Details of a Researcher - KOJIMA Takashi

Papers - KOJIMA Takashi

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細胞密度に依存的なLSRの膜での局在変化はミオシン活性と相関する

幸野貴之, 嶋田浩志, 金野匠, 小島隆

日本病理学会会誌 ( (一社)日本病理学会 ) 106 ( 1 ) 356 - 356 2017.03

Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer

Hiroshi Shimada, Shyuetsu Abe, Takayuki Kohno, Seiro Satohisa, Takumi Konno, Syunta Takahashi, Tsubasa Hatakeyama, Chihiro Arimoto, Takuya Kakuki, Yakuto Kaneko, Ken-ichi Takano, Tsuyoshi Saito, Takashi Kojima

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP ) 7 2017.01 [Refereed]

Lipolysis-stimulated lipoprotein receptor (LSR) is a unique molecule of tricellular contacts of normal and cancer cells. We investigated how the loss of LSR induced cell migration, invasion and proliferation in endometrial cancer cell line Sawano. mRNAs of amphiregulin (AREG) and TEA domain family member 1 (TEAD1) were markedly upregulated by siRNA-LSR. In endometrial cancer tissues, downregulation of LSR and upregulation of AREG were observed together with malignancy, and Yes-associated protein (YAP) was present in the nuclei. siRNA-AREG prevented the cell migration and invasion induced by siRNA-LSR, whereas treatment with AREG induced cell migration and invasion. LSR was colocalized with TRIC, angiomotin (AMOT), Merlin and phosphorylated YAP (pYAP). siRNA-LSR increased expression of pYAP and decreased that of AMOT and Merlin. siRNA-YAP prevented expression of the mRNAs of AREG and TEAD1, and the cell migration and invasion induced by siRNA-LSR. Treatment with dobutamine and 2-deoxy-D-glucose and glucose starvation induced the pYAP expression and prevented the cell migration and invasion induced by siRNA-LSR. siRNA-AMOT decreased the Merlin expression and prevented the cell migration and invasion induced by siRNA-LSR. The loss of LSR promoted cell invasion and migration via upregulation of TEAD1/AREG dependent on YAP/pYAP and AMOT/Merlin in human endometrial cancer cells.

DOI PubMed

Histone deacetylase inhibition prevents cell death induced by loss of tricellular tight junction proteins in temperature-sensitive mouse cochlear cells.

Kenichi Takano, Takuya Kakuki, Yakuto Kaneko, Takayuki Kohno, Shin Kikuchi, Tetsuo Himi, Takashi Kojima

PloS one 12 ( 8 ) e0182291 2017 [International journal]

Tricellular tight junctions (tTJs) are specialized structures that occur where the corners of three cells meet to seal adjacent intercellular space. The molecular components of tTJs include tricellulin (TRIC) and lipolysis-stimulated lipoprotein receptor (LSR) which recruits TRIC, are required for normal hearing. Although loss of TRIC causes hearing loss with degeneration of cochlear cells, the detailed mechanisms remains unclear. In the present study, by using temperature-sensitive mouse cochlear cells, US/VOT-E36 cell line, we investigated the changes of TRIC and LSR during cochlear cell differentiation and the effects of histone deacetylase (HDAC) inhibitors against cell degeneration induced by loss of TRIC and LSR. During cell differentiation induced by the temperature change, expression of TRIC and LSR were clearly induced. Treatment with metformin enhanced expression TRIC and LSR via AMPK during cell differentiation. Loss of TRIC and LSR by the siRNAs induced cell death in differentiated cells. Treatment with HDAC inhibitors trichostatin A and HDAC6 inhibitor prevented the cell death induced by loss of TRIC and LSR. Collectively, these findings suggest that both tTJ proteins TRIC and LSR have crucial roles for the differentiated cochlear cell survival, and that HDAC inhibitors may be potential therapeutic agents to prevent hearing loss.

DOI PubMed

Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3

Keisuke Yamamoto, Soh Yamamoto, Noriko Ogasawara, Kenichi Takano, Tsukasa Shiraishi, Toyotaka Sato, Ryo Miyata, Takuya Kakuki, Ryuta Kamekura, Takashi Kojima, Hiroyuki Tsutsumi, Tetsuo Himi, Shin-ichi Yokota

PHARMACOLOGICAL RESEARCH ( ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD ) 111 804 - 814 2016.09 [Refereed]

Macrolide antibiotics exert immunomodulatory activity by reducing pro-inflammatory cytokine production by airway epithelial cells, fibroblasts, vascular endothelial cells, and immune cells. However, the underlying mechanism of action remains unclear. Here, we examined the effect of clarithromycin (CAM) on pro-inflammatory cytokine production, including interferons (IFNs), by primary human nasal epithelial cells and lung epithelial cell lines (A549 and BEAS-2B cells) after stimulation by Toll-like receptor (TLR) and RIG-I-like receptor (RLR) agonists and after infection by human respiratory syncytial virus (RSV). CAM treatment led to a significant reduction in poly I:C-and RSV-mediated IL-8, CCL5, IFN-beta and -lambda production. Furthermore, IFN-beta promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM. CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus. We conclude that CAM acts a crucial modulator of the innate immune response, particularly IFN production, by modulating IRF-3 dimerization and subsequent translocation to the nucleus of airway epithelial cells. This newly identified immunomodulatory action of CAM will facilitate the discovery of new macrolides with an anti-inflammatory role. (C) 2016 Elsevier Ltd. All rights reserved.

DOI

Dysregulation of junctional adhesion molecule-A via p63/GATA-3 in head and neck squamous cell carcinoma

Takuya Kakuki, Makoto Kurose, Ken-ichi Takano, Atsushi Kondoh, Kazufumi Obata, Kazuaki Nomura, Ryo Miyata, Yakuto Kaneko, Takumi Konno, Syunta Takahashi, Tsubasa Hatakeyama, Takayuki Kohno, Tetsuo Himi, Takashi Kojima

ONCOTARGET ( IMPACT JOURNALS LLC ) 7 ( 23 ) 33887 - 33900 2016.06 [Refereed]

Junctional adhesion molecule-A (JAM-A), which belongs to the IgG superfamily, is a tight junction molecule associated with epithelial and endothelial barrier function. Overexpression of JAM-A is also closely associated with invasion and metastasis of cancers such as breast cancer, lung cancer and pancreatic cancer. However, little is known about the mechanism in overexpression of JAM-A in head and neck squamous cell carcinoma (HNSCC). In the present study, we found high expression of JAM-A at the protein and mRNA levels in HNSCC tissues, including those of the oropahrynx, larynx, and hypopharynx, together with high protein expression of beta-catenin, p63, Delta Np63 and GATA-3. Furthermore, in ELISA, a significant increase of soluble JAM-A in the sera of HNSCC patients was observed compared to healthy subjects. Knockdown of JAM-A by siRNA inhibited cell proliferation, invasion and migration in the HNSCC cell line Detroit562 in vitro. JAM-A expression in Detroit562 was increased via a distinct signal transduction pathway including NF-kappa B. Expression of JAM-A, beta-catenin, p63 and Delta Np63 in Detroit562 was decreased under hypoxia. Knockdown of p63, Delta Np63 or GATA-3 by siRNAs reduced JAM-A expression in Detroit562. In primary cultured HNSCC cells in which CK7, p63, Delta Np63 and GATA-3 were detected, JAM-A expression was decreased by knockdown of p63 or Delta Np63. These results indicate that JAM-A is a biomarker of malignancy in HNSCC and that plasma soluble JAM-A may contribute to serum-based diagnosis of HNSCC. The mechanism of dysregulation of JAM-A via p63/GATA-3 is important in possible molecular targeted therapy for HNSCC.

DOI PubMed

The roles of tricellular tight junction protein lipolysis-stimulated lipoprotein receptor in malignancy of human endometrial cancer cells

Hiroshi Shimada, Seiro Satohisa, Takayuki Kohno, Syunta Takahashi, Tsubasa Hatakeyama, Takumi Konno, Mitsuhiro Tsujiwaki, Tsuyoshi Saito, Takashi Kojima

ONCOTARGET ( IMPACT JOURNALS LLC ) 7 ( 19 ) 27735 - 27752 2016.05 [Refereed]

Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a novel molecular constituent of tricellular contacts that have a barrier function for the cellular sheet. LSR recruits tricellulin (TRIC), which is the first molecular component of tricellular tight junctions. Knockdown of LSR increases cell motility and invasion of certain cancer cells. However, the behavior and the roles of LSR in endometrial cancer remain unknown. In the present study, we investigated the behavior and roles of LSR in normal and endometrial cancer cells in vivo and in vitro. In endometriosis and endometrial cancer, LSR was observed not only in the subapical region but also throughout the lateral region as well as in normal endometrial epithelial cells in the secretory phase, and LSR in the cancer was reduced in correlation with the malignancy. Knockdown of LSR by the siRNA in cells of the endometrial cancer cell line Sawano, induced cell migration, invasion and proliferation, while TRIC relocalized from the tricellular region to the bicellular region at the membrane. In Sawano cells and normal HEEs, a decrease of LSR induced by leptin and an increase of LSR induced by adiponectin and the drugs for type 2 diabetes metformin and berberine were observed via distinct signaling pathways including JAK2/STAT. In Sawano cells, metformin and berberine prevented cell migration and invasion induced by downregulation of LSR by the siRNA and leptin treatment. The dissection of the mechanism in the downregulation of endometrial LSR during obesity is important in developing new diagnostic and therapy for endometrial cancer.

DOI PubMed

Junctional adhesion molecule - A in head and neck squamous cell carcinoma

Makoto Kurose, Takuya Kakuki, Kenichi Takano, Atsushi Kondo, Kazufumi Obata, Kazuaki Nomura, Ryo Miyata, Yakuto Kaneko, Takumi Konno, Takayuki Kohno, Takashi Kojima, Tetsuo Himi

Advances in Oto-Rhino-Laryngology ( S. Karger AG ) 77 92 - 97 2016 [Refereed]

Junctional adhesion molecule-A (JAM-A), which belongs to the IgG superfamily, is one of the tight junction molecules. JAM-A is dysregulated in various cancers and is closely associated with the invasion and metastasis of cancers such as breast cancer, lung cancer and pancreatic cancer. In the present study, we found a high expression of JAM-A in head and neck squamous cell carcinoma (HNSCC) as well as β-catenin in immunohistochemistry. The expression of JAM-A and β-catenin was of a low level in differentiation-induced cancer pearl regions of HNSCC. Real-time PCR showed the high expression of JAM-A mRNA through all differentiated stages (well, moderate, poor) of HNSCC. When we performed ELISA using the serum of HNSCC patients to measure plasma-soluble JAM-A, it was found to be higher in HNSCC patients than healthy subjects. These results indicate that JAM-A is one of the malignancy markers of HNSCC as well as β-catenin in histopathology, and the plasma-soluble JAM-A may contribute to a serum diagnosis of HNSCC. JAM-A is a promising molecular target for diagnosis and therapy in HNSCC.

DOI PubMed

Behavior of Primary Cilia and Tricellular Tight Junction Proteins during Differentiation in Temperature-Sensitive Mouse Cochlear Precursor Hair Cells.

Kakuki T, Kaneko Y, Takano K, Ninomiya T, Kohno T, Kojima T, Himi T

Adv. Otorhinolaryngol. 77:27-32. 2016 [Refereed]

PubMed

The behavior and role of lipolysis-stimulated lipoprotein receptor, a component of tricellular tight junctions, in head and neck squamous cell carcinomas.

Takano K, Kakuki T, Obata K, Nomura K, Miyata R, Kondo A, Kurose M, Kakiuch A, Kaneko Y, Kohno T, Himi T, Kojima T

Anticancer Research 36(11):5895-5904. 2016 [Refereed]

PubMed

Claudin-4 binder C-CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway.

Tsuyoshi Kono, Masuo Kondoh, Daisuke Kyuno, Tatsuya Ito, Yasutoshi Kimura, Masafumi Imamura, Takayuki Kohno, Takumi Konno, Tomohisa Furuhata, Norimasa Sawada, Koichi Hirata, Takashi Kojima

Pharmacology research & perspectives 3 ( 6 ) e00196 2015.12 [Refereed] [International journal]

The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) modulates the tight junction protein claudin and disrupts the tight junctional barrier. It also can enhance the effectiveness of anticancer agents. However, the detailed mechanisms of the effects of C-CPE remain unclear in both normal and cancerous cells. The C-CPE mutant called C-CPE 194 binds only to claudin-4, but the C-CPE 194 mutant called C-CPE m19 binds not only to claudin-4 but also to claudin-1. In the present study, to investigate the mechanisms of the effects of C-CPE on claudin expression, the tight junctional functions and the cytotoxicity of anticancer agents, human pancreatic cancer cells, and normal human pancreatic duct epithelial cells (HPDEs) were treated with C-CPE 194 and C-CPE m19. In well-differentiated cells of the pancreatic cancer cell line HPAC, C-CPE 194 and C-CPE m19 disrupted both the barrier and fence functions without changes in expression of claudin-1 and -4, together with an increase of MAPK phosphorylation. C-CPE 194, but not C-CPE m19, enhanced the cytotoxicity of the anticancer agents gemcitabine and S-1. In poorly differentiated pancreatic cancer cell line PANC-1, C-CPE 194, but not C-CPE m19, decreased claudin-4 expression and enhanced MAPK activity and the cytotoxicity of the anticancer agents. In normal HPDEs, C-CPE 194 and C-CPE m19 decreased claudin-4 expression and enhanced the MAPK activity, whereas they did not affect the cytotoxicity of the anticancer agents. Our findings suggest that the claudin-4 binder C-CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway.

DOI PubMed

肥満によるヒト子宮内膜癌の悪性化におけるlipolysis-stimulated lipoprotein receptorの役割

小島隆, 嶋田浩志, 郷久晴朗, 金野匠, 高橋俊太, 畠山翔翼, 有元千尋, 野島伊世里, 齋藤豪, 幸野貴之

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 ( (公社)日本生化学会 ) 88回・38回 [3T18p - 01(3P1048)] 2015.12

Poly(I:C) induced microRNA-146a regulates epithelial barrier and secretion of proinflammatory cytokines in human nasal epithelial cells

Ryo Miyata, Takuya Kakuki, Kazuaki Nomura, Tsuyoshi Ohkuni, Noriko Ogasawara, Ken-ichi Takano, Takumi Konno, Takayuki Kohno, Norimasa Sawada, Tetsuo Himi, Takashi Kojima

EUROPEAN JOURNAL OF PHARMACOLOGY ( ELSEVIER SCIENCE BV ) 761 375 - 382 2015.08 [Refereed]

Human nasal epithelial cells (HNECs) are important in the tight junctional barrier and innate immune defense protecting against pathogens invading via Toll-like receptors (TERs). MicroRNAs (miRNAs) I egulate expression of tight junctions as direct or indirect targeting genes and maintain the barrier Function. However, the roles of miRNAs in the epithelial barrier of HNECs via TLRs remain unknown. In the present study, to investigate the effects of miRNAs on the epithelial barrier of HNECs via TLRs, primary cultured HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs), were treated with the TLR3 ligand poly(I:C) and miRNA array analysis was performed. In the miRNA array of the cells treated with poly(I:C), upregulation of miR-187, -146a, -574, -4274, -4433, -4455 and -4750, and downregulation of miR-4785 by more than twofold compared to the control were observed. When control HNECs were treated with mimics and inhibitors of these miRNAs, an miR-146a mimic induced expression of tight junction proteins claudin-1, occludin and JAM-A together with an increase of the epithelial barrier function. The poly(I:C)-induced miR-146a was regulated via the distinct TLR3-mediatecl signal pathways PI3K, JNK and NE-kappa B. Furthermore, the miR-146a mimic prevented downregulation of claudin-1 and JAM-A and the secretion of proinflammatory cytokines IL-8 and TNF-alpha induced by poly (I:C) by targeting TRAFG. These findings indicate that, in HNECs, miRNA-146a plays crucial roles in maintenance of the tight junction barrier and innate immune defense protecting against invading pathogens. (C) 2015 Elsevier B.V. All rights reserved.

DOI

Staurosporine Induces Formation of Two Types of Extra-Long Cell Protrusions: Actin-Based Filaments and Microtubule-Based Shafts

Takayuki Kohno, Takafumi Ninomiya, Shin Kikuchi, Takumi Konno, Takashi Kojima

MOLECULAR PHARMACOLOGY ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 87 ( 5 ) 815 - 824 2015.05 [Refereed]

Staurosporine (STS) has been known as a classic protein kinase C inhibitor and is a broad-spectrum inhibitor targeting over 250 protein kinases. In this study, we observed that STS treatment induced drastic morphologic changes, such as elongation of a very large number of nonbranched, actin-based long cell protrusions that reached up to 30 mu m in an hour without caspase activation or PARP cleavage in fibroblasts and epithelial cells. These cell protrusions were elongated not only from the free cell edge but also from the cell-cell junctions. The elongation of STS-dependent protrusions was required for ATP hydrolysis and was dependent on myosin-X and fascin but independent of Cdc42 and VASP. Interestingly, in the presence of an actin polymerization inhibitor, namely, cytochalasin D, latrunculin A, or jasplakinolide, STS treatment induced excess tubulin polymerization, which resulted in the formation of many extra-long microtubule (MT)-based protrusions toward the outside of the cell. The unique MT-based protrusions were thick and linear compared with the STS-induced filaments or stationary filopodia. These protrusions, which were composed of microtubules, have been scarcely observed in cultured non-neuronal cells. Taken together, our findings revealed that STS-sensitive kinases are essential for the maintenance of normal cell morphology, and a common unidentified molecular mechanism is involved in the formation of the following two different types of protrusions: actin-based filaments and MT-based shafts.

DOI PubMed

Irsogladine maleate regulates gap junctional intercellular communication-dependent epithelial barrier in human nasal epithelial cells.

Miyata R, Nomura K, Kakuki T, Takano K, Kohno T, Konno T, Sawada N, Himi T, Kojima T

The Journal of membrane biology ( 2 ) 248 327 - 336 2015.04 [Refereed]

DOI PubMed

Aberrant expression of claudin-4 and -7 in hepatocytes in the cirrhotic human liver

Tsujiwaki M, Murata M, Takasawa A, Hiratsuka Y, Fukuda R, Sugimoto K, Ono Y, Nojima M, Tanaka S, Hirata K, Kojima T, Sawada N

Med Mol Morphol 48 ( 1 ) 33 - 43 2015.03 [Refereed]

DOI PubMed

扁桃・アデノイドはなぜあるのか?鼻はなにをしているのか? 粘膜免疫・粘膜防御の最前線を探る

氷見徹夫, 高野賢一, 山下恵司, 小笠原徳子, 山本圭佑, 堤裕幸, 小島隆, 一宮慎吾, 澤田典均, 横田伸一

顎顔面口腔育成会誌 ( 顎顔面口腔育成研究会 ) 3 ( 1 ) 3 - 6 2015.03

粘膜防御機構は自然免疫の最前線であり、上皮細胞に加えて免疫系細胞などを含む複合的なシステムで構築されている。耳鼻咽喉科領域では扁桃・アデノイドに代表される粘膜関連リンパ装置は、その抗原捕捉機構を駆使して、免疫記憶の形成と特異的抗体産生機構に関与している。一方、上気道の最前線である鼻粘膜もまた抗原捕捉に伴う免疫反応を行っているとともに、ウイルス・細菌感染やアレルギー炎症の場としても重要である。われわれは、扁桃やアデノイド、そして鼻粘膜の上皮についての研究を行い、機械的バリアを含む自然免疫の新しい概念を提唱してきた。ここでは、われわれの研究より得られた知見をもとに、扁桃、鼻粘膜の基本的な免疫臓器としての機能解析と、それぞれの類似性・相違性、自然免疫・獲得免疫での位置づけについて言及する。(著者抄録)

Claudin-binder C-CPE mutants enhance permeability of insulin across human nasal epithelial cells.

Kojima T, Kondoh M, Keira T, Takano KI, Kakuki T, Kaneko Y, Miyata R, Nomura K, Obata K, Kohno T, Konno T, Sawada N, Himi T

Drug Deliv. 23(8):2703-2710 2015 [Refereed]

PubMed

c-Jun N-terminal kinase inhibitor SP600125 enhances barrier function and elongation of human pancreatic cancer cell line HPAC in a Ca-switch model.

Konno T, Ninomiya T, Kohno T, Kikuchi S, Sawada N, Kojima T

Histochem. Cell Biol. 143(5):471-9. 2015 [Refereed]

PubMed

Tight junction protein claudin-4 is modulated via ΔNp63 in human keratinocytes.

Kubo T, Sugimoto K, Kojima T, Sawada N, Sato N, Ichimiya S

Biochem Biophys Res Commun 455 ( 3-4 ) 205 - 211 2014.12 [Refereed]

DOI PubMed

Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer.

Daisuke Kyuno, Hiroshi Yamaguchi, Tatsuya Ito, Tsuyoshi Kono, Yasutoshi Kimura, Masafumi Imamura, Takumi Konno, Koichi Hirata, Norimasa Sawada, Takashi Kojima

World journal of gastroenterology ( 31 ) 20 ( 31 ) 10813 - 24 2014.08 [Refereed] [International journal]

Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and -18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1, -7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition (EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.

DOI PubMed

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Papers - KOJIMA Takashi