Faculty Profiles - Otsuka Motoyuki

Papers - Otsuka Motoyuki

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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

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

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

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

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

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

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

Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.

DOI： 10.1038/onc.2017.222

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

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

Liver fibrosis, leading to cirrhosis and liver failure, can occur after chronic liver injury. The transition of hepatic stellate cells (HSCs) from quiescent cells into proliferative and fibrogenic cells is a central event in liver fibrosis. Here, we show that RAS protein activator like-1 (RASAL1), a RAS-GTPase-activating protein, which switches off RAS activity, is significantly decreased during HSC activation, and that HSC activation can be antagonized by forced expression of the RASAL1 protein. We demonstrate that RASAL1 suppresses HSC proliferation by regulating the Ras-MAPK pathway, and that RASAL1 suppresses HSC fibrogenic activity by regulating the PKA-LKB1-AMPK-SRF pathway by interacting with angiotensin II receptor, type 1. We also show that RASAL1-deficient mice are more susceptible to liver fibrosis. These data demonstrate that deregulated RASAL1 expression levels and the affected downstream intracellular signaling are central mediators of perpetuated HSC activation and fibrogenesis in the liver.

DOI： 10.18632/oncotarget.17609

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

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

The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras-and TGF beta/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGF beta receptor type 2 (TGF beta R2) deletion were first generated by crossing LSL-Kras(G12D), Tgfbr2(flox/flox), and K19(CreERT) mice (KT-K19(CreERT)). However, KT-K19CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreERT mice were crossed with CDH1flox/flox mice (KTCK19CreERT). Surprisingly, KTC-K19CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high (l)evels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGF beta R2 mutations in the development of ECC, and anti-IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.

DOI： 10.1073/pnas.1619416114

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. Because immune cells, such as natural killer (NK) cells, recognize virally infected or transformed cells and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells, MICA expression levels are associated with NK cell-mediated immunity. Here, we report that an engineered clustered regularly interspaced short palindromic repeats-Cas9-related complex targeting MICA gene promoter sequences activates transcription of the MICA gene from its endogenous locus. Inhibiting microRNA function, which targets the 3' untranslated region of the MICA gene, enhances this activation. These results demonstrate that the combination of Cas9-based transcriptional activators and simultaneous modulation of microRNA function may be a powerful tool for enhancing MICA protein expression and efficient anti-pathogenic cell immunity. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2017.03.076

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

Language：English Publisher：NATURE PUBLISHING GROUP

The biological roles of microRNAs (miRNAs) have been extensively studied. miRNA122 represents more than half of the miRNAs expressed in the liver and has various physiological and pathological functions, which include enhancing hepatitis virus replication, regulating lipid metabolism and suppressing hepatocellular carcinoma. miRNAs, whether globally or individually, have been linked with hepatocarcinogenesis. Furthermore, some miRNAs have been shown to be involved in the pathogenesis of nonalcoholic steatohepatitis. Using nucleotide-based strategies, these miRNAs may be developed as potential therapeutic targets. Because changes in miRNA expression can be measured in sera, they may be used as non-invasive biomarkers if they correctly reflect the pathological state of the liver. In this review, we show the biological roles of representative miRNAs in liver disease and discuss the current issues that remain to be clarified for future clinical applications.

DOI： 10.1038/jhg.2016.53

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

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

The interplay between viral and host factors plays a major role in viral pathogenesis. Hepatitis B virus (HBV) infection is a global health problem that leads to liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV proteins have been studied extensively about their implication in hepatocarcinogenesis, the molecular mechanisms of oncogenesis are still largely unknown. A recent concept in gene regulation, in which competitive endogenous RNAs compete for common microRNAs (miRNAs), suggests that mRNA targets are key elements in the regulation of miRNA availability. Here, we show that HBV mRNA in the preS2 region can be targeted by host miRNA let-7 g. This leads to the sequestration of let-7 g and inhibition of let-7 g function. The expression of HBV transcripts, including the preS2 region, de-repressed let-7 g targets, which may contribute to long-term oncogenesis. HBV transcript-expressing transgenic mice, but not non-targeted transcript-expressing mice, were more prone to chemically induced hepatoocarcinogenesis. Let-7 target protein expression was upregulated in human HCC tissues derived from HBV-infected patients. On the other hand, let-7 g inhibited HBV preS2 protein expression and viral products. These results suggest that the interplay between viral intermediate transcripts during HBV replication and host miRNAs is crucial to the pathogenesis of chronic viral infection.

DOI： 10.1038/srep23237

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Immune cells, such as natural killer (NK) cells, recognize virally infected and transformed cells, and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells. Shedding of NKG2D ligands is thought to be a type of counter-mechanism employed by pathogenic cells to evade from NKG2D-mediated immune surveillance. MHC class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. We previously reported that, in soluble form, MICA expression levels are significantly associated with hepatitis virus-induced hepatocellular carcinoma. Here, we report a MICA shedding assay that utilizes membrane-bound MICA tagged at its N-terminus with a nano-luciferase reporter to quantify MICA shedding into culture media. Using this method, we screened a compound library and identified putative regulators of MICA shedding that have the potential to enhance the immune reaction by simultaneously increasing cell surface MICA levels and decreasing soluble MICA levels. This shedding assay may be useful for screening regulators of cell surface molecule shedding. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.08.081

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

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

The reduced expression levels and functional impairment of global miRNAs are related to various human diseases, including cancers. However, relatively little is known about how global miRNA function may be upregulated. Here, we report that global miRNA function can be enhanced by Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors. The regulation of miRNA function by ROCK inhibitors is mediated, at least in part, by poly(A)-binding protein-interacting protein 2 (PAIP2), which enhances poly(A)-shortening of miRNA-targeted mRNAs and leads to global upregulation of miRNA function. In the presence of a ROCK inhibitor, PAIP2 expression is enhanced by the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) through increased ROCK1 nuclear localization and enhanced ROCK1 association with HNF4A. Our data reveal an unexpected role of ROCK1 as a cofactor of HNF4A in enhancing PAIP2 transcription. ROCK inhibitors may be useful for the various pathologies associated with the impairment of global miRNA function.

DOI： 10.1093/nar/gkv728

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

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

Pancreatic cancer remains difficult to treat and has a high mortality rate. It is difficult to diagnose early, mainly due to the lack of screening imaging modalities and specific biomarkers. Consequently, it is important to develop biomarkers that enable the detection of early stage tumors. Emerging evidence is accumulating that tumor cells release substantial amounts of RNA into the bloodstream that strongly resist RNases in the blood and are present at sufficient levels for quantitative analyses. These circulating RNAs are upregulated in the serum and plasma of cancer patients, including those with pancreatic cancer, compared with healthy controls. The majority of RNA biomarker studies have assessed circulating microRNAs (miRs), which are often tissue-specific. There are few reports of the tumor-specific upregulation of other types of small non-coding RNAs (ncRNAs), such as small nucleolar RNAs and Piwi-interacting RNAs. Long ncRNAs (lncRNAs), such as HOTAIR and MALAT1, in the serum/plasma of pancreatic cancer patients have also been reported as diagnostic and prognostic markers. Among tissue-derived RNAs, some miRs show increased expression even in pre-cancerous tissues, and their expression profiles may allow for the discrimination between a chronic inflammatory state and carcinoma. Additionally, some miRs and lncRNAs have been reported with significant alterations in expression according to disease progression, and they may thus represent potential candidate diagnostic or prognostic biomarkers that may be used to evaluate patients once detection methods in peripheral blood are well established. Furthermore, recent innovations in high-throughput sequencing techniques have enabled the discovery of unannotated tumor-associated ncRNAs and tumor-specific alternative splicing as novel and specific biomarkers of cancers. Although much work is required to clarify the release mechanism, origin of tumor-specific circulating RNAs, and selectivity of carrier complexes, and technical advances must also be achieved, such as creating a consensus normalization protocol for quantitative data analysis, circulating RNAs are largely unexplored and might represent novel clinical biomarkers.

DOI： 10.3748/wjg.v21.i28.8527

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

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

Hepatitis B virus (HBV) infection is a major global health problem. Although current therapies, such as the use of nucleos(t) ide analogs, inhibit HBV replication efficiently, they do not eliminate covalently closed circular DNA (cccDNA), which persists in hepatocyte nuclei. As HBV cccDNA is a viral transcription template, novel therapeutic approaches to directly target HBV cccDNA are necessary to completely eradicate persistent HBV infections. HBV cccDNA levels in HBV-infected human liver cells are extremely low; thus, more reliable and simple measurement methods are needed to correctly monitor their levels during therapeutic treatment. Although reverse transcription-polymerase chain reaction or Southern blot procedures are currently used in research studies, these methods are not completely reliable and are also time-consuming and labor-intensive. Genome editing technologies, such as zinc finger nucleases, transcription activator-like effector nucleases, and the clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) system, which are designed to target specific DNA sequences, represent highly promising potential therapeutic tools. In particular, the CRISPR/Cas9 system is an easily customizable sequences-pecific nuclease with high flexibility and may be the most feasible approach to target HBV cccDNA. Further research to develop easier, safer, and more effective protocols should be pursued.

DOI： 10.3748/wjg.v21.i23.7084

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

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

Because p38 alpha plays a critical role in inflammation, it has been an attractive target for the development of anti-inflammation therapeutics. However, p38 alpha inhibitors showed side effects, including severe liver toxicity, that often prevailed over the benefits in clinical studies, and the mechanism of toxicity is not clear. In this study, we demonstrate that p38 alpha regulates the inflammatory responses in acute liver inflammation in a tissue-specific manner, and liver toxicity by p38 alpha inhibitors may be a result of the inhibition of protective activity of p38 alpha in the liver. Genetic ablation of p38 alpha in T and NKT cells protected mice from liver injury in Con A-induced liver inflammation, whereas liver-specific deletion of p38 alpha aggravated liver pathology. We found that p38 alpha deficiency in the liver increased the expression of chemokines to recruit more inflammatory cells, indicating that p38 alpha in the liver plays a protective anti-inflammatory role during acute liver inflammation. Therefore, our results suggest that p38 alpha regulates the inflammatory responses in a tissue-specific manner, and that the tissue-specific p38 alpha targeting strategies can be used for the development of an effective anti-inflammation treatment with an improved side-effect profile.

DOI： 10.4049/jimmunol.1402954

Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine Reviewed

Takahiro Kishikawa, Motoyuki Otsuka, Poh Seng Tan, Motoko Ohno, Xiaochen Sun, Takeshi Yoshikawa, Chikako Shibata, Akemi Takata, Kentaro Kojima, Kenji Takehana, Maki Ohishi, Sana Ota, Tomoyuki Noyama, Yuji Kondo, Masaya Sato, Tomoyoshi Soga, Yujin Hoshida, Kazuhiko Koike

Oncotarget 6 ( 10 ) 8339 - 8352 2015

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

Reduced expression of microRNA122 (miR122), a liver-specific microRNA, is frequent in hepatocellular carcinoma (HCC). However, its biological significances remain poorly understood. Because deregulated amino acid levels in cancers can affect their biological behavior, we determined the amino acid levels in miR122- silenced mouse liver tissues, in which intracellular arginine levels were significantly increased. The increased intracellular arginine levels were through upregulation of the solute carrier family 7 (SLC7A1), a transporter of arginine and a direct target of miR122. Arginine is the substrate for nitric oxide (NO) synthetase, and intracellular NO levels were increased in miR122-silenced HCC cells, with increased resistance to sorafenib, a multikinase inhibitor. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib. Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib. These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.

DOI： 10.18632/oncotarget.3234

Diagnostic and therapeutic application of noncoding RNAs for hepatocellular carcinoma Reviewed

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

World Journal of Hepatology 7 ( 1 ) 1 - 6 2015

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

MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression posttranscriptionally, targeting thousands of messenger RNAs. Long noncoding RNAs (lncRNAs), another class of noncoding RNAs, have been determined to be also involved in transcription regulation and translation of target genes. Since deregulated expression levels or functions of miRNAs and lncRNAs in hepatocellular carcinoma (HCC) are frequently observed, clinical use of noncoding RNAs for novel diagnostic and therapeutic applications in the management of HCCs is highly and emergently expected. Here, we summarize recent findings regarding deregulated miRNAs and lncRNAs for their potential clinical use as diagnostic and prognostic biomarkers of HCC. Specifically, we emphasize the deregulated expression levels of such noncoding RNAs in patients' sera as noninvasive biomarkers, a field that requires urgent improvement in the clinical surveillance of HCC. Since nucleotide-based strategies are being applied to clinical therapeutics, we further summarize clinical and preclinical trials using oligonucleotides involving the use of miRNAs and small interfering RNAs against HCC as novel therapeutics. Finally, we discuss current open questions, which must be clarified in the near future for realistic clinical applications of these new strategies.

DOI： 10.4254/wjh.v7.i1.1

Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBP alpha Reviewed

Keisuke Yamamoto, Keisuke Tateishi, Yotaro Kudo, Tomohiko Sato, Shinzo Yamamoto, Koji Miyabayashi, Keisuke Matsusaka, Yoshinari Asaoka, Hideaki Ijichi, Yoshihiro Hirata, Motoyuki Otsuka, Yousuke Nakai, Hiroyuki Isayama, Tsuneo Ikenoue, Mineo Kurokawa, Masashi Fukayama, Norihiro Kokudo, Masao Omata, Kazuhiko Koike

CARCINOGENESIS 35 ( 11 ) 2404 - 2414 2014.11

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

Genetic mutations in pancreatic ductal adenocarcinoma (PDAC) with critical roles have been well examined The recent discovery of alterations in genes encoding histone modifiers suggests their possible roles in the complexity of cancer development. We previously reported loss of heterozygosity of the KDM6B gene, which encodes a histone demethylase for trimethylated histone 113 lysine 27, a repressive chromatin mark, in PDAC cells. In this study, we demonstrated that loss of KDM6B enhanced aggressiveness of PDAC cells. KDM6B has been regarded as a tumor suppressor that mediates oncogenic KRAS-induced senescence. Consistently, KDM6B was highly expressed in pancreatic precancerous lesions (pancreatic intraepithelial neoplasms); then, the expression decreased as the malignant grade progressed. We found that knockdown of KDM6B in PDAC cells promoted tumor sphere formation and increased peritoneal dissemination and liver metastasis in vivo. Microarray and chromatin immunoprecipitation analysis implicated CEBPA for aggressiveness induced by KDM6B knockdown. CEBPA knockdown recapitulated the phenotypic change of PDAC cells after KDM6B knockdown, which was reversed by forced expression of C/EBP alpha. Moreover, similar protein expression patterns of KDM6B and C/EBP alpha in human PDAC emphasized their functional correlation. Notably, pharmacological inhibition of the H3K27 methylase EZH2 in PDAC cells inhibited tumor sphere formation along with the upregulation of CEBPA expression, and this effect was impaired in KDM6B knockdown cells, highlighting the role for KDM6B in the activation of CEBPA. Together, our results propose a significant role for the KDM6B-C/EBP alpha axis in the PDAC phenotype.

DOI： 10.1093/carcin/bgu136

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