Details of a Researcher - KOUNO Takayuki

Papers - KOUNO Takayuki

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Guanylate binding protein-1-mediated epithelial barrier in human salivary gland duct epithelium.

Takumi Konno, Kenichi Takano, Yakuto Kaneko, Takuya Kakuki, Kazuaki Nomura, Ryoto Yajima, Akito Kakiuchi, Takayuki Kohno, Tetsuo Himi, Takashi Kojima

Experimental cell research 371 ( 1 ) 31 - 41 2018.10 [Refereed] [International journal]

Guanylate-binding protein-1 (GBP-1) is an interferon-inducible large GTPase involved in the epithelial barrier at tight junctions. To investigate the role of GBP-1 in the epithelial barrier, primary human salivary gland duct epithelial cells were treated with the the proinflammatory cytokines IFNγ, IL-1β, TNFα and the growth factor TGF-β. Treatment with IFNγ, IL-1β, or TNFα markedly enhanced GBP-1 and the epithelial barrier function, and induced not only CLDN-7 but also the tricellular tight junction molecule lipolysis-stimulated lipoprotein receptor (LSR). Knockdown of GBP-1 by its siRNA induced endocytosis of tight junction molecules, and prevented the increases of CLDN-7 and LSR with the upregulation of the epithelial barrier function induced by treatment with IFNγ or TNFα. Treatment with a PKCα inhibitor induced expression of GBP-1, CLDN-7 and LSR and enhanced the epithelial barrier function. In almost intact salivary gland ducts from patients with IgG4-related disease (IgG4-RD) indicated significant infiltration of IgG-positive plasma cells, expression of GBP-1, CLDN-7 and LSR was increased. These findings indicated that GBP-1 might play a crucial role in barrier function of normal human salivary gland duct epithelium and perform a preventive role in the duct epithelium of IgG4-RD disease.

DOI PubMed

The role of claudin-2 on the malignancy of human endometrioid carcinoma tissues

Satohisa Seiro, Shimada Hiroshi, Kohno Takayuki, Konno Takumi, Tamate Masato, Matsuura Motoki, Teramoto Mizue, Akimoto Taishi, Iwasaki Masahiro, Kojima Takashi, Saito Tsuyoshi

International Journal of Gynecological Cancer ( BMJ PUBLISHING GROUP ) 28 109 - 109 2018.10 [Refereed]

Cobalt inhibits motility of axonal mitochondria and induces axonal degeneration in cultured dorsal root ganglion cells of rat.

Shin Kikuchi, Takafumi Ninomiya, Takayuki Kohno, Takashi Kojima, Haruyuki Tatsumi

Cell biology and toxicology 34 ( 2 ) 93 - 107 2018.04 [Refereed] [International journal]

Cobalt is a trace element that localizes in the human body as cobalamin, also known as vitamin B12. Excessive cobalt exposure induces a peripheral neuropathy, the mechanisms of which are yet to be elucidated. We investigated how cobalt may affect mitochondrial motility in primary cultures of rat dorsal root ganglion (DRG). We observed mitochondrial motility by time-lapse imaging after DsRed2 tagging via lentivirus, mitochondrial structure using transmission electron microscopy (TEM), and axonal swelling using immunocytochemical staining. The concentration of cobaltous ion (Co2+) required to significantly suppress mitochondrial motility is lower than that required to induce axonal swelling following a 24-h treatment. Exposure to relatively low concentrations of Co2+ for 48 h suppressed mitochondrial motility without leading to axonal swelling. TEM images indicated that Co2+ induces mitochondrial destruction. Our results show that destruction of the axonal mitochondria precedes the axonal degeneration induced by Co2+ exposure.

DOI PubMed

The role of transcriptional factors FOXM1/KLF4 in glucose metabolism during EMT of pancreatic cancer

Kyuno, Takuro, Kojima, Takashi, Konno, Takumi, Kohno, Takayuki, Yamaguchi, Hiroshi, Imamura, Masafumi, Kimura, Yasutoshi, Takemasa, Ichiro

Cancer Science 2018

LOSS OF ASPP2 PROMOTES CELL INVASION AND MIGRATION VIA YAP IN HUMAN ENDOMETRIAL CANCER

Shimada, H, Satohisa, S, Konno, T, Matsuura, M, Teramoto, M, Kohno, T, Iwasaki, M, Kojima, T, Saito, T

International Journal of Gynecological Cancer 2018

Downregulation of lipolysis-stimulated lipoprotein receptor promotes cell invasion via claudin-1-mediated matrix metalloproteinases in human endometrial cancer.

Hiroshi Shimada, Seiro Satohisa, Takayuki Kohno, Takumi Konno, Ken-Ichi Takano, Syunta Takahashi, Tsubasa Hatakeyama, Chihiro Arimoto, Tsuyoshi Saito, Takashi Kojima

Oncology letters ( SPANDIDOS PUBL LTD ) 14 ( 6 ) 6776 - 6782 2017.12 [Refereed] [International journal]

Lipolysis-stimulated lipoprotein receptor (LSR) is a novel molecule present at tricellular contacts which recruits tricellulin (TRIC), a molecular component of tricellular tight junctions (tTJs). LSR and TRIC are colocalized with the bicellular tight junction (bTJ) protein claudin (CLDN)-1-based tight junction strands at tricellular corners. Knockdown of LSR in normal epithelial cells affects tTJ formation and the epithelial barrier function. In cancer cells knockdown of LSR has been demonstrated to increase cell invasion. However, the detailed mechanisms of how the downregulation of LSR enhances cell invasion in cancer remain unclear. In the present study, knockdown of LSR by small interfering RNA (siRNA) in Sawano human endometrial adenocarcinoma cells induced cell invasion. In LSR-knockdown Sawano cells, upregulation of CLDN-1 protein, which contributes to the cell invasion via matrix metalloproteinases (MMPs), was observed compared with the control group by western blotting and immunostaining. Knockdown of LSR significantly induced Sp1 transcription factor activity in the CLDN-1 promoter region. In LSR-knockdown Sawano cells, DNA microarray analysis demonstrated that MMP-1, MMP-2 and MMP-10 mRNA levels were increased, and the protein levels of membrane-type 1-MMP, MMP-2, MMP-9 and MMP-10 were shown to be increased on western blots. Knockdown of CLDN-1 with siRNA prevented the upregulation of cell invasion induced by the knockdown of LSR in Sawano cells. On the invasive front of human endometrial carcinoma tissue samples, a decrease in LSR and increase in CLDN-1 protein levels were observed using immunohistochemical methods. In conclusion, the results indicate that the downregulation of LSR promotes cell invasion of human endometrial cancer via CLDN-1 mediation of MMPs. This mechanism is important for studying the association of tTJs with the cellular invasion of cancer.

DOI PubMed

Regulation of claudin-4 via p63 in human epithelial cells.

Takashi Kojima, Takayuki Kohno, Terufumi Kubo, Yakuto Kaneko, Takuya Kakuki, Akito Kakiuchi, Makoto Kurose, Ken-Ichi Takano, Noriko Ogasawara, Kazufumi Obata, Kazuaki Nomura, Ryo Miyata, Takumi Konno, Shingo Ichimiya, Tetsuo Himi

Annals of the New York Academy of Sciences ( WILEY ) 1405 ( 1 ) 25 - 31 2017.10 [Refereed] [International journal]

P63 is a regulator of cell-cell junction complexes in the epidermis. Claudin-4 is regulated via various factors in normal epithelial cells and diseases. We found that claudin-4 was directly regulated via p63 (TAp63 and ΔNp63) in human keratinocytes and nasal epithelial cells. In the epidermis of atopic dermatitis (AD), which contains ΔNp63-deficient keratinocytes, high expression of claudin-4 was observed. In primary keratinocytes, downregulation of ΔNp63 by treatment with short interfering RNA (siRNA)-p63 induced claudin-4 expression. In nasal epithelial cells in the context of rhinitis or nasal polyps, upregulation of TAp63 and downregulation of claudin-4 were observed. In primary nasal epithelial cells transfected with the human telomerase reverse transcriptase gene, knockdown of p63 by siRNAs induced claudin-4 expression. Taken together, these findings indicate that p63 is a negative regulator of claudin-4 expression. Understanding the regulation of claudin-4 via p63 in human epithelial cells may be important for developing therapies for allergies and drug delivery systems.

DOI PubMed

The role of transcriptional factor p63 in regulation of epithelial barrier and ciliogenesis of human nasal epithelial cells.

Yakuto Kaneko, Takayuki Kohno, Takuya Kakuki, Ken-Ichi Takano, Noriko Ogasawara, Ryo Miyata, Shin Kikuchi, Takumi Konno, Tsuyoshi Ohkuni, Ryoto Yajima, Akito Kakiuchi, Shin-Ichi Yokota, Tetsuo Himi, Takashi Kojima

Scientific reports ( NATURE PUBLISHING GROUP ) 7 ( 1 ) 10935 - 10935 2017.09 [Refereed] [International journal]

Disruption of nasal epithelial tight junctions (TJs) and ciliary dysfunction are found in patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs), along with an increase of p63-positive basal cells and histone deacetylase (HDAC) activity. To investigate these mechanisms, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were transfected with siRNAs of TAp63 and ΔNp63, treated with the NF-kB inhibitor curucumin and inhibitors of HDACs, and infected with respiratory syncytial virus (RSV). In TERT-HNECs, knockdown of p63 by siRNAs of TAp63 and ΔNp63, induced claudin-1 and -4 with Sp1 activity and enhanced barrier and fence functions. The knockdown of p63 enhanced the number of microvilli with the presence of cilia-like structures. Treatment with curcumin and inhibitors of HDACs, or infection with RSV prevented expression of p63 with an increase of claudin-4 and the number of microvilli. The knockdown or downregulation of p63 inhibited phospho-p38MAPK, and the p38MAPK inhibitor downregulated p63 and upregulated the barrier function. Thus, epithelial barrier and ciliogenesis of nasal epithelium are regulated in a p63-negative manner in normal and upper airway diseases. Understanding of the regulation of p63/p38 MAPK/NF-κB may be important in the therapy for airway allergy and its drug delivery system.

DOI PubMed

がん細胞の上皮バリアおよび悪性化における糖代謝の役割

金野匠, 幸野貴之, 及能大輔, 嶋田浩志, 郷久晴朗, 角木拓也, 金子躍人, 高野賢一, 齋藤豪, 小島隆

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 69回 95 - 95 2017.05

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 ( PUBLIC LIBRARY SCIENCE ) 12 ( 8 ) e0182291 2017 [Refereed] [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

The Behavior and Role of Lipolysis-stimulated Lipoprotein Receptor, a Component of Tricellular Tight Junctions, in Head and Neck Squamous Cell Carcinomas

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

ANTICANCER RESEARCH ( INT INST ANTICANCER RESEARCH ) 36 ( 11 ) 5895 - 5904 2016.11 [Refereed]

Background/Aim: Lipolysis-stimulated lipoprotein receptor (LSR) knockdown has also been reported to increase the motility and invasiveness of certain cancer cells. Here, we describe, for the first time, the behavior and role of LSR in head and neck squamous cell carcinoma (HNSCC) in vivo and in vitro. Materials and Methods: Samples of HNSCC, normal palatine tonsils, the pharynx carcinoma cell line Detroit562 and primary cultured HNSCC were characterized by immunostaining, western blot, real-time polymerase chain reaction (PCR), Matrigel invasion and proliferation assays. Results: Protein and mRNA of LSR were strongly expressed, as well as claudin-1 in HNSCC tissues than in normal tissues, especially in invasive tissues. Knock-down of LSR and claudin-1 (CLDN-1), but not tricellulin (TRIC) by siRNAs, markedly induced invasiveness of Detroit562 cells and primary cultured HNSCC. LSR inhibited the development and progression of HNSCC. Conclusion: LSR is a potential target for new forms of head and neck cancer therapy.

DOI PubMed

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

Takashi Kojima, Masuo Kondoh, Takashi Keira, Ken-Ichi Takano, Takuya Kakuki, Yakuto Kaneko, Ryo Miyata, Kazuaki Nomura, Kazufumi Obata, Takayuki Kohno, Takumi Konno, Norimasa Sawada, Tetsuo Himi

Drug Delivery ( Taylor and Francis Ltd ) 23 ( 8 ) 2703 - 2710 2016.10 [Refereed]

Objective: Intranasal insulin administration has therapeutic potential for Alzheimer's disease and in intranasal administration across the nasal mucosa, the paracellular pathway regulated by tight junctions is important. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds the tight junction protein claudin and disrupts the tight junctional barrier without a cytotoxic effect. The C-CPE mutant called C-CPE 194 binds only to claudin-4, whereas the C-CPE 194 mutant called C-CPE m19 binds not only to claudin-4 but also to claudin-1. Methods: In the present study, to investigate the effects of C-CPE mutants on the tight junctional functions of human nasal epithelial cells (HNECs) and on the permeability of human recombinant insulin across the cells, HNECs were treated with C-CPE 194 and C-CPE m19. Results: C-CPE 194 and C-CPE m19 disrupted the barrier and fence functions without changes in expression of claudin-1, -4, -7, and occludin or cytotoxicity, whereas they transiently increased the activity of ERK1/2 phosphorylation. The disruption of the barrier function caused by C-CPE 194 and C-CPE m19 was prevented by pretreatment with the MAPKK inhibitor U0126. Furthermore, C-CPE 194 and C-CPE m19 significantly enhanced the permeability of human recombinant insulin across HNECs and the permeability was also inhibited by U0126. Conclusion: These findings suggest that C-CPE mutants 194 and m19 can regulate the permeability of insulin across HNECs via the MAPK pathway and may play a crucial role in therapy for the diseases such as Alzheimer's disease via the direct intranasal insulin administration.

DOI PubMed

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

Behavior of primary cilia and tricellular tight junction proteins during differentiation in temperature-sensitive mouse cochlear precursor hair cells

Takuya Kakuki, Yakuto Kaneko, Kenichi Takano, Takafumi Ninomiya, Takayuki Kohno, Takashi Kojima, Tetsuo Himi

Advances in Oto-Rhino-Laryngology ( S. Karger AG ) 77 27 - 32 2016 [Refereed]

In the sensory hair cells of the mammalian cochlea, the primary cilia in the planar cell polarity as well as the tight junctions in the epithelial cell polarity and the barrier are important to maintain normal hearing. Temperature-sensitive mouse cochlear precursor hair cells were used to investigate the behavior of primary cilia and tricellular tight junction proteins during the differentiation of sensory hair cells. In undifferentiated cells (incubated at 33°C), many acetylated tubulin-positive primary cilia were observed, and each was accompanied with an γ-tubulin-positive basal body. The primary cilia had a '9 + 0' architecture with nine outer microtubule doublets but lacking a central pair of microtubules. In differentiated cells (incubated at 39°C), acetylated tubulin-positive primary cilia as well as acetylated tubulin-positive cilia-like structures were partially observed on the cell surface. In differentiated cells, the number of primary cilia was markedly reduced compared with undifferentiated cells, and innumerable cilia-like structures with no ciliary pockets were partially observed on the cell surface. In undifferentiated cells, few tricellulin molecules and lipolysis-stimulated lipoprotein receptors (LSRs) were observed in the cytoplasm. In differentiated cells, many tricellulin molecules and LSRs were observed on the membranes and within the cytoplasm. Conditional immortalized mouse cochlear precursor hair cells may be useful to investigate the roles of primary cilia and tricellular tight junctions during cellular differentiation and degeneration such as apoptosis.

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

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

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Papers - KOUNO Takayuki