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| 1.
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論文
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Watashi, Koichi ; Liang, Guoxin ; Iwamoto, Masashi ; Marusawa, Hiroyuki ; Uchida, Nanako ; Daito, Takuji ; Kitamura, Kouichi ; Muramatsu, Masamichi ; Ohashi, Hirofumi ; Kiyohara, Tomoko ; Suzuki, Ryosuke ; Li, Jisu ; Tong, Shuping ; Tanaka, Yasuhito ; Murata, Kazumoto ; Aizaki, Hideki ; Wakita, Takaji ; 喜多村, 晃一 ; 村松, 正道
概要:
金沢大学医薬保健研究域医学系<br />Virus infection is restricted by intracellular immune responses in host cells, and this is typically
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modulated by stimulation of cytokines. The cytokines and host factors that determine the host cell restriction against hepatitis B virus (HBV) infection are not well understood. We screened 36 cytokines and chemokines to determine which were able to reduce the susceptibility of HepaRG cells to HBV infection. Here, we found that pretreatment with IL-1β and TNFα remarkably reduced the host cell susceptibility to HBV infection. This effect was mediated by activation of the NF-κB signaling pathway. A cytidine deaminase, activation-induced cytidine deaminase (AID), was up-regulated by both IL-1β and TNFα in a variety of hepatocyte cell lines and primary human hepatocytes. Another deaminase APOBEC3G was not induced by these proinflammatory cytokines. Knockdown of AID expression impaired the anti-HBV effect of IL-1β, and overexpression of AID antagonized HBV infection, suggesting that AID was one of the responsible factors for the anti-HBV activity of IL-1/TNFα. Although AID induced hypermutation of HBV DNA, this activity was dispensable for the anti-HBV activity. The antiviral effect of IL-1/TNFα was also observed on different HBV genotypes but not on hepatitis C virus. These results demonstrate that proinflammatory cytokines IL-1/TNFα trigger a novel antiviral mechanism involving AID to regulate host cell permissiveness to HBV infection.
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| 2.
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Nakanishi, Yosuke ; Kondo, Satoru ; Wakisaka, Naohiro ; Tsuji, Akira ; Endo, Kazuhira ; Murono, Shigeyuki ; Ito, Makoto ; Kitamura, Kouichi ; Muramatsu, Masamichi ; Yoshizaki, Tomokazu ; 近藤, 悟 ; 脇坂, 尚宏 ; 辻, 亮 ; 遠藤, 一平 ; 室野, 重之 ; 喜多村, 晃一 ; 村松, 正道 ; 吉崎, 智一
概要:
金沢大学医薬保健研究域医学系<br />Purpose:In humans, activation-induced cytidine deaminase (AID) expression results due to inflammatio
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n and this deaminase activity is also involved in carcinogenesis. The aim of this study is to investigate the correlation between AID expression and the clinical classification of oral cancer tissues.Experimental Design:The current study investigated the correlation between AID expression and the clinical classification of oral cancer tissues from 27 patients who underwent surgical resection using immunohistochemistry. Specific AID expression and its induction by cytokine stimulation were investigated in cultured HSC oral cancer cell lines by reverse transcriptase PCR.Results:AID expression was detected in 10 of 27 specimens (37.0%). AID expression was more frequently detected in early-stage cancer, especially in early stage T, than in late-stage cancer (T1/T2 vs. T3/4; P = 0.0493, N0 vs. N1/2/3; P = 0.0793). HSC-2, a nonmetastatic oral cancer cell line, abundantly expressed endogenous AID, whereas no such expression was observed in HSC-3, a metastatic oral cancer cell line. Moreover, AID expression was substantially induced in HSC-2 cells by stimulation of an inflammation-related cytokine, TNF-α.Conclusions:Aberrant AID expression in the oral epithelium would contribute to the initiation of oral squamous cell carcinoma. Avoiding persistent AID inducible condition such as frequent cleaning of oral cavity would play an important role for the prevention of developing oral cancer. © 2013 Nakanishi et al.
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| 3.
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論文
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Seishima, Noriko ; Kondo, Satoru ; Wakaea, Kousho ; Wakisaka, Naohiro ; Kobayashi, Eiji ; Kano, Makoto ; Moriyama-Kita, Makiko ; Nakanishi, Yosuke ; Endo, Kazuhira ; Imoto, Tomoko ; Ishikawa, Kazuya ; Sugimoto, Hisashi ; Hatano, Miyako ; Ueno, Takayoshi ; Koura, Miki ; Kitamura, Kouichi ; Muramatsu, Masamichi ; Yoshizaki, Tomokazu ; 近藤, 悟 ; 脇坂, 尚宏 ; 喜多, 万紀子 ; 遠藤, 一平 ; 波多野, 都 ; 小浦, 美樹 ; 喜多村, 晃一 ; 村松, 正道 ; 吉崎, 智一
概要:
金沢大学医薬保健研究域医学系<br />Activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA-editing catalytic polypeptide
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3 (A3) family are cytidine deaminases that play critical roles in B-cell maturation, antiviral immunity and carcinogenesis. Adenoids and palatine tonsils are secondary lymphoid immune organs, in which AID and A3s are thought to have several physiological or pathological roles. However, the expression of AID or A3s in these organs has not been investigated. Therefore, we investigated the expression profiles of AID and A3s, using 67 samples of adenoids and palatine tonsils from patients, with reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical analyses. AID and A3s expression levels in the adenoids and the palatine tonsils of the same individual significantly correlated with each other. Of note, AID expression level in the adenoids negatively correlated with the age (r = −0.373, P = 0.003). The younger group with adenoid vegetation and tonsillar hypertrophy showed more abundant AID expression than the older group with recurrent tonsillitis and peritonsillar abscesses (P = 0.026). Moreover, immunohistochemical analysis revealed the distribution of AID and A3s in the epithelial cells as well as germinal centres. The localisation of AID expression and its relation to age may contribute to adenoid vegetation and inflammation.<br />Ministry of Education, Culture, Sports, Science and Technology B23390396,A24689064
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| 4.
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Wakaea, Kousho ; Nishiyama, Tomoaki ; Kondo, Satoru ; Izuka, Takashi ; Que, Lusheng ; Chen, Cong ; Kase, Kina ; Kitamura, Kouichi ; Md , Monjurul ; Wang, Zhe ; Ahasan, Md Monjurul ; Nakamura, Mitsuhiro ; Fujiwara, Hiroshi ; Yoshizaki, Tomokazu ; Hosomochi, Kazuyoshi ; Tajima, Atsushi ; Nakahara, Tomomi ; Kiyono, Tohru ; Muramatsu, Masamichi ; 西山, 智明 ; 近藤, 悟 ; 加瀬, 希奈 ; 喜多村, 晃一 ; 中村, 充宏 ; 藤原, 浩 ; 吉崎, 智一 ; 村松, 正道
概要:
金沢大学医薬保健研究域医学系<br />Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved
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in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discussed. © 2018 The Author(s).
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| 5.
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論文
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Kitamura, Kouichi ; Que, Lusheng ; Shimadu, Miyuki ; Koura, Miki ; Ishihara, Yuuki ; Wakaea, Kousho ; Nakamura, Takashi ; Watashi, Koichi ; Wakita, Takaji ; Muramatsu, Masamichi ; 喜多村, 晃一 ; 島津, 美幸 ; 小浦, 美樹 ; 村松, 正道
概要:
金沢大学医薬保健研究域医学系<br />Hepatitis B virus (HBV) is one of the major etiological pathogens for liver cirrhosis and hepatocell
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ular carcinoma. Chronic HBV infection is a key factor in these severe liver diseases. During infection, HBV forms a nuclear viral episome in the form of covalently closed circular DNA (cccDNA). Current therapies are not able to efficiently eliminate cccDNA from infected hepatocytes. cccDNA is a master template for viral replication that is formed by the conversion of its precursor, relaxed circular DNA (rcDNA). However, the host factors critical for cccDNA formation remain to be determined. Here, we assessed whether one potential host factor, flap structure-specific endonuclease 1 (FEN1), is involved in cleavage of the flap-like structure in rcDNA. In a cell culture HBV model (Hep38.7-Tet), expression and activity of FEN1 were reduced by siRNA, shRNA, CRISPR/Cas9-mediated genome editing, and a FEN1 inhibitor. These reductions in FEN1 expression and activity did not affect nucleocapsid DNA (NC-DNA) production, but did reduce cccDNA levels in Hep38.7-Tet cells. Exogenous overexpression of wild-type FEN1 rescued the reduced cccDNA production in FEN1-depleted Hep38.7-Tet cells. Anti-FEN1 immunoprecipitation revealed the binding of FEN1 to HBV DNA. An in vitro FEN activity assay demonstrated cleavage of 5′-flap from a synthesized HBV DNA substrate. Furthermore, cccDNA was generated in vitro when purified rcDNA was incubated with recombinant FEN1, DNA polymerase, and DNA ligase. Importantly, FEN1 was required for the in vitro cccDNA formation assay. These results demonstrate that FEN1 is involved in HBV cccDNA formation in cell culture system, and that FEN1, DNA polymerase, and ligase activities are sufficient to convert rcDNA into cccDNA in vitro.
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