Faculty Profiles - Otsuka Motoyuki

Papers - Otsuka Motoyuki

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HBx-induced degradation of Smc5/6 complex impairs homologous recombination-mediated repair of damaged DNA. Reviewed International journal

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 2021.8

Language：English Publishing type：Research paper (scientific journal)

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

Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals. Reviewed International journal

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 2021.7

Language：English Publishing type：Research paper (scientific journal)

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

Aberrant expression of a novel circular RNA in pancreatic cancer. Reviewed International journal

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 2021.2

Language：English Publishing type：Research paper (scientific journal)

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

Should Level of HBV RNA be Used to Determine When Patients Should Stop Treatment With Nucleos(t)ide Analogues. Reviewed International journal

Motoyuki Otsuka, Kazuhiko Koike

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 18 ( 3 ) 551 - 552 2020.3

Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus. Reviewed International journal

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 2019.5

Language：English Publishing type：Research paper (scientific journal)

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

Repression of MicroRNA Function Mediates Inflammation-associated Colon Tumorigenesis Reviewed

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 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Nature Communications 7 ( 1 ) 13006 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：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

Quantitation of circulating satellite RNAs in pancreatic cancer patients. Reviewed International journal

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

JCI insight 1 ( 8 ) e86646 2016.6

Language：English Publishing type：Research paper (scientific journal)

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

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

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 2015.12

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

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 2013.10

Language：English Publishing type：Research paper (scientific journal) Publisher：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

Serum metabolomics reveals gamma-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease Reviewed

Tomoyoshi Soga, Masahiro Sugimoto, Masashi Honma, Masayo Mori, Kaori Igarashi, Kasumi Kashikura, Satsuki Ikeda, Akiyoshi Hirayama, Takehito Yamamoto, Haruhiko Yoshida, Motoyuki Otsuka, Shoji Tsuji, Yutaka Yatomi, Tadayuki Sakuragawa, Hisayoshi Watanabe, Kouei Nihei, Takafumi Saito, Sumio Kawata, Hiroshi Suzuki, Masaru Tomita, Makoto Suematsu

Journal of Hepatology 55 ( 4 ) 896 - 905 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Background & Aims: We applied a metabolome profiling approach to serum samples obtained from patients with different liver diseases, to discover noninvasive and reliable biomarkers for rapid-screening diagnosis of liver diseases.
Methods: Using capillary electrophoresis and liquid chromatography mass spectrometry, we analyzed low molecular weight metabolites in a total of 248 serum samples obtained from patients with nine types of liver disease and healthy controls.
Results: We found that gamma-glutamyl dipeptides, which were bio-synthesized through a reaction with gamma-glutamylcysteine synthetase, were indicative of the production of reduced glutathione, and that measurement of their levels could distinguish among different liver diseases. Multiple logistic regression models facilitated the discrimination between specific and other liver diseases and yielded high areas under receiver-operating characteristic curves. The area under the curve values in training and independent validation data were 0.952 and 0.967 in healthy controls, 0.817 and 0.849 in drug-induced liver injury, 0.754 and 0.763 in asymptomatic hepatitis B virus infection, 0.820 and 0.762 in chronic hepatitis B, 0.972 and 0.895 in hepatitis C with persistently normal alanine transaminase, 0.917 and 0.707 in chronic hepatitis C, 0.803 and 0.993 in cirrhosis type C, and 0.762 and 0.803 in hepatocellular carcinoma, respectively. Several gamma-glutamyl dipeptides also manifested potential for differentiating between nonalcoholic steatohepatitis and simple steatosis.
Conclusions: gamma-Glutamyl dipeptides are novel biomarkers for liver diseases, and varying levels of individual or groups of these peptides have the power to discriminate among different forms of hepatic disease. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2011.01.031

MicroRNA122 is a key regulator of alpha-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma Reviewed

Kentaro Kojima, Akemi Takata, Charles Vadnais, Motoyuki Otsuka, Takeshi Yoshikawa, Masao Akanuma, Yuji Kondo, Young Jun Kang, Takahiro Kishikawa, Naoya Kato, Zhifang Xie, Weiping J. Zhang, Haruhiko Yoshida, Masao Omata, Alain Nepveu, Kazuhiko Koike

Nature Communications 2 338 2011.6

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

alpha-fetoprotein (AFP) is not only a widely used biomarker in hepatocellular carcinoma (HCC) surveillance, but is also clinically recognized as linked with aggressive tumour behaviour. Here we show that deregulation of microRNA122, a liver-specific microRNA, is a cause of both AFP elevation and a more biologically aggressive phenotype in HCC. We identify CUX1, a direct target of microRNA122, as a common central mediator of these two effects. Using liver tissues from transgenic mice in which microRNA122 is functionally silenced, an orthotopic xenograft tumour model, and human clinical samples, we further demonstrate that a microRNA122/CUX1/microRNA214/ZBTB20 pathway regulates AFP expression. We also show that the microRNA122/CUX1/RhoA pathway regulates the aggressive characteristics of tumours. We conclude that microRNA122 and associated signalling proteins may represent viable therapeutic targets, and that serum AFP levels in HCC patients may be a surrogate marker for deregulated intracellular microRNA122 signalling pathways in HCC tissues.

DOI： 10.1038/ncomms1345

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

Vinod Kumar, Naoya Kato, Yuji Urabe, Atsushi Takahashi, Ryosuke Muroyama, Naoya Hosono, Motoyuki Otsuka, Ryosuke Tateishi, Masao Omata, Hidewaki Nakagawa, Kazuhiko Koike, Naoyuki Kamatani, Michiaki Kubo, Yusuke Nakamura, Koichi Matsuda

Nature Genetics 43 ( 5 ) 455 - + 2011.5

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

To identify the genetic susceptibility factor(s) for hepatitis C virus-induced hepatocellular carcinoma (HCV-induced HCC), we conducted a genome-wide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC (cases) and 2,890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association (P < 1 x 10(-5)) in the genome-wide association study were further genotyped in 673 cases and 2,596 controls. We found a previously unidentified locus in the 5' flanking region of MICA on 6p21.33 (rs2596542, P-combined = 4.21 x 10(-13), odds ratio = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P = 0.61) but is significantly associated with progression from CHC to HCC (P = 3.13 x 10(-8)). We also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (P = 1.38 x 10(-13)).

DOI： 10.1038/ng.809

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

Motoyuki Otsuka, Young Jun Kang, Jianlin Ren, Huiping Jiang, Yinbin Wang, Masao Omata, Jiahuai Han

Gastroenterology 138 ( 4 ) 1255 - U83 2010.4

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

Motoyuki Otsuka, Min Zheng, Masaaki Hayashi, Jing-Dwan Lee, Osamu Yoshino, Shengcai Lin, Jiahuai Han

Journal of Clinical Investigation 118 ( 5 ) 1944 - 1954 2008.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL INVESTIGATION INC

The microRNA (miRNA) processing enzyme Dicer1 is required for zygotic and embryonic development, but the early embryonic lethality of Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth and development. To address this question, we used a mouse mutant with a hypomorphic Dicer1 allele (Dicer(d/d)) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicer(d/d) mice was caused by corpus luteum (CL) insufficiency and resulted, at least in part, from the impaired growth of new capillary vessels in the ovary. We found that the impaired CL angiogenesis in Dicer(d/d) mice was associated with a lack of miR17-5p and let7b, 2 miRNAs that participate in angiogenesis by regulating the expression of the antiangiogenic factor tissue inhibitor of metalloproteinase 1. Furthermore, injection of miR17-5p and let7b into the ovaries of Dicer(d/d) mice partially normalized tissue inhibitor of metalloproteinase 1 expression and CL angiogenesis. Our data indicate that the development and function of the ovarian CL is a physiological process that appears to be regulated by miRNAs and requires Dicer1 function.

DOI： 10.1172/JCI33680

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

Motoyuki Otsuka, Qing Jing, Philippe Georgel, Liguo New, Jianming Chen, Johann Mols, Young Jun Kang, Zhengfan Jiang, Xin Du, Ryan Cook, Subash C. Das, Asit K. Pattnaik, Bruce Beutler, Jiahuai Han

Immunity 27 ( 1 ) 123 - 134 2007.7

Language：English Publishing type：Research paper (scientific journal) Publisher：CELL PRESS

Dicer is essential for plant, Caenorhabditis elegans, and Drosophila antiviral responses because of its role in generating small interfering RNA (siRNA) from viral genomes. We show that because of impaired miRNA production, mice with a variant Dicer1 allele (Dicer1(d/d)) were more susceptible to vesicular stomatitis virus (VSV) infection. We did not detect VSV genome-derived siRNA in wild-type cells or any alteration of interferon-mediated antiviral responses by Dicer1 deficiency. Rather, we found that host miR24 and miR93 could target viral large protein (L protein) and phosphoprotein (P protein) genes, and a lack of miR24 and miR93 was responsible for increased VSV replication in Dicer1(d/d) cells. Our data suggest that host miRNA can play a role in host interactions with viruses.

DOI： 10.1016/j.immuni.2007.05.014

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

Young Jun Kang, Sung Ouk Kim, Shigeki Shimada, Motoyuki Otsuka, Alim Seit-Nebi, Byoung S. Kwon, Tania H. Watts, Jiahuai Han

Nature Immunology 8 ( 6 ) 601 - 609 2007.6

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of the cytokine tumor necrosis factor (TNF). TNF production occurs within 1 h of TLR stimulation and is sustained for 1 d. Here we document a function for the TNF family member 4-1BB ligand (4-1BBL) in sustaining TLR-induced TNF production. TLR signaling induced 4-1BBL, and 4-1BBL interacted with TLRs on the macrophage surface. The influence of 4-1BBL on TNF production was independent of its receptor (4-1BB) and did not require the adaptors MyD88 or TRIF. It did not influence TLR4-induced activation of transcription factor NF-kappa B (an early response) but was required for TLR4-induced activation of transcription factors CREB and C/EBP ( a late event). Transient TLR4-MyD88 complexes appeared during the first hour after lipopolysaccharide stimulation, and TLR4-4-1BBL interactions were detected between 2 h and 8 h after lipopolysaccharide stimulation. Our results indicate that two different TLR4 complexes sequentially form and selectively control early and late TNF production.

DOI： 10.1038/ni1471

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

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 2025.3

Language：English Publishing type：Research paper (scientific journal)

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

Unraveling a Rare Case: Diarrhea, Alopecia, and Polyposis. International journal

Hidetaka Mizushima, Hideaki Kinugasa, Motoyuki Otsuka

Gastroenterology 2025.2

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

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 2025.2

Language：English Publishing type：Research paper (scientific journal)

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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