Faculty Profiles - Otsuka Motoyuki

Papers - Otsuka Motoyuki

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Inflammation and de-differentiation in pancreatic carcinogenesis. Reviewed International journal

Takahiro Seimiya, Motoyuki Otsuka, Takuma Iwata, Eri Tanaka, Tatsunori Suzuki, Kazuma Sekiba, Mari Yamagami, Rei Ishibashi, Kazuhiko Koike

World journal of clinical cases 6 ( 15 ) 882 - 891 2018.12

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

Pancreatic cancer is a malignancy with an extremely poor prognosis. Chronic pancreatitis is a well-known risk factor for pancreatic cancer. Inflammation is thought to influence carcinogenesis through DNA damage and activation of intracellular signaling pathways. Many transcription factors and signaling pathways co-operate to determine and maintain cell identity at each phase of pancreatic organogenesis and cell differentiation. Recent studies have shown that carcinogenesis is promoted through the suppression of transcription factors related to differentiation. Pancreatitis also demonstrates transcriptional changes, suggesting that multifactorial epigenetic changes lead to impaired differentiation. Taken together, these factors may constitute an important framework for pancreatic carcinogenesis. In this review, we discuss the role of inflammation and de-differentiation in the development of pancreatic cancer, as well as the future of novel therapeutic applications.

DOI： 10.12998/wjcc.v6.i15.882

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Circular RNA and exosomes in pancreatic cancer progression

Takahiro Seimiya, Motoyuki Otsuka, Hung-Yin Liu, Tatsunori Suzuki, Kazuma Sekiba, Mari Yamagami, Eri Tanaka, Rei Ishibashi, Kazuhiko Koike

Translational Cancer Research 7 S745 - S747 2018.8

Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer. Reviewed International journal

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

Molecular cancer research : MCR 16 ( 8 ) 1255 - 1262 2018.8

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

Highly repetitive tandem arrays such as satellite sequences in the centromeric and pericentromeric regions of chromosomes, which were previously considered to be silent, are actively transcribed in various biological processes, including cancers. In the pancreas, this aberrant expression occurs even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To determine the biological role of satellite RNAs in carcinogenesis in vivo, we constructed mouse major satellite (MajSAT) RNA-expressing transgenic mice. However, these transgenic mice did not show spontaneous malignant tumor formation under normal breeding. Importantly, however, DNA damage was increased in pancreatic tissues induced by caerulein treatment or high-fat diet, which may be due to impaired nuclear localization of Y-Box Binding Protein 1 (YBX1), a component of the DNA damage repair machinery. In addition, when crossed with pancreas-specific Kras-mutant mice, MajSAT RNA expression resulted in an earlier increase in PanIN formation. These results suggest that aberrant MajSAT RNA expression accelerates oncogenesis by increasing the probability of a second driver mutation, thus accelerating cells to exit from the breakthrough phase to the expansion phase.Implications: Aberrant expression of satellite RNAs accelerates oncogenesis through a mechanism involving increased DNA damage. Mol Cancer Res; 16(8); 1255-62. ©2018 AACR.

DOI： 10.1158/1541-7786.MCR-18-0139

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CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. Reviewed International journal

Naoto Fujiwara, Hayato Nakagawa, Kenichiro Enooku, Yotaro Kudo, Yuki Hayata, Takuma Nakatsuka, Yasuo Tanaka, Ryosuke Tateishi, Yohko Hikiba, Kento Misumi, Mariko Tanaka, Akimasa Hayashi, Junji Shibahara, Masashi Fukayama, Junichi Arita, Kiyoshi Hasegawa, Hadassa Hirschfield, Yujin Hoshida, Yoshihiro Hirata, Motoyuki Otsuka, Keisuke Tateishi, Kazuhiko Koike

Gut 67 ( 8 ) 1493 - 1504 2018.8

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

OBJECTIVE: Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration. DESIGN: Non-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated. RESULTS: The extensive accumulation of acylcarnitine species was seen in HCC tissues and in the serum of HFD-fed mice. A similar increase was found in the serum of patients with NASH-HCC. The accumulation of acylcarnitine could be attributed to the downregulation of carnitine palmitoyltransferase 2 (CPT2), which was also seen in human SH-HCC. CPT2 downregulation induced the suppression of fatty acid β-oxidation, which would account for the steatotic changes in HCC. CPT2 knockdown in HCC cells resulted in their resistance to lipotoxicity by inhibiting the Src-mediated JNK activation. Additionally, oleoylcarnitine enhanced sphere formation by HCC cells via STAT3 activation, suggesting that acylcarnitine accumulation was a surrogate marker of CPT2 downregulation and directly contributed to hepatocarcinogenesis. HFD feeding and carnitine supplementation synergistically enhanced HCC development accompanied by acylcarnitine accumulation in vivo. CONCLUSION: In obesity-driven and NASH-driven HCC, metabolic reprogramming mediated by the downregulation of CPT2 enables HCC cells to escape lipotoxicity and promotes hepatocarcinogenesis.

DOI： 10.1136/gutjnl-2017-315193

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Hepatitis B virus pathogenesis: Fresh insights into hepatitis B virus RNA. Reviewed International journal

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

World journal of gastroenterology 24 ( 21 ) 2261 - 2268 2018.6

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

Hepatitis B virus (HBV) is still a worldwide health concern. While divergent factors are involved in its pathogenesis, it is now clear that HBV RNAs, principally templates for viral proteins and viral DNAs, have diverse biological functions involved in HBV pathogenesis. These functions include viral replication, hepatic fibrosis and hepatocarcinogenesis. Depending on the sequence similarities, HBV RNAs may act as sponges for host miRNAs and may deregulate miRNA functions, possibly leading to pathological consequences. Some parts of the HBV RNA molecule may function as viral-derived miRNA, which regulates viral replication. HBV DNA can integrate into the host genomic DNA and produce novel viral-host fusion RNA, which may have pathological functions. To date, elimination of HBV-derived covalently closed circular DNA has not been achieved. However, RNA transcription silencing may be an alternative practical approach to treat HBV-induced pathogenesis. A full understanding of HBV RNA transcription and the biological functions of HBV RNA may open a new avenue for the development of novel HBV therapeutics.

DOI： 10.3748/wjg.v24.i21.2261

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Identification of PTBP1 responsible for caspase dependent YRNA cleavage Reviewed

Jun Ogata, Yuki Sugiura, Akinori Kanai, Masafumi Tanaka, Hirotaka Matsui, Masato Ohtsuka, Toshiya Inaba, Motoyuki Otsuka, Ai Kotani

BioRxiv doi: https://doi.org/10.1101/298851 2018.5

Publishing type：Research paper (other academic) Publisher：Cold Spring Harbor Laboratory

<title>ABSTRACT</title>Some RNAs such as 28S rRNA, U1 snRNA, and Y RNAs are known to be cleaved during apoptosis. As the underlying mechanism is yet unclear, the functions and biological significance of RNA degradation in apoptosis remain elusive. We previously identified novel, functional small RNAs named AGO-taxis small RNA (ASR) that are specifically bound to AGO1. Here, we investigated ASR biogenesis, which appears to be non-canonical. Y RNAs, non-coding RNAs degraded during apoptosis, were identified as the precursors of several ASRs. Cell-free analysis combined with fractionation methods revealed that the apoptosis-specific biogenesis of ASRs or Y RNA degradation was induced by PTBP1—an endoribonuclease inhibitor of Y RNAs. PTBP1, a splicing factor, was truncated by caspase 3, which subsequently activated endoribonuclease to induce biogenesis of ASRs and Y RNA cleavage.

DOI： 10.1101/298851

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DHX9 regulates production of hepatitis B virus-derived circular RNA and viral protein levels. Reviewed International journal

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

Oncotarget 9 ( 30 ) 20953 - 20964 2018.4

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

Hepatitis B virus (HBV) infection, which is a major health concern worldwide, can lead to liver cirrhosis and hepatocellular carcinoma. Although current nucleos(t)ide analogs efficiently inhibit viral reverse transcription and viral DNA load clinically, episomal viral covalently closed circular DNA (cccDNA) minichromosomes and transcripts from cccDNA continue to be expressed over the long term. We hypothesized that, under these conditions, viral transcripts may have biological functions involved in pathogenesis. Here, we show that the host protein DExH-box helicase 9 (DXH9) is associated with viral RNAs. We also show that viral-derived circular RNA is produced during HBV replication, and the amount is increased by knockdown of the DHX9 protein, which, in turn, results in decreased viral protein levels but does not affect the levels of HBV DNA. These phenomena were observed in the HBV-producing cell culture model and HBV mini-circle model mimicking HBV cccDNA, as well as in human primary hepatocytes infected with HBV. Based on these results, we conclude that, in HBV infection, the RNA binding factor DHX9 is a novel regulator of viral circular RNA and viral protein levels.

DOI： 10.18632/oncotarget.25104

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ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells. Reviewed International journal

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

NPJ aging and mechanisms of disease 4 11 - 11 2018

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

During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2. However, in this study, the constitutive expression of ISGs in human-derived senescent fibroblasts and in fibroblasts from a patient with Werner syndrome, which leads to premature aging, was mediated mainly by the unphosphorylated forms of STATs in the absence of INF production. Under homeostatic conditions, STAT1, STAT2, and IRF9 were localized to the nucleus of aged cells. Although knockdown of JAK1, a key kinase of STAT1 and STAT2, did not affect ISG expression or IFN-stimulated response element (ISRE)-mediated promoter activities in these senescent cells, knockdown of STAT1 or STAT2 decreased ISG expression and ISRE activities. These results suggest that the ISGF3 complex without clear phosphorylation is required for IFN-independent constitutive ISG transcription in senescent cells.

DOI： 10.1038/s41514-018-0030-6

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Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation Reviewed

T. Nakatsuka, K. Tateishi, Y. Kudo, K. Yamamoto, H. Nakagawa, H. Fujiwara, R. Takahashi, K. Miyabayashi, Y. Asaoka, Y. Tanaka, H. Ijichi, Y. Hirata, M. Otsuka, M. Kato, J. Sakai, M. Tachibana, H. Aburatani, Y. Shinkai, K. Koike

ONCOGENE 36 ( 45 ) 6262 - 6271 2017.11

膵発癌過程における反復配列RNA異常発現の生物学的意義の検討 Reviewed

岸川孝弘, 大塚基之, 大野元子, 山上まり, 石橋嶺, 關場一磨, 鈴木辰典, 小池和彦

日本消化器病学会雑誌 114 ( 臨増大会 ) A743 - A743 2017.9

RASAL1 is a potent regulator of hepatic stellate cell activity and liver fibrosis Reviewed

Akemi Takata, Motoyuki Otsuka, Takahiro Kishikawa, Mari Yamagami, Rei Ishibashi, Kazuma Sekiba, Tatsunori Suzuki, Motoko Ohno, Yui Yamashita, Takaya Abe, Ryota Masuzaki, Tsuneo Ikenoue, Kazuhiko Koike

ONCOTARGET 8 ( 39 ) 64840 - 64852 2017.9

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands Reviewed

Hayato Nakagawa, Nobumi Suzuki, Yoshihiro Hirata, Yohko Hikiba, Yoku Hayakawa, Hiroto Kinoshita, Sozaburo Ihara, Koji Uchino, Yuji Nishikawa, Hideaki Ijichi, Motoyuki Otsuka, Junichi Arita, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Norihiro Kokudo, Keisuke Tateishi, Kazuhiko Koike

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 114 ( 19 ) E3806 - E3815 2017.5

Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system Reviewed

Kazuma Sekiba, Mari Yamagami, Motoyuki Otsuka, Tatsunori Suzuki, Takahiro Kishikawa, Rei Ishibashi, Motoko Ohno, Masaya Sato, Kazuhiko Koike

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 486 ( 2 ) 521 - 525 2017.4

MicroRNAs and liver disease Reviewed

Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Mari Yamagami, Motoko Ohno, Akemi Takata, Chikako Shibata, Rei Ishibashi, Kazuhiko Koike

JOURNAL OF HUMAN GENETICS 62 ( 1 ) 75 - 80 2017.1

Mutual antagonism between hepatitis B viral mRNA and host microRNA let-7 Reviewed

Akemi Takata, Motoyuki Otsuka, Motoko Ohno, Takahiro Kishikawa, Takeshi Yoshikawa, Kazuhiko Koike

SCIENTIFIC REPORTS 6 23237 2016.3

Development of a screening method to identify regulators of MICA shedding Reviewed

Takahiro Kishikawa, Motoyuki Otsuka, Motoko Ohno, Takeshi Yoshikawa, Masaya Sato, Kazuhiko Koike

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 465 ( 4 ) 764 - 768 2015.10

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression Reviewed

Takeshi Yoshikawa, Jianfeng Wu, Motoyuki Otsuka, Takahiro Kishikawa, Motoko Ohno, Chikako Shibata, Akemi Takata, Felicia Han, Young Jun Kang, Chyi-Ying A. Chen, Ann-Bin Shyu, Jiahuai Han, Kazuhiko Koike

NUCLEIC ACIDS RESEARCH 43 ( 15 ) 7577 - 7589 2015.9

Circulating RNAs as new biomarkers for detecting pancreatic cancer Reviewed

Takahiro Kishikawa, Motoyuki Otsuka, Motoko Ohno, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike

WORLD JOURNAL OF GASTROENTEROLOGY 21 ( 28 ) 8527 - 8540 2015.7

Novel therapeutic approaches for hepatitis B virus covalently closed circular DNA Reviewed

Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike

WORLD JOURNAL OF GASTROENTEROLOGY 21 ( 23 ) 7084 - 7088 2015.6

Tissue-Specific Regulation of p38 alpha-Mediated Inflammation in Con A-Induced Acute Liver Damage Reviewed

Young Jun Kang, Bo-Ram Bang, Motoyuki Otsuka, Kinya Otsu

JOURNAL OF IMMUNOLOGY 194 ( 10 ) 4759 - 4766 2015.5

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Papers - Otsuka Motoyuki