亜裕子; 大畑 雅典
    第76回 日本癌学会学術総会 2017年09月 ポスター発表 横浜 日本癌学会
  • CREB，NF-κBおよびTaxによって相乗的に活性化されたFOSB遺伝子発現は，結果的にHTLV-1感染細胞の生存能に関与する  [通常講演]
    樋口 智紀; 稗島 州雄; 中山 隆志; 義江 修
    第74回 日本癌学会学術総会 2015年10月 ポスター発表 名古屋 日本癌学会
  • SOX4はHDAC8を発現誘導し，皮膚T細胞リンパ腫の細胞増殖に寄与する  [通常講演]
    樋口 智紀; 中山 隆志; 義江 修
    第73回 日本癌学会学術総会 2014年09月 ポスター発表 横浜 日本癌学会
  • 成人T細胞白血病の発がんにおけるFra-2-SOX4経路の役割  [通常講演]
    樋口 智紀; 中山 隆志; 義江 修
    第72回 日本癌学会学術総会 2013年10月 口頭発表（一般） 横浜 日本癌学会
  • ウイルス学的シナプス形成によるCCR4陽性T細胞選択的HTLV-1伝播はHTLV-1感染細胞でのTax依存的なFosB誘導性CCL22発現に起因する．  [通常講演]
    樋口 智紀; 稗島 州雄; 中山 隆志; 義江 修
    第71回 日本癌学会学術総会 2012年10月 札幌 日本癌学会
  • Fra-2-SOX4 oncogenic cascade plays a critical role in cell growth of CCR4+ mature T-cell malignancies  [通常講演]
    樋口 智紀; 中山 隆志; 井上 暁子; 義江 修
    JSICR-MMCB2011 2011年05月 JSICR-MMCB2011
  • CCR4発現T細胞リンパ腫における新規発癌遺伝子Fra-2.  [通常講演]
    中山 隆志; 樋口 智紀; 稗島 州雄; 義江 修
    第75回 日本インターフェロン・サイトカイン学会 2010年06月 第75回 日本インターフェロン・サイトカイン学会
  • Common oncogenic role of Fra-2 in mature T-cell malignancies expressing CCR4.  [通常講演]
    義江 修; 中山 隆志; 樋口 智紀; 稗島 州雄
    Gordon Reserch Conferences 2010年06月 Gordon Reserch Conferences
  • Identification of Fra-2-SOX4 oncogenic cascade in CCR4+ mature T-cell malignancies  [通常講演]
    樋口 智紀; 中山 隆志; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修
    14th International Congress of Immunology 2010年 14th International Congress of Immunology
  • Common oncogenic role of FRA-2 in mature T-cell lymphoma expressing CCR4.  [通常講演]
    義江 修; 樋口 智紀; 中山 隆志
    International Association of Inflammation Societie T-cell Lymphoma Forum 2010年01月 International Association of Inflammation Societie T-cell Lymphoma Forum
  • ケモカインEotaxin-3/CCL26のCX3CR1を介した細胞傷害性リンパ球遊走作用.  [通常講演]
    中山 隆志; 樋口 智紀; 重田 暁子; 稗島 州雄; 義江 修; 渡邉賀子
    日本分子生物学会年会 2009年12月 日本分子生物学会年会
  • Taxによる翻訳伸長因子eEF1A2の誘導とそのHTLV－1によるT細胞がん化での役割の解明  [通常講演]
    稗島 州雄; 重田 暁子; 中山 隆志; 樋口 智紀; 義江 修
    第２回HTLV-1研究会 2009年08月 東京 第２回HTLV-1研究会
     
    我々は最近、Taxを発現しているHTLV-1感染細胞株においてTax siRNAにより発現が変動する遺伝子をマイクロアレイにより解析した結果、Tax依存性発現の可能性のある多数の遺伝子を同定した。その中に最近注目を浴びている翻訳伸長因子のeukaryotic elongation factor 1 alpha 2 (eEF1A2)が含まれていた。eEF1A2はEF-1αサブユニットのイソ型で、eEF1A1がハウスキーピング遺伝子として筋肉以外の多くの組織で発現しているのに対し、eEF1A2は主に筋肉と神経で発現している。両者は異なる染色体上にマップされ、92％のアミノ酸相同性を持つものの互いに排他的な発現調節を受けている。さらに興味深いことに、異所性に発現したeEF1A2はがん化との関連が報告されている。したがって、eEF1A2は発がん遺伝子としての性格も有しているが、その作用メカニズムについてはまだ十分明らかにされていない。 我々がeEF1A2に特に注目する理由は、最近明らかになってきているeEF1A2の翻訳伸長因子以外の作用である。eEF
  • Fra-2 and c-Myb oncogenic cascade is involved in cell growth in CD4+ mature T-cell lymphomas  [通常講演]
    樋口 智紀; 中山 隆志; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修
    日本分子生物学会 2009年 日本分子生物学会
  • The role of Fra-2 and c-Myb oncogenic cascade in CD4+ mature T-cell lymphomas  [通常講演]
    樋口 智紀; 中山 隆志; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修
    日本癌学会 2009年 日本癌学会
  • HTLV-1感染におけるTh2関連転写因子c-Mafの機能解析  [通常講演]
    稗島 州雄; 中山 隆志; 長久保 大輔; 重田 暁子; 樋口 智紀; 白川 愛子; 義江 修
    第６８回 日本癌学会学術総会 2008年10月 名古屋 第６８回 日本癌学会学術総会
  • Taxにより誘導されるCXCR7の発現はHTLV-1感染T細胞の増殖を促進する.  [通常講演]
    長久保 大輔; 白川 愛子; 中山 隆志; 重田 暁子; 樋口 智紀; 稗島 州雄; 義江 修; 竹川 澄男
    日本癌学会 2008年 日本癌学会
  • CCR4を発現するATLとCTCLにおけるFra-2の異常発現.  [通常講演]
    中山 隆志; 樋口 智紀; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修; 竹川 澄男
    日本癌学会 2008年 日本癌学会
  • 前立腺progenitor cellの生物学的特性と病理組織学的意義について  [通常講演]
    島田啓司; 中村光利; 石田英和; 小西 登; 樋口 智紀
    日本病理学会 2008年 日本病理学会
  • 前立腺癌新規遺伝子PCA-1の機能解析  [通常講演]
    樋口 智紀; 島田啓司; 石田英和; 中村光利; 小西登
    日本病理学会 2008年 日本病理学会
  • 組織多様性を示す悪性神経膠腫におけるTMZ感受性因子としてのO6-MGMT遺伝子の検索  [通常講演]
    中村光利; 島田啓司; 石田英和; 田崎正人; 小西登; 樋口 智紀
    日本病理学会 2008年 日本病理学会
  • 組織多様性を示すglioblastomaにおけるgenotype解析の有用性  [通常講演]
    田崎正人; 中村光利; 島田啓司; 石田英和; 小西登; 樋口 智紀
    日本病理学会 2008年 日本病理学会
  • 前立腺癌Gleason gradeにおける分子マーカーの検討  [通常講演]
    石田英和; 中村光利; 島田啓司; 小西登; 樋口 智紀
    日本病理学会 2008年 日本病理学会
  • Clonal analysis in histological heterogenous gliomas.  [通常講演]
    樋口 智紀; Tomonori Higuchi; Mitsutoshi Nakamura; Keiji Shimada; Eiwa Ishida; Noboru Konishi
    日本癌学会 2007年 日本癌学会
  • O6-MGMT methylation as marker of response to temozolomide in gliomas showing intratumoral histological heterogeneity.  [通常講演]
    Mitsutoshi Nakamura; Keiji Shimada; Eiwa Ishida; Noboru Konishi; 樋口 智紀
    日本癌学会 2007年 日本癌学会
  • A novel molecular mechanisms of urothelial carcinoma invasion.  [通常講演]
    Keiji Shimada; Mitsutoshi Nakamura; Eiwa Ishida; Motoyoshi Tanaka; Noboru Konishi; 樋口 智紀
    日本癌学会 2007年 日本癌学会
  • Analysis of neuroendocrine differentiation in prostate cancer.  [通常講演]
    Eiwa Ishida; Mitsutoshi Nakamura; Keiji Shimada; Noboru Konishi; 樋口 智紀
    日本癌学会 2007年 日本癌学会
  • HRK inactivation associated with promoter methylation and LOH in prostate cancer.  [通常講演]
    Masato Ohshima; 樋口 智紀; Mitsutoshi Nakamura; Keiji Shimada; Eiwa Ishida; Noboru Konishi
    日本癌学会 2007年 日本癌学会
  • 組織多様性を示す脳神経膠腫におけるgenotype解析の有用性  [通常講演]
    樋口 智紀; 中村光利; 島田啓司; 石田英和; 松吉修一; 小西登
    日本病理学会 2007年 日本病理学会
  • Oligodendrogliomaにおける病理組織学的診断と遺伝子解析の有用性  [通常講演]
    中村光利; 島田啓司; 石田英和; 松吉修一; 小西登; 樋口 智紀
    日本病理学会 2007年 日本病理学会
  • 膀胱尿路上皮癌における新規浸潤メカニズムとその病理学的意義について  [通常講演]
    島田啓司; 中村光利; 松吉修一; 石田英和; 小西登; 樋口 智紀
    日本病理学会 2007年 日本病理学会
  • 前立腺癌における神経内分泌分化の検討  [通常講演]
    石田英和; 中村光利; 島田啓司; 松吉修一; 小西登; 樋口 智紀
    日本病理学会 2007年 日本病理学会
  • 乳癌におけるBcl-2リン酸化の意義  [通常講演]
    松吉修一; 島田啓司; 中村光利; 石田英和; 小西登; 樋口 智紀
    日本病理学会 2007年 日本病理学会
  • 動脈硬化発症におけるマクロファージ・間質相互作用、エラスチン接触とTNFα発現  [通常講演]
    森一郎; 覚道健一; 樋口 智紀
    日本病理学会 2007年 日本病理学会
  • 小児脳腫瘍における遺伝子変異の検索  [通常講演]
    樋口 智紀; 中村光利; 島田啓司; 石田英和; 松吉修一; 小西登
    日本癌学会 2006年 日本癌学会
  • Oligodendrogliomaにおける病理組織学的診断と遺伝子解析の有用性  [通常講演]
    中村光利; 島田啓司; 石田英和; 松吉修一; 小西登; 樋口 智紀
    日本癌学会 2006年 日本癌学会
  • 前立腺癌における神経内分泌分化の検討  [通常講演]
    石田英和; 中村光利; 島田啓司; 松吉修一; 小西登; 樋口 智紀
    日本癌学会 2006年 日本癌学会
  • 乳癌における新規抗癌剤感受性因子の検討  [通常講演]
    松吉修一; 島田啓司; 中村光利; 石田英和; 小西登; 樋口 智紀
    日本癌学会 2006年 日本癌学会
  • 前立腺癌における間質細胞のepigeneticな遺伝子変異の検討  [通常講演]
    大嶋正人; 樋口 智紀; 中村光利; 島田啓司; 石田英和; 小西登
    日本癌学会 2006年 日本癌学会
  • マクロファージにおけるelastin-laminin receptorを介したtumor necrosis factor alphaの発現とアテローム性動脈硬化  [通常講演]
    樋口 智紀; 森一郎; 中村美砂; 中村靖司; 安岡弘直; 尾崎敬; 覚道健一
    日本脈管学会 2005年 日本脈管学会
  • エラスチン‐ラミニン受容体を介したマクロファージの活性化とアテローム性動脈硬化  [通常講演]
    樋口 智紀; 森一郎; 中村美砂; 中村靖司; 覚道健一
    日本分子生物学会 2004年 日本分子生物学会
  • Elastin induced upregulation of M-CSF in Macrophage is mediated by elastin-laminin receptor.  [通常講演]
    Ichiro Mori; Misa Nakamura; Yasushi Nakamura; Hirotoshi Utsunomiya; Kennichi Kakudo; 樋口 智紀
    The XIIIth International Vascular Biology Meeting 2004年 The XIIIth International Vascular Biology Meeting

MISC

  • バクテリオファージKHP30の感染能に及ぼすピロリ菌保有制限 修飾系の解析
    松澤 佑一; 内山 淳平; 竹内 啓晃; 氏原 隆子; 橋田 裕美子; 樋口 智紀; 田中 望紅; 冨永 宗一竜; 大畑 雅典; 松崎 茂展 日本細菌学雑誌 72 (1) 95 -95 2017年02月
  • 松澤 佑一; 内山 淳平; 竹内 啓晃; 氏原 隆子; 橋田 裕美子; 樋口 智紀; 田中 望紅; 冨永 宗一竜; 大畑 雅典; 松崎 茂展 日本細菌学雑誌 72 (1) 95 -95 2017年02月

共同研究・競争的資金等の研究課題

  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2022年04月 -2025年03月 
    代表者 : 橋田 裕美子; 大畑 雅典; 樋口 智紀
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2021年04月 -2024年03月 
    代表者 : 北村 直也; 橋田 裕美子; 樋口 智紀; 笹部 衣里; 大畑 雅典; 山本 哲也
     
    マイクロバイオーム（微生物叢）が癌の発生や病態に関与することがわかってきた。これまでの口腔マイクロバイオーム研究は、主に細菌に主眼が置かれ、ウイルスと口腔腫瘍との関連については十分に解明されていない。本研究では、口腔扁平上皮癌（OSCC）およびOSCC患者に高頻度に併発する上部消化管領域の重複癌において、口腔に潜在するウイルス群の関与を究明する。準備段階の研究で、われわれの研究グループは約20％のOSCCで原発癌組織およびその転移組織や重複癌組織中にメルケル細胞ポリオーマウイルスを検出した。この研究成果を発展させるべく、 ① OSCCおよび他臓器重複癌における口腔潜在ウイルス群の感染頻度を網羅的に解析し、個々の感染ウイルス量やウイルス共感染パターンを明らかにする。 ② さらにわれわれの研究グループは、口腔ポリオーマウイルスには日本人特有の遺伝子型があることを世界に先駆けて突き止めており、感染ウイルスのゲノム多型を詳細に解析する。 ③ ウイルス感染の有無に基づいて、OSCCの臨床的特徴の層別化を試みる。 これらの研究により、ウイルス感染といった新たな観点からOSCCの病態解明の一端に迫る。本研究で創生される基盤データを基に、中咽頭癌のようにウイルス感染が予後や治療反応性などを予測できるバイオマーカーになり得るかを検証する研究につなげる。
  • ヒトパピローマウイルス関連中咽頭がんにおける個別医療を目指した予後予測因子の同定と新規制御法の開発
    グラクソ・スミスクライン株式会社：2021年度GSKジャパン研究助成金
    研究期間 : 2021年10月 -2023年03月 
    代表者 : 樋口智紀
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 藤枝 幹也; 樋口 智紀; 橋田 裕美子; 大畑 雅典
     
    木村病（軟部好酸球肉芽腫）は、頭頸部皮下組織に腫瘤を形成し、再発・再燃を繰り返し慢性の経過をたどる疾患である。末梢血と組織での好酸球増多を伴い、東アジア人、特に日本人の若年者に多く発症することが特徴である。従来、木村病の発生には微生物感染によるⅠ型アレルギーの関与が推測されてきたが、原因は同定されていなかった。そこで我々は木村病と皮膚指向性ヒトポリオーマウイルスの関連性について検討している。 これまでに、木村病のパラフィン包埋組織からヒトポリオーマウイルス6型のDNAが高率に検出されることを見出した。そこで、ヒトポリオーマウイルス6型のゲノムが検出された症例において、木村病組織でウイルス抗原の発現が認められるかを調べた。ヒトポリオーマウイルス6型のST（small T）抗原に反応する抗体を用いて免疫染色をおこなった。その結果、一部の症例において散在するリンパ球の核および細胞質に陽性所見が認められた。一方、ヒトポリオーマウイルス6型DNA陰性の木村病では調べた全例でこの抗体との反応性はみられなかった。またアイソタイプを一致させた陰性コントロール抗体においても反応はなかった。ヒトポリオーマウイルス6型DNAの検出のみならず、ウイルス抗原の発現が認められたことは、ヒトポリオーマウイルス6型が一部の木村病の発症や病態修飾に関与することを示唆するものである。
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 樋口 智紀; 橋田 裕美子; 大畑 雅典
     
    皮膚T細胞腫瘍には、皮膚T細胞リンパ腫（CTCL）や皮膚病変を呈する成人T細胞白血病/リンパ腫（ATL）も含まれる。現在、抗CCR4抗体薬やヒストン脱アセチル化酵素阻害薬はATLやCTCLなどの難治性皮膚T細胞腫瘍で治療が奏功しているが、これら腫瘍の高い治療抵抗性や予後改善に向けた早期診断など、未だ臨床上の大きな課題が残されている。治療抵抗性などの特性は腫瘍細胞集団中に存在する少数の腫瘍細胞で構成されることが考えられ、皮膚T細胞腫瘍の臨床上の問題解決には単一細胞レベルでの難治化特性の把握が重要な課題となる。 細胞分裂の制御で重要な分裂期キナーゼの1つであるPolo-like kinase 1（PLK1）の過剰発現は胃がんや乳がん、肝臓がんなど様々な悪性腫瘍で報告され、腫瘍細胞の生存・増殖の促進や放射線治療・化学療法への強い抵抗性に深く関与する。昨年度、我々はPLK1の発現解析を行った結果、ATL細胞株および悪性度がより高い患者末梢血細胞においてその過剰発現が認められ、ATLの進展とPLK1の発現異常に関連性があることが示唆された。そこで本年度は、PLK1の発現異常とATL細胞の増殖・生存への関連性を示すため、siRNAによるPLK1発現抑制系を用いた細胞増殖アッセイを行った。その結果、ATL細胞株におけるPLK1の発現低下は有意な細胞増殖抑制を示した。また、この細胞増殖抑制はATL細胞のアポトーシス誘導と細胞周期におけるG2/M期の停止が原因であることが明らかとなった。したがって、PLK1はATL細胞の増殖・生存に寄与し、ATLの新規治療標的となる可能性が示唆された。
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 樋口 智紀
     
    悪性リンパ腫の発症には、ウイルス感染やそれに伴う慢性炎症が関与することが多い。びまん性大細胞型B細胞リンパ腫（diffuse large B-cell lymphoma, DLBCL）の中でも「DLBCL associated with chronic inflammation（DLBCL-CI）」というカテゴリーが設けられている。DLBCL-CIの多くはEpstein-Barr ウイルス（EBウイルス）感染を伴い、そのウイルス感染と長期的な慢性炎症が腫瘍の発生と密接に関連する。EBウイルスが関わる悪性リンパ腫の中には明確な免疫不全をもたらす基礎疾患を背景にもたない免疫適格患者においても発症することがある。 本研究では、一連のケモカイン/ケモカイン受容体分子の発現がDLBCL-CIの病態形成にどのように関わっているかを検討している。DLBCL-CIのプロトタイプである膿胸関連リンパ腫に焦点を当て、これまでに膿胸関連リンパ腫細胞株においてサイトカイン発現解析を行った。びまん性大細胞型B細胞リンパ腫細胞株に比べてCXCR3リガンドであるCXCL9やCXCL10、CCR5リガンドであるCCL3、CCL4およびCCL5、CCR4リガンドであるCCL17やCCL22などのケモカインの発現が強く認められることが明らかになった。一方、膿胸関連リンパ腫細胞株におけるケモカインレセプター発現解析では、CXCR2、CXCR4、CCR6、CCR7、CCR10などが高発現していた。
  • 好酸球性皮膚炎症疾患の誘因および病態に関与する新規ウイルスの探求
    公益財団法人 武田科学振興財団：2020年度「医学系研究助成」
    研究期間 : 2020年09月 -2022年03月 
    代表者 : 樋口智紀
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 谷口 亜裕子; 樋口 智紀; 大畑 雅典
     
    B細胞腫瘍患者におけるCD20発現の陰性化はリツキシマブなどの抗CD20抗体治療の効果が十分に得られないことを意味し、患者予後不良に直結する重要な問題である。CD20陰性B細胞リンパ腫には抗CD20抗体治療後にCD20陰性化するリンパ腫と初診時からCD20発現が認められないリンパ腫の二通りがある。これらについてこれまでに明らかにされていないCD20陰転化機序の解明につながる手がかりをつかむことを目的にした。 我々は、CD20陽性B細胞リンパ腫患者から、リツキシマブ投与前および投与後に耐性になった2つのリンパ腫細胞株(P20とN20)の樹立に成功した。P20細胞株はCD20陽性であるが、N20細胞株のCD20は陰転していた。両細胞株は同一患者より樹立された同一クローン細胞由来であることが証明されており、CD20陽性からのCD20陰転化機序の解明に有用なペアBリンパ腫細胞株である。 解析の結果、N20細胞株のCD20ゲノム自体が欠落していることが判明した。そこで、CD20遺伝子の7つのエクソン領域にそれぞれプライマーを設定し、定量的リアルタイムPCR(qPCR)で各々のゲノム量を測定した。解析した全てのCD20遺伝子エクソン領域の欠損がみられた。しかし、N20の初期培養細胞の解析では、他のエクソン領域に比べて、エクソン8領域ゲノムがわずかながら残存していたことから、CD20でも欠損しやすい領域があることが示唆された。
  • 文部科学省：科学研究費補助金（基盤研究（C)）・分担
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 谷口 亜裕子
     
    B細胞腫瘍患者におけるCD20発現の陰性化はリツキシマブなどの抗CD20抗体治療の効果が十分に得られないことを意味し、患者予後不良に直結する重要な問題である。CD20陰性B細胞リンパ腫には抗CD20抗体治療後にCD20陰性化するリンパ腫と初診時からCD20発現が認められないリンパ腫の二通りがある。これらについてこれまでに明らかにされていないCD20陰転化機序の解明に取り組み、CD20陰性化を早期に発見できる検査法の開発に向けての基盤を作るとともに、予後不良であるCD20陰性B細胞リンパ腫に対峙できる新規治療戦略につながる手がかりをつかむ。
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 樋口 智紀; 橋田 裕美子; 大畑 雅典
     
    がん治療で用いられる広域的なHDAC阻害薬は重篤な副作用の問題を抱えているため、治療に有用なHDAC選択的な分子基盤の解明が必要となる。本研究では、難治性皮膚T細胞リンパ腫である成人T細胞白血病/リンパ腫（ATL）でHDAC4が高発現し、ATL細胞の増殖に関与することを見出した。また、ATL細胞株にHDAC4選択的阻害薬を処理すると、アポトーシス誘導によって細胞増殖を抑制することも明らかにした。したがって、これらの知見はHDAC4がATLの腫瘍形成において重要な役割をもつことを示し、個別化医療を視野に入れた難治性皮膚T細胞リンパ腫でのHDAC選択的な治療戦略において有用な情報を提供する。
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 大畑 雅典; 松崎 茂展; 樋口 智紀; 橋田 裕美子
     
    悪性リンパ腫の発症には、ウイルスなどの微生物感染や慢性炎症が関与することが多い。その多くはEpstein-Barr（EB）ウイルス感染を伴い、その感染と長期的な慢性炎症が腫瘍化と密接に関連する。 今回、慢性炎症関連EBウイルス陽性リンパ腫細胞はケモカインCCL12とCCL22を発現し、その受容体であるCCR4陽性制御性T（Treg）細胞を自らの腫瘍部位におびき寄せることを見出した。免疫を抑制する働きのあるTreg細胞を腫瘍部位に遊走させることで、腫瘍が免疫の監視から逃れてがん化を促進することが示唆された。
  • 文部科学省：科学研究費補助金（基盤研究（C)）・分担
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 大畑 雅典
  • 文部科学省：科学研究費補助金（基盤研究（C)）
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 樋口 智紀
     
    分子標的薬の登場・発展に伴い、患者個々の薬効の違いなどが明らかになり、癌医療は個別化医療へと進みつつある。個別化医療の実現には、治療効果の予測や適切な薬剤・治療選択、予後予測に用いるバイオマーカーの発見が必要不可欠である。これまでに、我々はFra-2-SOX4経路の下流遺伝子としてヒストン脱アセチル化酵素（HDAC）の１つであるHDAC8が存在し、HDAC8がATL細胞の増殖・生存に寄与することを明らかにした。HDACファミリーは悪性腫瘍をはじめとする病態と関連することが知られており、実際にCTCLをはじめ、HDAC阻害薬を用いた癌治療戦略が飛躍的な進展をみせている。しかしながら、多種多様なHDACアイソザイムの存在は、広域作用性である既存のHDAC阻害薬の重篤な副作用を生じさせる治療上の問題となっている。したがって、HDACアイソザイム選択的な治療に有用な分子基盤の解明が必要となる。本研究では、HDACアイソザイム選択的な皮膚T細胞腫瘍の発癌に与える影響や個別化医療を意識した新たな治療戦略および診断に有用な因子を見出すことを目的としている。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 義江 修; 中山 隆志; 角田 郁生; 樋口 智紀; 金井 亨輔; 藤田 貢
     
    CCL28遺伝子欠損マウスでは、大腸粘膜でのIgA産生細胞の減少と分布異常、糞便中のIgA量の著明な減少、および個々のIgA産生細胞のIgA産生量の低下が見いだされ、CCL28は大腸粘膜でのIgA産生に重要な役割を担っていることが確認された。さらにCCL28遺伝子欠損マウスの糞便ではバシラス綱が相対的に増加していた。大腸でのIgA産生量の低下と細菌叢の変化と関連して、CCL28遺伝子欠損マウスではデキストラン硫酸誘発腸炎の増悪が見られ、それは抗菌薬投与で軽減された。
  • 文部科学省：科学研究費補助金(基盤研究(C))
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 樋口 智紀
  • 文部科学省：科学研究費補助金(基盤研究(C))
    研究期間 : 2011年04月 -2014年03月 
    代表者 : 樋口 智紀; 義江 修; 中山 隆志
     
    これまでに我々は、成人T細胞白血病/リンパ腫（ATL）や皮膚T細胞リンパ腫（CTCL)でFra-2が一貫して発現し、CCR4発現誘導や細胞増殖に関与することを明らかにしてきた。本研究では、ATLとCTCL発癌におけるSOX4発現とその役割について検討した結果、ATLとCTCLにおいて、Fra-2-JunDが直接SOX4の転写活性を促進し、SOX4下流標的遺伝子として見出したGCKR、NAP1、HDAC8を発現誘導することでこれらの腫瘍の細胞増殖能を高めることを明らかにした。したがって、これらの知見からFra-2-SOX4経路はATLとCTCL発癌において重要な役割を有することが示唆された。
  • 文部科学省：科学研究費補助金(基盤研究(C))・分担
    研究期間 : 2011年04月 -2014年03月 
    代表者 : 中山 隆志; 義江 修; 樋口 智紀
     
    本研究において研究代表者は、成熟T細胞リンパ腫での新規c-Myb標的遺伝子として薬物トランスポーターABCG2/BCRPを同定した。c-MybとABCG2/BCRPは、成熟T細胞リンパ腫において共発現することが確認された。さらにABCG2/BCRP特異的阻害剤であるKo143は、ドキソルビシンのATLL細胞株に対する抗腫瘍活性を優位に促進した。これらの結果より、c-Myb-ABCG2/BCRP経路は成熟T細胞リンパ腫の抗がん剤耐性機構において重要な役割を果たすことが示唆された。
  • 文部科学省：科学研究費補助金(基盤研究(C))・分担
    研究期間 : 2011年 -2013年 
    代表者 : 義江 修; 中山 隆志; 樋口 智紀
     
    我々は、成人T細胞白血病/リンパ腫（ATL）でのCCR4発現に関わる転写因子としてAP-1ファミリーのFRA-2を同定し、FRA-2はJUNDと共同してATLの増殖を促進するとともにc-Myb、SOX4などの原癌遺伝子の発現を誘導することを明らかにした。本研究では、ATLおよび皮膚T細胞リンパ腫（CTCL）でのCCR7発現に関与する転写因子を検討し、新規DNA結合配列GAGGAGを同定し、その部位にはZFYVE19が結合することを明らかにした。本研究から、ATLやCTCLでの新たな発がん遺伝子カスケードの存在が示唆され、これらの成熟型T細胞性腫瘍の診断や治療に有用な情報が提供された。

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