Faculty Profiles - ENOMOTO, Atsushi

Papers - ENOMOTO, Atsushi

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神経内分泌細胞の形態を有する乳がんにおけるインスリノーマ関連タンパク質1(INSM1)の発現応用法と将来の展望(Insulinoma-associated protein 1(INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future prospective)

川崎朋範, 田島知明, 中村泰大, 堀田洋介, 藤本章博, 宮口和也, 宇佐見陽子, 今井久雄, 解良恭一, 村田有也, 谷山清己, 村松千左子, 齋藤正夫, 榎本篤, 近藤哲夫, 良沢昭銘, NEN project team

日本組織細胞化学会総会・学術集会講演プログラム・予稿集 Vol. 62回 page： 72 - 72 2021.9

The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model. Reviewed International journal

Naoki Yoshioka, Miyako Tanaka, Kozue Ochi, Akiko Watanabe, Kenji Ono, Makoto Sawada, Tomoo Ogi, Michiko Itoh, Ayaka Ito, Yukihiro Shiraki, Atsushi Enomoto, Masatoshi Ishigami, Mitsuhiro Fujishiro, Yoshihiro Ogawa, Takayoshi Suganami

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Vol. 140 page： 111738 - 111738 2021.8

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

BACKGROUND: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. METHODS: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. FINDINGS: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. INTERPRETATION: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.

DOI： 10.1016/j.biopha.2021.111738

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PubMed

The CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia. Reviewed International journal

Kei Kozawa, Miho Sekai, Kenji Ohba, Shoko Ito, Hiroaki Sako, Takeshi Maruyama, Mai Kakeno, Takanobu Shirai, Keisuke Kuromiya, Tomoko Kamasaki, Koki Kohashi, Shinya Tanaka, Susumu Ishikawa, Nanami Sato, Shota Asano, Hironori Suzuki, Nobuyuki Tanimura, Yohei Mukai, Noriko Gotoh, Mishie Tanino, Shinya Tanaka, Ken Natsuga, Tomoyoshi Soga, Tomonori Nakamura, Yukihiro Yabuta, Mitinori Saitou, Takahiro Ito, Kenkyo Matsuura, Makoto Tsunoda, Toyone Kikumori, Tadashi Iida, Yasuyuki Mizutani, Yuki Miyai, Kozo Kaibuchi, Atsushi Enomoto, Yasuyuki Fujita

Current biology : CB Vol. 31 ( 14 ) page： 3086 - + 2021.7

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

At the early stage of cancer development, oncogenic mutations often cause multilayered epithelial structures. However, the underlying molecular mechanism still remains enigmatic. By performing a series of screenings targeting plasma membrane proteins, we have found that collagen XVII (COL17A1) and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. In addition, the expression of COL17A1 and CD44 is also regulated by cell density and upon apical cell extrusion. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and reactive oxygen species (ROS) production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. To further understand the functional role of COL17A1, we performed comprehensive metabolome analysis and compared intracellular metabolites between RasV12 and COL17A1-knockout RasV12 cells. The data imply that COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I through succinate, thereby suppressing the ROS production. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions.

DOI： 10.1016/j.cub.2021.04.078

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Meflin defines mesenchymal stem cells and/or their early progenitors with multilineage differentiation capacity. Reviewed International journal

Akitoshi Hara, Katsuhiro Kato, Toshikazu Ishihara, Hiroki Kobayashi, Naoya Asai, Shinji Mii, Yukihiro Shiraki, Yuki Miyai, Ryota Ando, Yasuyuki Mizutani, Tadashi Iida, Mikito Takefuji, Toyoaki Murohara, Masahide Takahashi, Atsushi Enomoto

Genes to cells : devoted to molecular & cellular mechanisms Vol. 26 ( 7 ) page： 495 - 512 2021.7

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Mesenchymal stem cells (MSCs) are the likely precursors of multiple lines of mesenchymal cells. The existence of bona fide MSCs with self-renewal capacity and differentiation potential into all mesenchymal lineages, however, has been unclear because of the lack of MSC-specific marker(s) that are not expressed by the terminally differentiated progeny. Meflin, a glycosylphosphatidylinositol-anchored protein, is an MSC marker candidate that is specifically expressed in rare stromal cells in all tissues. Our previous report showed that Meflin expression becomes down-regulated in bone marrow-derived MSCs cultured on plastic, making it difficult to examine the self-renewal and differentiation of Meflin-positive cells at the single-cell level. Here, we traced the lineage of Meflin-positive cells in postnatal and adult mice, showing that those cells differentiated into white and brown adipocytes, osteocytes, chondrocytes and skeletal myocytes. Interestingly, cells derived from Meflin-positive cells formed clusters of differentiated cells, implying the in situ proliferation of Meflin-positive cells or their lineage-committed progenitors. These results, taken together with previous findings that Meflin expression in cultured MSCs was lost upon their multilineage differentiation, suggest that Meflin is a useful potential marker to localize MSCs and/or their immature progenitors in multiple tissues.

DOI： 10.1111/gtc.12855

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The BMP antagonist gremlin 1 contributes to the development of cortical excitatory neurons, motor balance and fear responses. Reviewed International journal

Mari Ichinose, Nobumi Suzuki, Tongtong Wang, Hiroki Kobayashi, Laura Vrbanac, Jia Q Ng, Josephine A Wright, Tamsin R M Lannagan, Krystyna A Gieniec, Martin Lewis, Ryota Ando, Atsushi Enomoto, Simon Koblar, Paul Thomas, Daniel L Worthley, Susan L Woods

Development (Cambridge, England) Vol. 148 ( 14 ) 2021.7

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

Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here, we show that expression of the BMP antagonist Grem1 marks committed layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA-seq analysis of differentially expressed transcripts between FACS-sorted Grem1-positive and -negative cells was performed. We also generated Emx1-cre-mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI, and impaired motor balance and fear sensitivity compared with littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.

DOI： 10.1242/dev.195883

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Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages. Reviewed International journal

Masahide Inoue, Koji Sakamoto, Atsushi Suzuki, Shinya Nakai, Akira Ando, Yukihiko Shiraki, Yoshio Nakahara, Mika Omura, Atsushi Enomoto, Ikuhiko Nakase, Makoto Sawada, Naozumi Hashimoto

Particle and fibre toxicology Vol. 18 ( 1 ) page： 21 - 21 2021.6

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

BACKGROUND: As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties. RESULTS: We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH2) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH2 induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH2 was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs. CONCLUSIONS: Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.

DOI： 10.1186/s12989-021-00415-0

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A new primate model of hypophyseal dysfunction. International journal

Teppei Kawabata, Hidetaka Suga, Kazuhito Takeuchi, Yuichi Nagata, Mayu Sakakibara, Kaori Ushida, Chikafumi Ozone, Atsushi Enomoto, Ikuo Kawamoto, Iori Itagaki, Hideaki Tsuchiya, Hiroshi Arima, Toshihiko Wakabayashi

Scientific reports Vol. 11 ( 1 ) page： 10729 - 10729 2021.5

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

For pituitary regenerative medicine, the creation of a hypophyseal model in monkeys is necessary to conduct future preclinical studies; however, previous studies reported that hypophysectomy in monkeys is not always safe or satisfactory. This study aimed to create a hypophyseal dysfunction model in a cynomolgus monkey using a safer surgical technique and establish the protocol of pituitary hormone replacement therapy for this model. Surgical resection of the pituitary gland of a 7.8-year-old healthy adult cynomolgus male monkey weighing 5.45 kg was performed to create a hypophyseal dysfunction model for future regenerative studies. Endoscopic transoral transsphenoidal surgery was used to perform hypophysectomy under navigation support. These procedures were useful for confirming total removal of the pituitary gland without additional bone removal and preventing complications such as cerebrospinal fluid leakage. Total removal was confirmed by pathological examination and computed tomography. Hypopituitarism was verified with endocrinological examinations including stimulation tests. Postoperatively, the monkey's general condition of hypopituitarism was treated with hormone replacement therapy, resulting in long-term survival. The success of a minimally invasive and safe surgical method and long-term survival indicate the creation of a hypophyseal dysfunction model in a cynomolgus monkey; hence, this protocol can be employed in the future.

DOI： 10.1038/s41598-021-90209-3

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CD4+ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. Reviewed International journal

Yoshinori Yasuda, Shintaro Iwama, Daisuke Sugiyama, Takayuki Okuji, Tomoko Kobayashi, Masaaki Ito, Norio Okada, Atsushi Enomoto, Sachiko Ito, Yue Yan, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Hiroshi Takagi, Daisuke Hagiwara, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Masahide Takahashi, Hiroyoshi Nishikawa, Hiroshi Arima

Science translational medicine Vol. 13 ( 593 ) 2021.5

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

Immune-related adverse events induced by anti-programmed cell death-1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

DOI： 10.1126/scitranslmed.abb7495

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Oncolytic activity of naturally attenuated herpes-simplex virus HF10 against an immunocompetent model of oral carcinoma. Reviewed International journal

Gaku Takano, Shinichi Esaki, Fumi Goshima, Atsushi Enomoto, Yoshimi Hatano, Haruka Ozaki, Takahiro Watanabe, Yoshitaka Sato, Daisuke Kawakita, Shingo Murakami, Takayuki Murata, Yukihiro Nishiyama, Shinichi Iwasaki, Hiroshi Kimura

Molecular therapy oncolytics Vol. 20 page： 220 - 227 2021.3

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

Prognosis for advanced oral carcinoma remains poor. Oncolytic virotherapy uses replication-competent viruses to infect and kill only the tumor cells. However, it has been difficult to investigate the oncolytic activity of viruses against oral carcinomas in mouse models. This study established a mouse model of oral cancer and investigated the in vitro and in vivo anti-tumor effects of HF10, a highly attenuated, replication-competent herpes simplex virus (HSV)-1. Mouse tongue cancer was induced by injecting 4-nitroquinoline 1-oxide into the mouse tongue. The murine oral cancer cell line isolated from this tumor, named NMOC1, formed invasive carcinoma within a week when injected into mouse tongue. HF10 successfully infected, replicated, and spread in the cancer cells in vitro. HF10 was able to kill cancer cells isolated from human or mouse tongue tumor. HF10 injection into tongue carcinomas prolonged mouse survival without any side effects or weight loss. Intertumoral injection of GFP-expressing HF10 confirmed that viral spread was confined within the tumors. Immunohistochemical staining showed that HF10 induced infiltration of CD8-positive T cells around HSV-infected cells in the tumor mass, implying increased anti-tumor immunity. We successfully established an oral cancer cell line and showed that HF10 is a promising therapeutic agent for oral cancer.

DOI： 10.1016/j.omto.2020.12.007

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The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis. Reviewed International journal

Hiroki Kobayashi, Krystyna A Gieniec, Josephine A Wright, Tongtong Wang, Naoya Asai, Yasuyuki Mizutani, Tadashi Lida, Ryota Ando, Nobumi Suzuki, Tamsin R M Lannagan, Jia Q Ng, Akitoshi Hara, Yukihiro Shiraki, Shinji Mii, Mari Ichinose, Laura Vrbanac, Matthew J Lawrence, Tarik Sammour, Kay Uehara, Gareth Davies, Leszek Lisowski, Ian E Alexander, Yoku Hayakawa, Lisa M Butler, Andrew C W Zannettino, M Omar Din, Jeff Hasty, Alastair D Burt, Simon J Leedham, Anil K Rustgi, Siddhartha Mukherjee, Timothy C Wang, Atsushi Enomoto, Masahide Takahashi, Daniel L Worthley, Susan L Woods

Gastroenterology Vol. 160 ( 4 ) page： 1224 - + 2021.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. METHODS: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. RESULTS: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. CONCLUSIONS: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

DOI： 10.1053/j.gastro.2020.11.011

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Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice. Reviewed International journal

Quang Linh Nguyen, Noriko Okuno, Takeru Hamashima, Son Tung Dang, Miwa Fujikawa, Yoko Ishii, Atsushi Enomoto, Takakuni Maki, Hoang Ngoc Nguyen, Van Tuyen Nguyen, Toshihiko Fujimori, Hisashi Mori, Johanna Andrae, Christer Betsholtz, Keizo Takao, Seiji Yamamoto, Masakiyo Sasahara

Angiogenesis Vol. 24 ( 1 ) page： 35 - 46 2021.2

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

Blood-brain barrier (BBB) dysfunction underlies the pathogenesis of many neurological diseases. Platelet-derived growth factor receptor-alpha (PDGFRα) induces hemorrhagic transformation (HT) downstream of tissue plasminogen activator in thrombolytic therapy of acute stroke. Thus, PDGFs are attractive therapeutic targets for BBB dysfunction. In the present study, we examined the role of PDGF signaling in the process of tissue remodeling after middle cerebral arterial occlusion (MCAO) in mice. Firstly, we found that imatinib increased lesion size after permanent MCAO in wild-type mice. Moreover, imatinib-induced HT only when administrated in the subacute phase of MCAO, but not in the acute phase. Secondly, we generated genetically mutated mice (C-KO mice) that showed decreased expression of perivascular PDGFRα. Additionally, transient MCAO experiments were performed in these mice. We found that the ischemic lesion size was not affected; however, the recruitment of PDGFRα/type I collagen-expressing perivascular cells was significantly downregulated, and HT and IgG leakage was augmented only in the subacute phase of stroke in C-KO mice. In both experiments, we found that the expression of tight junction proteins and PDGFRβ-expressing pericyte coverage was not significantly affected in imatinib-treated mice and in C-KO mice. The specific implication of PDGFRα signaling was suggestive of protective effects against BBB dysfunction during the subacute phase of stroke. Vascular TGF-β1 expression was downregulated in both imatinib-treated and C-KO mice, along with sustained levels of MMP9. Therefore, PDGFRα effects may be mediated by TGF-β1 which exerts potent protective effects in the BBB.

DOI： 10.1007/s10456-020-09742-w

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Tumor microenvironment stimulates induction of cancer associated fibroblasts

Nakahara, R; Kato, M; Jiang, JR; Nishida, M; Tsuchida, R; Shimamura, T; Enomoto, A; Osawa, T

CANCER SCIENCE Vol. 112 page： 723 - 723 2021.2

CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling

Mii, S; Taki, T; Shiraki, Y; Enomoto, A; Takahashi, M

CANCER SCIENCE Vol. 112 page： 815 - 815 2021.2

CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling. Reviewed International journal

Tetsuro Taki, Yukihiro Shiraki, Atsushi Enomoto, Liang Weng, Chen Chen, Naoya Asai, Yoshiki Murakumo, Kohei Yokoi, Masahide Takahashi, Shinji Mii

Cancer science Vol. 111 ( 12 ) page： 4616 - 4628 2020.12

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

Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109-deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF-β binding protein-1 (LTBP1) as a CD109-interacting protein using mass spectrometry and confirmed their interaction by co-immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF-β activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF-β signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease.

DOI： 10.1111/cas.14673

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The Daple-CK1ε complex regulates Dvl2 phosphorylation and canonical Wnt signaling. Reviewed International journal

Nobutoshi Esaki, Atsushi Enomoto, Maki Takagishi, Yasuyuki Mizutani, Tadashi Iida, Kaori Ushida, Yukihiro Shiraki, Shinji Mii, Masahide Takahashi

Biochemical and biophysical research communications Vol. 532 ( 3 ) page： 406 - 413 2020.11

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

The canonical Wnt signaling pathway plays a crucial role in embryonic development, tissue homeostasis and cancer progression. The binding of Wnt ligands to their cognate receptors, the Frizzled (Fzd) family of proteins, recruits Dishevelled segment polarity protein (Dvl) to the plasma membrane and induces its phosphorylation via casein kinase 1 (CK1), which leads to the activation of β-catenin. Previous studies showed that Dishevelled-associating protein with a high frequency of leucine residues (Daple) is an important component of the Wnt signaling pathway and essential for Dvl phosphorylation. However, the mechanism by which Daple promotes CK1-mediated phosphorylation of Dvl is not fully understood. In this study, we found that Daple overexpression induced CK1ε-mediated Dvl2 phosphorylation at threonine 224 (Thr224). A Daple mutant (Daple ΔGCV) that lacks a carboxyl-terminal motif to associate with Dvl, retained the ability to interact with CK1ε, but did not induce Dvl phosphorylation, suggesting the importance of the Daple/Dvl/CK1ε trimeric protein complex. We further found that Thr224 phosphorylation of Dvl was required for full activation of β-catenin transcriptional activity. Consistent with this, wild-type Daple promoted β-catenin transcriptional activity, following dissociation of β-catenin and axin. Finally, Wnt3a stimulation increased the membrane localization of Daple and its association with Dvl, and Daple knockdown attenuated Wnt3a-mediated β-catenin transcriptional activity. Collectively, these data suggested a essential role of spatial Daple localization in CK1ε-mediated activation of Dvl in the canonical Wnt signaling pathway.

DOI： 10.1016/j.bbrc.2020.08.066

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Stromal imbalance of bone morphogenetic protein signaling drives colorectal carcinogenesis

Kobayashi, H; Gieniec, K; Wright, J; Wang, T; Asai, N; Mizutani, Y; Ida, T; Ando, R; Suzuki, N; Lannagan, T; Ng, J; Hara, A; Shiraki, Y; Mii, S; Ichinose, M; Vrbanac, L; Lawrence, M; Sammour, T; Uehara, K; Davies, G; Lisowski, L; Alexander, I; Hayakawa, Y; Butler, L; Zannettino, A; Din, MO; Hasty, J; Burt, A; Leedham, S; Rustgi, A; Wang, ST; Wang, TC; Enomoto, A; Takahashi, M; Worthley, D; Woods, S

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Vol. 35 page： 160 - 160 2020.11

Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells. Reviewed International journal

Chen Chen, Atsushi Enomoto, Liang Weng, Tetsuro Taki, Yukihiro Shiraki, Shinji Mii, Ryosuke Ichihara, Mitsuro Kanda, Masahiko Koike, Yasuhiro Kodera, Masahide Takahashi

Cancer science Vol. 111 ( 11 ) page： 4303 - 4317 2020.11

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

The actin-binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage-induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV-mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics.

DOI： 10.1111/cas.14637

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Generation of a mouse model of gastric adenocarcinoma and proximal polyposis of the stomach that causes stomach hyperplasia

Suzuki, N; Wright, J; Kobayashi, H; Wang, T; Ichinose, M; Vrbanac, L; Ng, J; Gieniec, K; Lannagan, T; Fujiwara, H; Enomoto, A; Chenevix-Trench, G; Hayakawa, Y; Koike, K; Woods, S; Worthley, D

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Vol. 35 page： 165 - 165 2020.11

Melanoma cell adhesion molecule defines a proliferative subset of leptin receptor-lineage cells that substantially contribute to the colorectal cancer stroma

Gieniec, K; Kobayashi, H; Lannagan, T; Wang, T; Asai, N; Mizutani, Y; Ida, T; Ando, R; Suzuki, N; Ichinose, M; Wright, J; Vrbanac, L; Ng, J; Lawrence, M; Sammour, T; Hayakawa, Y; Klebe, S; Shin, AE; Asfaha, S; Arpaia, N; Butler, L; Burt, A; Leedham, S; Rustgi, A; Mukherjee, S; Takahashi, M; Wang, T; Enomoto, A; Woods, S; Worthley, D

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Vol. 35 page： 163 - 163 2020.11

Connective tissue growth factor produced by cancer‑associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma. Reviewed International journal

Yuuki Ohara, Atsushi Enomoto, Yuta Tsuyuki, Kotaro Sato, Tadashi Iida, Hiroki Kobayashi, Yasuyuki Mizutani, Yuki Miyai, Akitoshi Hara, Shinji Mii, Jun Suzuki, Kyoko Yamashita, Fumiya Ito, Yashiro Motooka, Nobuaki Misawa, Takayuki Fukui, Koji Kawaguchi, Kohei Yokoi, Shinya Toyokuni

Oncology reports Vol. 44 ( 3 ) page： 838 - 848 2020.9

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

Malignant mesothelioma is an aggressive neoplasm for which effective treatments are lacking. We often encounter mesothelioma cases with a profound desmoplastic reaction, suggesting the involvement of cancer‑associated fibroblasts (CAFs) in mesothelioma progression. While the roles of CAFs have been extensively studied in other tumors and have led to the view that the cancer stroma contains heterogeneous populations of CAFs, their roles in mesothelioma remain unknown. We previously showed that connective tissue growth factor (CTGF), a secreted protein, is produced by both mesothelioma cells and fibroblasts and promotes the invasion of mesothelioma cells in vitro. In this study, we examined the clinical relevance of CAFs in mesothelioma. Using surgical specimens of epithelioid malignant pleural mesothelioma, we evaluated the clinicopathological significance of the expression of α‑smooth muscle actin (αSMA), the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry and Elastica‑Masson staining. We also analyzed the expression of mesenchymal stromal cell‑ and fibroblast‑expressing Linx paralogue (Meflin; ISLR), a recently reported CAF marker that labels cancer‑restraining CAFs and differ from αSMA‑positive CAFs, by in situ hybridization. The extent of fibrosis and CTGF expression in mesothelioma cells did not correlate with patient prognosis. However, the expression of αSMA and CTGF, but not Meflin, in CAFs correlated with poor prognosis. The data suggest that CTGF+ CAFs are involved in mesothelioma progression and represent a potential molecular target for mesothelioma therapy.

DOI： 10.3892/or.2020.7669

Web of Science

PubMed

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<ENOMOTO, Atsushi>

Papers - ENOMOTO, Atsushi