Faculty Profiles - Otsuka Motoyuki

Papers - Otsuka Motoyuki

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PTBP1 protects Y RNA from cleavage leading to its apoptosis-specific degradation. Reviewed International journal

Takeshi Kamakura, Kazuaki Kameda, Masahiko Manabe, Kan Torii, Yuki Sugiura, Seiko Ito, Shunya Nakayama, Takanobu Shimizu, Etsuko Nagashima, Kosuke Kamiya, Masahiro Oka, Masafumi Tanaka, Motoyuki Otsuka, Masato Ohtsuka, Ai Kotani

Cell death discovery 10 ( 1 ) 322 - 322 2024.7

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

Some RNAs such as 28S rRNA, U1 small nuclear RNA (snRNA), and Y RNAs are known to be cleaved during apoptosis. The underlying mechanism, functions, and biological significance of RNA degradation in apoptosis remain elusive. Y RNAs are non-coding RNAs widely conserved from bacteria to mammals, and are major components of Ro ribonucleoprotein (RNP) complexes which contain the 60 kDa Ro protein (SS-A) and the 50 kDa La protein (SS-B). The autoantigenic Ro and La proteins were identified by autoantibodies present in the sera from patients with Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SjS). We previously identified novel, functional small RNAs named AGO-taxis small RNAs (ASRs) that are specifically bound to Argonaute protein 1 (AGO1), which are processed from Y RNAs. Cell-free analysis combined with fractionation methods revealed that the apoptosis-specific biogenesis of ASRs or cleavage of Y RNA was induced by truncation of polypyrimidine tract-binding protein 1 (PTBP1), which is an endoribonuclease inhibitor of Y RNAs by caspase 3. Caspase 3-resistant PTBP1 mutant protected cleavage of Y RNAs in apoptosis induced by staurosporine. Furthermore, caspase 3-resistant PTBP1 mutant knock-in mice showed elevated cytokines, dysregulation of the germinal center formation compared to the wild-type mice at LPS stimulation, and high positivity of antinuclear antibody. Those results suggest that cleavage of Y RNAs or biogenesis of ASR during apoptosis has critical biological functions and their deregulation result in immune dysregulation and the formation of autoantibody, possibly leading to the development of autoimmune diseases.

DOI： 10.1038/s41420-024-02080-6

Virtual indigo carmine chromoendoscopy images: A novel modality for peroral cholangioscopy using artificial intelligence technology (with video). Reviewed International journal

Ryosuke Sato, Kazuyuki Matsumoto, Hideaki Kinugasa, Masahiro Tomiya, Takayoshi Tanimoto, Akimitsu Ohto, Kei Harada, Nao Hattori, Taisuke Obata, Akihiro Matsumi, Kazuya Miyamoto, Kosaku Morimoto, Hiroyuki Terasawa, Yuki Fujii, Daisuke Uchida, Koichiro Tsutsumi, Shigeru Horiguchi, Hironari Kato, Yoshiro Kawahara, Motoyuki Otsuka

Gastrointestinal endoscopy 2024.6

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

BACKGROUND AND AIMS: Accurately diagnosing biliary strictures is crucial for surgical decisions, and although peroral cholangioscopy (POCS) aids in visual diagnosis, diagnosing malignancies or determining lesion margins via this route remains challenging. Indigo carmine is commonly used to evaluate lesions during gastrointestinal endoscopy. We aimed to establish the utility of virtual indigo carmine chromoendoscopy (VICI) converted from POCS images using artificial intelligence. METHODS: This single-center, retrospective study analyzed 40 patients with biliary strictures who underwent POCS using white light imaging (WLI) and narrow-band imaging (NBI). A "cycle-consistent adversarial network" (CycleGAN) was used to convert the WLI into VICI of POCS images. Three experienced endoscopists evaluated WLI, NBI, and VICI via POCS in all patients. The primary outcome was the visualization quality of surface structures, surface microvessels, and lesion margins. The secondary outcome was diagnostic accuracy. RESULTS: VICI showed superior visualization of the surface structures and lesion margins compared with WLI (P<0.001) and NBI (P<0.001). The diagnostic accuracies were 72.5%, 87.5%, and 90.0% in WLI alone, WLI and VICI simultaneously, and WLI and NBI simultaneously, respectively. WLI and VICI simultaneously tended to result in higher accuracy than WLI alone (P=0.083) and the results were not significantly different from WLI and NBI simultaneously (P=0.65). CONCLUSIONS: VICI in POCS proved valuable for visualizing surface structures and lesion margins and contributed to higher diagnostic accuracy comparable to NBI. In addition to NBI, VICI may be a novel supportive modality for POCS.

DOI： 10.1016/j.gie.2024.06.013

Innovative submucosal injection solution for endoscopic resection with phosphorylated pullulan: a preclinical study. Reviewed International journal

Takuya Satomi, Yukari Ochi, Takumi Okihara, Hiroki Fujii, Yasuhiro Yoshida, Katsumi Mominoki, Haruko Hirayama, Junki Toyosawa, Yasushi Yamasaki, Seiji Kawano, Yoshiro Kawahara, Hiroyuki Okada, Motoyuki Otsuka, Akihiro Matsukawa

Gastrointestinal endoscopy 99 ( 6 ) 1039 - 1047 2024.6

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

BACKGROUND AND AIMS: A submucosal injection solution is used to assist in endoscopic surgery. The high viscosity of current solutions makes them difficult to inject. In the present study, we developed an extremely low-viscosity, easy-to-use submucosal injection solution using phosphorylated pullulan (PPL). METHODS: The PPL solutions were prepared at different concentrations, and their viscosities were measured. The mucosal elevation capacity was evaluated using excised porcine stomachs. Controls included 0.4% sodium hyaluronate (SH), 0.6% sodium alginate (SA), and saline. To evaluate the practicality, the catheter injectability of 0.7% PPL was measured, and EMR and endoscopic submucosal dissection (ESD) were performed using the stomach and colorectum of live pigs. As controls, 0.4% SH and saline were used. RESULTS: The PPL solutions were of extremely low viscosity compared to the solutions of 0.4% SH and 0.6% SA. Nevertheless, the mucosal elevation capacity of PPL solutions for up to 0.7% concentration was similar to that of 0.4% SH, and 0.7% PPL was less resistant to catheter infusion than 0.4% SH and 0.6% SA. In live pig experiments with endoscopic mucosal resection and ESD, snaring after submucosal injection of 0.7% PPL was easier than with 0.4% SH, ESD with 0.7% PPL produced less bubble formation than with 0.4% SH, and the procedure time tended to be shorter with 0.7% PPL than with 0.4% SH because of the shorter injection time. CONCLUSIONS: The PPL solution is an innovative and easy-to-use submucosal injection solution.

DOI： 10.1016/j.gie.2024.01.015

Methylation analysis of DCC gene in saliva samples is an efficient method for non-invasive detection of superficial hypopharyngeal cancer. Reviewed International journal

Ryosuke Hirai, Hideaki Kinugasa, Shumpei Yamamoto, Soichiro Ako, Koichiro Tsutsumi, Makoto Abe, Koji Miyahara, Masahiro Nakagawa, Motoyuki Otsuka

British journal of cancer 130 ( 10 ) 1725 - 1731 2024.3

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

BACKGROUND: Advances in upper gastrointestinal endoscopic technology have enabled early detection and treatment of hypopharyngeal cancer. However, in-depth pharyngeal observations require sedation and are invasive. It is important to establish a minimally invasive and simple evaluation method to identify high-risk patients. METHODS: Eighty-seven patients with superficial hypopharyngeal cancer and 51 healthy controls were recruited. We assessed the methylation status of DCC, PTGDR1, EDNRB, and ECAD, in tissue and saliva samples and verified the diagnostic accuracy by methylation analyses of their promoter regions using quantitative methylation-specific PCR. RESULTS: Significant differences between cancer and their surrounding non-cancerous tissues were observed in the methylation values of DCC (p = 0.003), EDNRB (p = 0.001), and ECAD (p = 0.043). Using receiver operating characteristic analyses of the methylation values in saliva samples, DCC showed the highest area under the curve values for the detection of superficial hypopharyngeal cancer (0.917, 95% confidence interval = 0.864-0.970), compared with those for EDNRB (0.680) and ECAD (0.639). When the cutoff for the methylation values of DCC was set at ≥0.163, the sensitivity to detect hypopharyngeal cancer was 82.8% and the specificity was 90.2%. CONCLUSIONS: DCC methylation in saliva samples could be a non-invasive and efficient tool for early detection of hypopharyngeal cancer in high-risk patients.

DOI： 10.1038/s41416-024-02654-2

MicroRNA-34a-5p: A pivotal therapeutic target in gallbladder cancer. Reviewed International journal

Takashi Oda, Koichiro Tsutsumi, Taisuke Obata, Eijiro Ueta, Tatsuya Kikuchi, Soichiro Ako, Yuki Fujii, Tatsuhiro Yamazaki, Daisuke Uchida, Kazuyuki Matsumoto, Shigeru Horiguchi, Hironari Kato, Hiroyuki Okada, Ryota Chijimatsu, Motoyuki Otsuka

Molecular therapy. Oncology 32 ( 1 ) 200765 - 200765 2024.3

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

Gallbladder cancer incidence has been increasing globally, and it remains challenging to expect long prognosis with the current systemic chemotherapy. We identified a novel nucleic acid-mediated therapeutic target against gallbladder cancer by using innovative organoid-based gallbladder cancer models generated from KrasLSL-G12D/+; Trp53f/f mice. Using comprehensive microRNA expression analyses and a bioinformatics approach, we identified significant microRNA-34a-5p downregulation in both murine gallbladder cancer organoids and resected human gallbladder cancer specimens. In three different human gallbladder cancer cell lines, forced microRNA-34a-5p expression inhibited cell proliferation and induced cell-cycle arrest at the G1 phase by suppressing direct target (CDK6) expression. Furthermore, comprehensive RNA sequencing revealed the significant enrichment of gene sets related to the cell-cycle regulators after microRNA-34a-5p expression in gallbladder cancer cells. In a murine xenograft model, locally injected microRNA-34a-5p mimics significantly inhibited gallbladder cancer progression and downregulated CDK6 expression. These results provide a rationale for promising therapeutics against gallbladder cancer by microRNA-34a-5p injection, as well as a strategy to explore therapeutic targets against cancers using organoid-based models, especially for those lacking useful genetically engineered murine models, such as gallbladder cancer.

DOI： 10.1016/j.omton.2024.200765

Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells. Reviewed International journal

Yu Miyakawa, Motoyuki Otsuka, Chikako Shibata, Takahiro Seimiya, Keisuke Yamamoto, Rei Ishibashi, Takahiro Kishikawa, Eri Tanaka, Takayuki Isagawa, Norihiko Takeda, Noriaki Kamio, Kenichi Imai, Mitsuhiro Fujishiro

Cellular and molecular gastroenterology and hepatology 17 ( 5 ) 745 - 767 2024.2

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

BACKGROUND & AIMS: Colorectal cancer (CRC) is the third most common cancer in the world. Gut microbiota has recently been implicated in the development of CRC. Actinomyces odontolyticus is one of the most abundant bacteria in the gut of patients with very early stages of CRC. A odontolyticus is an anaerobic bacterium existing principally in the oral cavity, similar to Fusobacterium nucleatum, which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of A odontolyticus on colonic oncogenesis. METHODS: We examined the induction of intracellular signaling by A odontolyticus in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut organoid model and mouse colon tissues in vivo. RESULTS: A odontolyticus secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive reactive oxygen species (ROS) in colon epithelial cells. We found that A odontolyticus secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by A odontolyticus-derived MVs was confirmed in the gut organoid model and also in mouse colon tissues. CONCLUSIONS: A odontolyticus secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.

DOI： 10.1016/j.jcmgh.2024.01.010

CA19-9-Positive Extracellular Vesicle Is a Risk Factor for Cancer-Associated Thrombosis in Pancreatic Cancer. Reviewed International journal

Chikako Shibata, Motoyuki Otsuka, Kazunaga Ishigaki, Takahiro Seimiya, Takahiro Kishikawa, Mitsuhiro Fujishiro

Gastro hep advances 3 ( 4 ) 551 - 561 2024

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

BACKGROUND AND AIMS: Cancer-associated venous thromboembolism (VTE) is a frequent complication associated with high mortality in patients with cancer, particularly pancreatic cancer. While biological factors such as coagulation factors released from cancer cells may underlie the mechanisms of cancer-associated VTE, the detailed mechanisms have not been determined. Here, we aimed to determine whether extracellular vesicles carrying a glycan sialyl-Lewisa, known as carbohydrate antigen 19-9 (CA19-9), which is a clinically used serum tumor marker and selectin ligand, are a significant cause of cancer-associated VTE. METHODS: Risk factors for cancer-associated VTE were determined using clinical data. EVs derived from CA19-9-deficient or overexpressing pancreatic cancer cells were characterized. The protein levels of coagulation factors on the surface of the EVs were quantified using our newly developed sensitive method. RESULTS: Higher CA19-9 levels in the sera of patients were significantly associated with the occurrence of VTE. Using CA19-9-negative or overexpressing pancreatic cancer cells, we found that EVs derived from these cells interacted with E-selectin of endothelial cells in a CA19-9-dependent manner in cell-based assays and in vitro blood vessel models. EVs derived from cancer cells have higher tissue factor levels on their surfaces, and increased tissue factor activity is induced locally, where CA19-9-positive EVs bind to activated endothelial cells. CONCLUSION: These results suggest that the binding between CA19-9-positive EVs released from cancer cells and endothelial cell E-selectin explains the increased frequency of VTE in patients with pancreatic cancer.

DOI： 10.1016/j.gastha.2024.02.005

MicroRNA-451a inhibits gemcitabine-refractory biliary tract cancer progression by suppressing the MIF-mediated PI3K/AKT pathway. Reviewed International journal

Taisuke Obata, Koichiro Tsutsumi, Eijiro Ueta, Takashi Oda, Tatsuya Kikuchi, Soichiro Ako, Yuki Fujii, Tatsuhiro Yamazaki, Daisuke Uchida, Kazuyuki Matsumoto, Shigeru Horiguchi, Hironari Kato, Hiroyuki Okada, Motoyuki Otsuka

Molecular therapy. Nucleic acids 34 102054 - 102054 2023.12

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

Gemcitabine is an effective chemotherapeutic agent for biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA). However, few other effective agents are currently available, particularly for GEM-refractory BTCs. We previously identified microRNA-451a (miR-451a) as a potential therapeutic target in GBC. To elucidate the antineoplastic effects of miR-451a and its underlying mechanisms, we transfected miR-451a into GBC, gemcitabine-resistant GBC (GR-GBC), and gemcitabine-resistant CCA (GR-CCA) cell lines. Furthermore, mimicking in vivo conditions, tumorigenic GBC organoids and three-dimensional (3D) cell culture systems were employed to investigate the anti-proliferative effects of miR-451a on BTCs, and its effect on stem cell properties. We found that miR-451a significantly inhibited cell proliferation, induced apoptosis, and reduced chemoresistant phenotypes, such as epithelial-mesenchymal transition, in both GBC and GR-GBC. The principal mechanism is probably the negative regulation of the phosphatidylinositol 3-kinase/AKT pathway, partially accomplished by directly downregulating macrophage migration inhibitory factor. The Gene Expression Omnibus database revealed that miR-451a was the most significantly downregulated microRNA in CCA tissues. The introduction of miR-451a resulted in similar antineoplastic effects in GR-CCA. Furthermore, miR-451a reduced cell viability in 3D spheroid models and tumorigenic GBC organoids. These findings suggest that the supplementation of miR-451a is a potential treatment strategy for GEM-refractory BTCs.

DOI： 10.1016/j.omtn.2023.102054

Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA. Reviewed International journal

Kazuyoshi Funato, Nozomi Miyake, Kazuma Sekiba, Yu Miyakawa, Takahiro Seimiya, Chikako Shibata, Takahiro Kishikawa, Motoyuki Otsuka

Hepatology communications 7 ( 11 ) 2023.11

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

BACKGROUND: Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. METHODS: Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. RESULTS: Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor-signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. CONCLUSIONS: Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV.

DOI： 10.1097/HC9.0000000000000313

Extracellular vesicle‑mediated RNA editing may underlie the heterogeneity and spread of hepatocellular carcinoma in human tissue and in vitro. Reviewed International journal

Chikako Shibata, Motoyuki Otsuka, Takayuki Shimizu, Takahiro Seimiya, Takahiro Kishikawa, Taku Aoki, Mitsuhiro Fujishiro

Oncology reports 50 ( 5 ) 2023.11

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

Extracellular vesicles (EVs) produced by various cells, including tumor cells, carry biomolecules to neighboring cells. In hepatocellular carcinoma (HCC), adenosine to inosine RNA editing of antizyme inhibitor 1 (AZIN1), specifically regulated by adenosine deaminase acting on RNA‑1 (ADAR1), promotes carcinogenesis. The present study examined if EVs and ADAR1 in the EVs released from HCC cells are transferred to neighboring cells in co‑culture systems and reporter assay. Distribution of the ADAR1 expression in human tissues were examined by immunohistochemistry. EVs released from HCC cells containing ADAR1 were delivered to neighboring HCC cells and non‑cancerous hepatocytes. The increased ADAR1 protein levels resulted in serine to glycine substitution at residue 367 of AZIN1, which augmented transformation potential and increased aggressive behavior of cancer cells. In clinically resected samples, ADAR1 distribution was highly heterogeneous within the tumor specimen and denser in non‑cancerous tissue surrounding the HCC tissue. These observations suggested that ADAR1 protein may be delivered from HCC cells to neighboring cells via EVs and that EV‑mediated RNA editing may serve a pivotal role in determining HCC heterogeneity and spread.

DOI： 10.3892/or.2023.8631

An unusual case of gastric polyposis. Reviewed International journal

Masaya Iwamuro, Seiji Kawano, Motoyuki Otsuka

Gastroenterology 165 ( 5 ) 1110 - 1113 2023.8

A rare case of severe colitis associated with a pancreatic neuroendocrine tumor. Reviewed International journal

Ryosuke Sato, Shigeru Horiguchi, Motoyuki Otsuka

Gastroenterology 166 ( 1 ) e13-e16 2023.7

Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals. Reviewed International journal

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

Journal of hepatology 2023.6

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

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

DOI： 10.1016/j.jhep.2023.05.042

Recent advances in extracellular vesicles in gastrointestinal cancer and lymphoma. Reviewed International journal

Motoyuki Otsuka, Ai Kotani

Cancer science 114 ( 6 ) 2230 - 2237 2023.2

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

Extracellular vesicles (EVs) are intercellular communication agents that transfer microRNAs (miRNAs), other non-coding RNAs (ncRNAs), messenger RNAs (mRNAs), proteins, lipids, metabolites, and other molecules from donor cells (e.g., cancer cells) to recipient cells (e.g., stromal cells). In 2007, miRNAs were reported to be abundant among the ncRNAs present in EVs. Since then, many studies have investigated the functions of miRNAs and have attempted to apply these molecules to aid in the diagnosis and treatment of cancer. Research on EVs has expanded, particularly in the field of cancer, because cancer cells heavily secrete EVs. The cargo of these EVs, especially those in small EVs such as exosomes, is assumed to work cooperatively and significantly in the tumor microenvironment and to promote metastasis. In this review, we first summarize recent studies on EVs in gastrointestinal cancer and highlight studies on human satellite II RNAs, which are a type of ncRNA found in EVs and possessing repetitive sequences. Second, since several recent studies have revealed that phospholipids, which are components of EV membranes, play important roles in intercellular communication and in the generation of lipid mediators in the tumor microenvironment, we review the reported roles of these molecules and discuss their potential use in the design of new cancer treatments.

DOI： 10.1111/cas.15771

Combination of serum human satellite RNA and miR-21-5p levels as a biomarker for pancreatic cancer. Reviewed International journal

Takahiro Seimiya, Tatsunori Suzuki, Takuma Iwata, Takahiro Kishikawa, Kazuma Sekiba, Chikako Shibata, Kazunaga Ishigaki, Hiroaki Fujiwara, Hiroki Oyama, Sachiko Kanai, Tatsuya Sato, Yousuke Nakai, Rei Ishibashi, Masaru Moriyama, Ryo Nakagawa, Hideaki Ijichi, Motoyuki Otsuka, Kazuhiko Koike

iScience 26 ( 2 ) 106021 - 106021 2023.2

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

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to the difficulty of its diagnosis. Because human satellite II (HSATII) RNA, a satellite repeat RNA, is highly and specifically expressed in human PDAC, the serum HSATII RNA level may be a biomarker of PDAC. To measure the serum HSATII RNA level with high sensitivity and reproducibility, we previously developed a convenient method, tandem repeat amplification by nuclease protection (TRAP) combined with droplet digital PCR (ddPCR). Here, we refined the original method by simultaneously measuring the serum miR-21-5p level to enhance the detection of PDAC. The resulting PDAC-Index, constructed using serum HSATII RNA and miR-21-5p levels, discriminated patients with PDAC with high accuracy. We verified the clinical usefulness of the PDAC-Index as a supportive test in difficult-to-diagnose cases. The PDAC-Index has satisfactory diagnostic performance and may routinely be applied for detecting PDAC.

DOI： 10.1016/j.isci.2023.106021

Overcoming T-cell exhaustion: new therapeutic targets in HCC immunotherapy. Invited Reviewed International journal

Takahiro Seimiya, Motoyuki Otsuka, Mitsuhiro Fujishiro

Hepatology (Baltimore, Md.) 78 ( 4 ) 1009 - 1011 2023.1

Lipolysis by pancreatic cancer-derived extracellular vesicles in cancer-associated cachexia via specific integrins. Reviewed International journal

Chikako Shibata, Motoyuki Otsuka, Takahiro Seimiya, Takahiro Kishikawa, Kazunaga Ishigaki, Mitsuhiro Fujishiro

Clinical and translational medicine 12 ( 11 ) e1089 2022.11

Circulating Tumor DNA Guiding Adjuvant Therapy in Colon Cancer. Reviewed International journal

Motoyuki Otsuka

The New England Journal of Medicine 387 ( 8 ) 759 - 760 2022.8

MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages. Reviewed International journal

Hiroyuki Kato, Keisuke Tateishi, Hiroaki Fujiwara, Takuma Nakatsuka, Keisuke Yamamoto, Yotaro Kudo, Yoku Hayakawa, Hayato Nakagawa, Yasuo Tanaka, Hideaki Ijichi, Motoyuki Otsuka, Dosuke Iwadate, Hiroki Oyama, Sachiko Kanai, Kensaku Noguchi, Tatsunori Suzuki, Tatsuya Sato, Ryunosuke Hakuta, Kazunaga Ishigaki, Kei Saito, Tomotaka Saito, Naminatsu Takahara, Takahiro Kishikawa, Tsuyoshi Hamada, Ryota Takahashi, Koji Miyabayashi, Suguru Mizuno, Hirofumi Kogure, Yousuke Nakai, Yoshihiro Hirata, Atsushi Toyoda, Kazuki Ichikawa, Wei Qu, Shinichi Morishita, Junichi Arita, Mariko Tanaka, Tetsuo Ushiku, Kiyoshi Hasegawa, Mitsuhiro Fujishiro, Kazuhiko Koike

Gastroenterology 162 ( 4 ) 1272 - 1287 2022.4

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

BACKGROUND & AIMS: Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers. METHODS: We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference. RESULTS: Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared with PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions compared with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes, including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv. CONCLUSIONS: Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.

DOI： 10.1053/j.gastro.2021.12.254

WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models. Reviewed International journal

Takahiro Kishikawa, Hiroshi Higuchi, Limei Wang, Nivedita Panch, Valerie Maymi, Sachem Best, Samuel Lee, Genso Notoya, Alex Toker, Lydia E Matesic, Gerburg M Wulf, Wenyi Wei, Motoyuki Otsuka, Kazuhiko Koike, John G Clohessy, Yu-Ru Lee, Pier Paolo Pandolfi

The Journal of clinical investigation 131 ( 24 ) 2021.12

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

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pervasive event in tumorigenesis due to PI3K mutation and dysfunction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Pharmacological inhibition of PI3K has resulted in variable clinical outcomes, however, raising questions regarding the possible mechanisms of unresponsiveness and resistance to treatment. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase frequently amplified and mutated in multiple cancers, as well as in the germ lines of patients predisposed to cancer, and was recently found to activate PI3K signaling through PTEN inactivation. Here, we demonstrate that PTEN dissociated from the plasma membrane upon treatment with PI3K inhibitors through WWP1 activation, whereas WWP1 genetic or pharmacological inhibition restored PTEN membrane localization, synergizing with PI3K inhibitors to suppress tumor growth both in vitro and in vivo. Furthermore, we demonstrate that WWP1 inhibition attenuated hyperglycemia and the consequent insulin feedback, which is a major tumor-promoting side effect of PI3K inhibitors. Mechanistically, we found that AMPKα2 was ubiquitinated and, in turn, inhibited in its activatory phosphorylation by WWP1, whereas WWP1 inhibition facilitated AMPKα2 activity in the muscle to compensate for the reduction in glucose uptake observed upon PI3K inhibition. Thus, our identification of the cell-autonomous and systemic roles of WWP1 inhibition expands the therapeutic potential of PI3K inhibitors and reveals new avenues of combination cancer therapy.

DOI： 10.1172/JCI140436

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