研究者詳細 - 大塚　基之

論文 - 大塚　基之

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HBx-induced degradation of Smc5/6 complex impairs homologous recombination-mediated repair of damaged DNA. 査読国際誌

Kazuma Sekiba, Motoyuki Otsuka, Kazuyoshi Funato, Yu Miyakawa, Eri Tanaka, Takahiro Seimiya, Mari Yamagami, Takeya Tsutsumi, Kazuya Okushin, Kei Miyakawa, Akihide Ryo, Kazuhiko Koike

Journal of hepatology 76 ( 1 ) 53 - 62 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND & AIMS: Hepatitis B virus (HBV) causes hepatocellular carcinoma (HCC). While the need for HBV regulatory protein X (HBx) for viral transcription via impairment of the structural maintenance of chromosome 5/6 (Smc5/6) complex was recently demonstrated, HBx is also a potent driver of HCC. However, the mechanism by which HBx expression induces hepatocarcinogenesis is unclear. METHODS: Degradation of Smc5/6 complex and accumulation of DNA damage were observed in both in vivo and in vitro HBV infection models. Rescue experiments were performed using nitazoxanide (NTZ), which inhibits degradation of the Smc5/6 complex by HBx. RESULTS: Degradation of the Smc5/6 complex triggered by HBx impaired homologous recombination (HR) repair of DNA double-strand breaks (DSBs), leading to cellular transformation. We found that DNA damage accumulated in the liver tissue of HBV-infected humanized chimeric mice, HBx-transgenic mice, and human tissues. HBx suppressed the HR repair of DSBs, including that induced by the clustered regularly interspaced short palindromic repeats-Cas9 system, in an Smc5/6-dependent manner, which was rescued by restoring the Smc5/6 complex. NTZ restored HR repair in, and colony formation by, HBx-expressing cells. CONCLUSIONS: Degradation of the Smc5/6 complex by HBx increases viral transcription and promotes cellular transformation by impairing HR repair of DSBs. LAY SUMMARY: HBV regulatory protein X (HBx) degrades the structural maintenance of chromosome 5/6 (Smc5/6) complex, which is required for viral replication. We found that degradation of the Smc5/6 complex also plays a key role in the accumulation of DNA damage, as well as in HBx-mediated tumorigenesis.

DOI： 10.1016/j.jhep.2021.08.010

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Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals. 査読国際誌

Tatsuya Minami, Ryosuke Tateishi, Naoto Fujiwara, Ryo Nakagomi, Takuma Nakatsuka, Masaya Sato, Koji Uchino, Kenichiro Enooku, Hayato Nakagawa, Hidetaka Fujinaga, Masashi Izumiya, Kazuyuki Hanajiri, Yoshinari Asaoka, Yuji Kondo, Yasuo Tanaka, Motoyuki Otsuka, Takamasa Ohki, Masahiro Arai, Atsushi Tanaka, Kiyomi Yasuda, Hideaki Miura, Itsuro Ogata, Toshiro Kamoshida, Kazuaki Inoue, Yukihiro Koike, Masatoshi Akamatsu, Hiroshi Mitsui, Hajime Fujie, Keiji Ogura, Hideo Yoshida, Tomonori Wada, Kiyohiko Kurai, Hisato Maekawa, Shuntaro Obi, Takuma Teratani, Naohiko Masaki, Kayo Nagashima, Takashi Ishikawa, Naoya Kato, Kyoji Moriya, Hiroshi Yotsuyanagi, Kazuhiko Koike

Liver cancer 10 ( 4 ) 309 - 319 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and Aims: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. Methods: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. Results: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51-4.25) and 2.56 (95% CI: 1.14-5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61-2.33). Conclusions: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.

DOI： 10.1159/000513705

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Aberrant expression of a novel circular RNA in pancreatic cancer. 査読国際誌

Takahiro Seimiya, Motoyuki Otsuka, Takuma Iwata, Eri Tanaka, Kazuma Sekiba, Chikako Shibata, Masaru Moriyama, Ryo Nakagawa, Reo Maruyama, Kazuhiko Koike

Journal of human genetics 66 ( 2 ) 181 - 191 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules that are produced from pre-mRNAs through a process known as back-splicing. Although circRNAs are expressed under specific conditions, current understanding of their comprehensive expression status is still limited. Here, we performed a large-scale circRNA profiling analysis in human pancreatic ductal adenocarcinoma (PDAC) tissues, using circular RNA-specific RNA sequencing. We identified more than 40,000 previously unknown circRNAs, some of which were upregulated in PDAC tissues, compared with normal pancreatic tissues. We determined the full-length sequence of a circRNA upregulated in PDAC, which was derived from two noncoding RNA loci on chromosome 12. The novel circRNA, named circPDAC RNA, was not expressed in normal human cells, but was expressed in PDAC and other carcinoma cells. While postulated biological functions, such as peptide production from the circPDAC RNA, were not detected, its aberrant expression was confirmed in other PDAC tissues and in serum from a PDAC patient. These results demonstrate that comprehensive studies are necessary to reveal the expression status of circRNAs and that the circPDAC RNA identified here might serve as a novel biomarker for cancers, including PDAC.

DOI： 10.1038/s10038-020-00826-5

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Should Level of HBV RNA be Used to Determine When Patients Should Stop Treatment With Nucleos(t)ide Analogues. 査読国際誌

Motoyuki Otsuka, Kazuhiko Koike

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 18 ( 3 ) 551 - 552 2020年3月

Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus. 査読国際誌

Kazuma Sekiba, Motoyuki Otsuka, Motoko Ohno, Mari Yamagami, Takahiro Kishikawa, Takahiro Seimiya, Tatsunori Suzuki, Eri Tanaka, Rei Ishibashi, Kazuyoshi Funato, Kazuhiko Koike

Hepatology (Baltimore, Md.) 69 ( 5 ) 1903 - 1915 2019年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hepatitis B virus (HBV) infection is a major health concern worldwide. To prevent HBV-related mortality, elimination of viral proteins is considered the ultimate goal of HBV treatment; however, currently available nucleos(t)ide analogs rarely achieve this goal, as viral transcription from episomal viral covalently closed circular DNA (cccDNA) is not prevented. HBV regulatory protein X was recently found to target the protein structural maintenance of chromosomes 5/6 (Smc5/6) for ubiquitination and degradation by DDB1-CUL4-ROC1 E3 ligase, resulting in enhanced viral transcription from cccDNA. This ubiquitin-dependent proteasomal pathway requires an additional ubiquitin-like protein for activation, neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8). Here, we show that pevonedistat, a NEDD8-activating enzyme inhibitor, works efficiently as an antiviral agent. Pevonedistat significantly restored Smc5/6 protein levels and suppressed viral transcription and protein production in the HBV minicircle system in in vitro HBV replication models and in human primary hepatocytes infected naturally with HBV. Conclusion: These results indicate that pevonedistat is a promising compound to treat chronic HBV infection.

DOI： 10.1002/hep.30491

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Repression of MicroRNA Function Mediates Inflammation-associated Colon Tumorigenesis 査読

Takeshi Yoshikawa, Jianfeng Wu, Motoyuki Otsuka, Takahiro Kishikawa, Nobumi Suzuki, Akemi Takata, Motoko Ohno, Rei Ishibashi, Mari Yamagami, Ryo Nakagawa, Naoya Kato, Masaaki Miyazawa, Jiahuai Han, Kazuhiko Koike

Gastroenterology 152 ( 3 ) 631 - 643 2017年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO-ELSEVIER INC

BACKGROUND & AIMS: Little is known about the mechanisms by which chronic inflammation contributes to carcinogenesis, such as the development of colon tumors in patients with inflammatory bowel diseases. Specific microRNA (miRNAs) can function as suppressors or oncogenes, and widespread alterations in miRNA expression have been associated with tumorigenesis. We studied whether alterations in miRNA function contribute to inflammation-associated colon carcinogenesis. METHODS: We studied the effects of inflammatory cytokines, such as tumor necrosis factor, interleukin-1 alpha (IL1A), and IL1 beta (IL1B), on miRNA function, measured by activity of reporter constructs containing miRNA-binding sites in their 30 untranslated regions, in human 293T embryonic kidney, Caco-2, HT29, and HCT116 colon carcinoma cells, as well as dicer(+/+) and dicer(-/-), and Apobec3(+/+) and Apobec3(-/-) mouse embryonic fibroblasts. Cells were analyzed by immunoblots, immunohistochemistry, and flow cytometry. We generated transgenic mice expressing reporter constructs regulated by LET7B, MIR122, and MIR29b response elements; some mice were given injections of miRNA inhibitors (anti-MIR122 or anti-LET7B), a negative control, or tumor necrosis factor. Liver tissues were collected and analyzed by immunoblotting. Reporter mice were given azoxymethane followed by dextran sulfate sodium to induce colitis and colon tumors; some mice were given the ROCK inhibitor fasudil along with these agents (ROCK inhibitors increase miRNA function). Colon tissues were collected and analyzed by immunohistochemistry, immunoblots, and fluorescence microscopy. RESULTS: Incubation of cell lines with inflammatory cytokines reduced the ability of miRNAs to down-regulate expression from reporter constructs; dicer was required for this effect, so these cytokines relieve miRNA-dependent reductions in expression. The cytokines promoted degradation of APOBEC3G, which normally promotes miRNA loading into argonaute 2-related complexes. Mice with colitis had reduced miRNA function, based on increased expression of reporter genes. Administration of fasudil to mice did not reduce the severity of colitis that developed but greatly reduced the numbers of colon tumors formed (mean 2 tumors/colon in mice given fasudil vs 9 tumors/colon in mice given control agent). We made similar observations in IL10-deficient mice. CONCLUSIONS: We found inflammatory cytokines to reduce the activities of miRNAs. In mice with colitis, activities of miRNAs are reduced; administration of an agent that increases miRNA function prevents colon tumor formation in these mice. This pathway might be targeted to prevent colon carcinogenesis in patients with inflammatory bowel diseases.

DOI： 10.1053/j.gastro.2016.10.043

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Satellite RNAs promote pancreatic oncogenic processes via the dysfunction of YBX1 査読

Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Hideaki Ijichi, Kazuhiko Koike

Nature Communications 7 ( 1 ) 13006 2016年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Nature

Highly repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered silent, are actively transcribed, particularly in cancer. This aberrant expression occurs even in K-ras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To examine the biological roles of the satellite RNAs in carcinogenesis, we construct mouse PanIN-derived cells expressing major satellite (MajSAT) RNA and show increased malignant properties. We find an increase in frequency of chromosomal instability and point mutations in both genomic and mitochondrial DNA. We identify Y-box binding protein 1 (YBX1) as a protein that binds to MajSAT RNA. MajSAT RNA inhibits the nuclear translocation of YBX1 under stress conditions, thus reducing its DNA-damage repair function. The forced expression of YBX1 significantly decreases the aberrant phenotypes. These findings indicate that during the early stage of cancer development, satellite transcripts may act as 'intrinsic mutagens' by inducing YBX1 dysfunction, which may be crucial in oncogenic processes.

DOI： 10.1038/ncomms13006

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Quantitation of circulating satellite RNAs in pancreatic cancer patients. 査読国際誌

Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Keisuke Yamamoto, Natsuyo Yamamoto, Ai Kotani, Kazuhiko Koike

JCI insight 1 ( 8 ) e86646 2016年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pancreatic ductal adenocarcinoma (Pdac) is a malignancy with a poor prognosis due to difficulties in early detection. Although promising biomarkers are increasingly reported, such methods are not yet easy to apply clinically, mainly due to their low reproducibility or technical difficulties. In this study, we developed a convenient and sensitive method for quantifying aberrantly expressed satellite repeat RNAs in sera, which can be used to efficiently detect patients with Pdac. Here, we introduce a Tandem Repeat Amplification by nuclease Protection (TRAP) method combined with droplet digital PCR (ddPCR) to detect human satellite II (HSATII) RNAs, which are specifically expressed in human Pdacs at greater levels than normal tissues but are difficult to measure due to their repetitive sequences and irregularities. HSATII RNA core sequence levels in sera were significantly higher in Pdac patients compared with noncancer patients (median copy number: 14.75 and 3.17 per μl in the training set and 17.35 and 2.9 in the validation set, respectively). In addition, patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous lesion of Pdac, could also be efficiently detected. This method can be routinely applied to screen patients with Pdac and high-risk patients, facilitating the development of preventive medicine for this disease.

DOI： 10.1172/jci.insight.86646

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Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling 査読

Young Jun Kang, Bo-Ram Bang, Kyung Ho Han, Lixin Hong, Eun-Jin Shim, Jianhui Ma, Richard A. Lerner, Motoyuki Otsuka

Nature Communications 6 ( 1 ) 8371 2015年12月

The TNF Family Member 4-1BBL Sustains Inflammation by Interacting with TLR Signaling Components During Late-Phase Activation 査読

Jianhui Ma, Bo-Ram Bang, Jiawei Lu, So-Young Eun, Motoyuki Otsuka, Michael Croft, Peter Tobias, Jiahuai Han, Osamu Takeuchi, Shizuo Akira, Michael Karin, Hideo Yagita, Young Jun Kang

Science Signaling 6 ( 295 ) ra87 2013年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC ADVANCEMENT SCIENCE

Activation of Toll-like receptor (TLR)-dependent signaling leads to the expression of genes encoding proinflammatory factors, such as tumor necrosis factor-alpha (TNF-alpha), and this proinflammatory gene expression is sustained for the duration of the inflammatory response. TLR4-mediated inflammation, which occurs in two phases, depends on the TNF family member 4-1BB ligand (4-1BBL) to sustain TNF-alpha production during late-phase signaling. We showed that Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP) and the kinase IRAK2 interacted with 4-1BBL to mediate late-phase TLR4 signaling. Expression of 4-1bbl depended on early TLR4 signaling that also induced Tnf expression, and 4-1BBL translocated to the plasma membrane, where it interacted with TLR4 to mediate late-phase signaling. TLR4-4-1BBL-mediated signaling depended on TIRAP and IRAK2, as well as a complex consisting of the E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6), the kinase TAK1 (transforming growth factor-beta-activated kinase 1), and the adaptor protein TAB1 (TAK-binding protein 1). Inhibition of this late-phase pathway reduced the extent of TNF-alpha production by mouse macrophages exposed to the TLR4 ligand lipopolysaccharide (LPS) and ameliorated LPS-induced sepsis in mice. Together, these data suggest that TIRAP and IRAK2 are critical for the sustained inflammatory response that is mediated by late-phase signaling by the TLR-4-1BBL complex.

DOI： 10.1126/scisignal.2004431

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Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease. 査読

Soga T, Sugimoto M, Honma M, Mori M, Igarashi K, Kashikura K, Ikeda S, Hirayama A, Yamamoto T, Yoshida H, Otsuka M, Tsuji S, Yatomi Y, Sakuragawa T, Watanabe H, Nihei K, Saito T, Kawata S, Suzuki H, Tomita M, Suematsu M

Journal of Hepatology 55 ( 4 ) 896 - 905 2011年10月

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma. 査読

Kojima K, Takata A, Vadnais C, Otsuka M, Yoshikawa T, Akanuma M, Kondo Y, Kang YJ, Kishikawa T, Kato N, Xie Z, Zhang WJ, Yoshida H, Omata M, Nepveu A, Koike K

Nature Communications 2 338 2011年6月

Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma 査読

Nature Genetics 43 ( 5 ) 455 - + 2011年5月

Distinct Effects of p38 alpha Deletion in Myeloid Lineage and Gut Epithelia in Mouse Models of Inflammatory Bowel Disease 査読

Gastroenterology 138 ( 4 ) 1255 - U83 2010年4月

Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice 査読

Journal of Clinical Investigation 118 ( 5 ) 1944 - 1954 2008年5月

Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression 査読

Immunity 27 ( 1 ) 123 - 134 2007年7月

Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages 査読

Nature Immunology 8 ( 6 ) 601 - 609 2007年6月

Acetic Acid-Indigo Carmine Chromocolonoscopy for Proximal Serrated Lesions: A Randomized, Three-Arm Colonoscopy Study. 国際誌

Hideaki Kinugasa, Sakiko Hiraoka, Sayo Kobayashi, Minoru Matsubara, Teruya Nagahara, Reiji Higashi, Kensuke Takei, Masayasu Ohmori, Takashi Nakamura, Takao Tsuzuki, Shouichi Tanaka, Ryosuke Hirai, Junki Toyosawa, Yuki Aoyama, Yasushi Yamasaki, Toshihiro Inokuchi, Masahiro Takahara, Takehiro Tanaka, Toshiharu Mitsuhashi, Motoyuki Otsuka

The American journal of gastroenterology 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Aggressive colorectal cancer (CRC) frequently originates from serrated lesions (SLs), particularly in the proximal colon, which are challenging to detect using standard screening colonoscopy. Although duplicate examinations or chromocolonoscopies are recommended for detecting proximal SLs, evidence from randomized trials is limited. We evaluated the effectiveness of tandem colonoscopy with an acetic acid-indigo carmine mixture (AIM) for detecting SLs in the proximal colon compared to white-light imaging (WLI) and indigo carmine (IC). METHODS: This three-arm, multicenter, randomized controlled trial involving nine institutions enrolled patients undergoing colonoscopy and assigned them randomly to the WLI, IC, or AIM group. The primary outcomes were the SL-detection rate (SDR) of proximal lesions during the second examination (SDR2nd) and SL additional rate (SAR). Secondary outcomes included the detection and additional rates of other polyps, factors contributing to SAR, and complications. RESULTS: Between 2021 and 2024, 1,319 participants with 1,267 polyps were included in the analysis. With AIM, the SDR2nd and SAR were significantly higher compared to WLI or IC (WLI vs. AIM: 2.7% vs. 14.0%, p<.001; IC vs. AIM: 7.9% vs. 14.0%, p=.002, and WLI vs. AIM: 22.4% vs. 69.3%, p<.001; IC vs. AIM: 45.8% vs. 69.3%, p=.001). AIM conferred a higher adenoma-detection rate (ADR)2nd than with WLI (10.5% vs. 24.7%; p<.001) and was an independent factor for SAR (odds ratio [95% confidence interval]: 7.79 [3.76-17.08]). No major adverse events were observed. CONCLUSIONS: AIM significantly improved proximal colon SDRs and outperformed WLI and IC. The relationship between SDR and CRC incidence warrants further investigation.

DOI： 10.14309/ajg.0000000000003411

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Unraveling a Rare Case: Diarrhea, Alopecia, and Polyposis. 国際誌

Hidetaka Mizushima, Hideaki Kinugasa, Motoyuki Otsuka

Gastroenterology 2025年2月

Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis. 国際誌

Yuki Aoyama, Sakiko Hiraoka, Eriko Yasutomi, Toshihiro Inokuchi, Takehiro Tanaka, Kensuke Takei, Shoko Igawa, Keiko Takeuchi, Masahiro Takahara, Junki Toyosawa, Yasushi Yamasaki, Hideaki Kinugasa, Jun Kato, Hiroyuki Okada, Motoyuki Otsuka

Scientific reports 15 ( 1 ) 5248 - 5248 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Leucine-rich alpha 2 glycoprotein (LRG) is one of the serum biomarkers for disease activity of ulcerative colitis (UC). We focused on the correlation between the changes of LRG and the changes of endoscopic and histologic activity of UC, in comparison to the changes of fecal calprotectin (Fcal), fecal immunochemical test (FIT), and C-reactive protein (CRP). Seventy-nine patients with two or more colonoscopies were enrolled, and 123 paired colonoscopies and 121 paired biopsies were examined. With regard to the change of endoscopic/histologic activity between the preceding and subsequent colonoscopy, there was improvement (n = 29/45), unchanging (n = 63/36), and worsening (n = 31/40). The correlations between the changes of marker levels and endoscopic/histologic activity were Fcal; r = 0.50/0.39 and FIT; r = 0.41/0.40, LRG; r = 0.42/0.40 and CRP; r = 0.22/0.17. Furthermore, when the correlation between the changes of LRG levels and the changes of endoscopic/histological activity was compared with those of other markers, the correlation of LRG tended to be superior to those of CRP (CRP vs. LRG; p = 0.08/0.01). LRG is equivalent to fecal markers and superior to CRP, when inferring changes in disease activity of UC based on changes in its level.

DOI： 10.1038/s41598-025-89615-8

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