論文 - 小山内　誠

Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice

Kohtaro Yamasaki, Yoshihiro Hayashi, Sumika Okamoto, Makoto Osanai, Gang-Hong Lee

CANCER SCIENCE ( WILEY-BLACKWELL PUBLISHING, INC )  101 ( 1 ) 65 - 72  2010年01月  [査読有り]

　概要を見る

Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F(1) littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration. (Cancer Sci 2009).

DOI PubMed

Expression of fascin-1, an actin-bundling protein, in migrating hepatoblasts during rat liver development

Yoshihiro Hayashi, Katsumi Toda, Toshiji Saibara, Sumika Okamoto, Makoto Osanai, Hideaki Enzan, Gang-Hong Lee

CELL AND TISSUE RESEARCH ( SPRINGER )  334 ( 2 ) 219 - 226  2008年11月  [査読有り]

　概要を見る

Fascin-1 is an actin-bundling protein localized at the core actin bundles within microvillar projections and filopodial extensions in migrating cells. It is expressed at a low level in normal epithelial cells, but at a high level in tumor cells, indicating its importance in the invasion and motility of tumor cells. In addition, fascin-1 is expressed in human and murine embryos, occurring at high levels especially in developing nervous tissues. In this study, we have investigated the expression patterns of fascin-1 immunohistochemically during the early stages of rat hepatogenesis. A high expression of fascin-1 was detected in the liver bud and hepatoblasts at embryonic day (ED) 10.5, ED11.5, and ED12.5. Expression fell by ED13.5 and was not detectable at ED14.5. These observations demonstrate that the expression of fascin-1 is correlated with the migration activity of hepatoblasts during the early stages of liver development in rats.

DOI PubMed

IGF-I regulates tight-junction protein claudin-1 during differentiation of osteoblast-like MC3T3-E1 cells via a MAP-kinase pathway.

Hatakeyama N, Kojima T, Iba K, Murata M, Thi MM, Spray DC, Osanai M, Chiba H, Ishiai S, Yamashita T, Sawada N

Cell and tissue research ( 2 )  334   243 - 254  2008年11月  [査読有り]

DOI PubMed

Protein kinase C enhances tight junction barrier function of human nasal epithelial cells in primary culture by transcriptional regulation.

Koizumi J, Kojima T, Ogasawara N, Kamekura R, Kurose M, Go M, Harimaya A, Murata M, Osanai M, Chiba H, Himi T, Sawada N

Molecular pharmacology ( 2 )  74   432 - 442  2008年08月  [査読有り]

DOI PubMed

Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca²⁺absorption between enterocytes

Hiroki Fujita, Kotaro Sugimoto, Shuichiro Inatomi, Toshihiro Maeda, Makoto Osanai, Yasushi Uchiyama, Yoko Yamamoto, Takuro Wada, Takashi Kojima, Hiroshi Yokozaki, Toshihiko Yamashita, Shigeaki Kato, Norimasa Sawada, Hideki Chiba

Molecular Biology of the Cell   19   1912 - 1921  2008年05月  [査読有り]

DOI PubMed

Transforming growth factor-beta induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes.

Kojima T, Takano K, Yamamoto T, Murata M, Son S, Imamura M, Yamaguchi H, Osanai M, Chiba H, Himi T, Sawada N

Liver international : official journal of the International Association for the Study of the Liver ( 4 )  28   534 - 545  2008年04月  [査読有り]

DOI PubMed

Transmembrane proteins of tight junctions.

Chiba H, Osanai M, Murata M, Kojima T, Sawada N

Biochimica et biophysica acta ( 3 )  1778   588 - 600  2008年03月  [査読有り]

DOI PubMed

Induction of claudins in passaged hTERT-transfected human nasal epithelial cells with an extended life span.

Kurose M, Kojima T, Koizumi J, Kamekura R, Ninomiya T, Murata M, Ichimiya S, Osanai M, Chiba H, Himi T, Sawada N

Cell and tissue research ( 1 )  330   63 - 74  2007年10月  [査読有り]

DOI PubMed

Changes of gap and tight junctions during differentiation of human nasal epithelial cells using primary human nasal epithelial cells and primary human nasal fibroblast cells in a noncontact coculture system.

Koizumi J, Kojima T, Kamekura R, Kurose M, Harimaya A, Murata M, Osanai M, Chiba H, Himi T, Sawada N

The Journal of membrane biology ( 1-3 )  218   1 - 7  2007年08月  [査読有り]

DOI PubMed

A novel monoclonal antibody against the second extracellular loop of occludin disrupts epithelial cell polarity.

Tokunaga Y, Kojima T, Osanai M, Murata M, Chiba H, Tobioka H, Sawada N

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society ( 7 )  55   735 - 744  2007年07月  [査読有り]

DOI PubMed

Inhibitory effects of retinoic acid receptor alpha stimulants on murine cataractogenesis through suppression of deregulated calpains

Nami Nishikiori, Makoto Osanai, Hideki Chiba, Takashi Kojima, Hiroshi Ohguro, Norimasa Sawada

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE ( ASSOC RESEARCH VISION OPHTHALMOLOGY INC )  48 ( 5 ) 2224 - 2229  2007年05月  [査読有り]

　概要を見る

PURPOSE. To determine whether retinoic acid (RA)-mediated inhibition of deregulated calpains had any effect on the development of cataract given that accumulating evidence has demonstrated a possible relationship between cataractogenesis and inappropriate activation of calpains. METHODS. The authors examined for Ca2+ influx and expression alteration of calpains in F9 cells with or without RAs, such as all-trans retinoic acid (ATRA), and specific stimulant of retinoic acid receptor alpha (RAR alpha; Am580) in the presence of oxidative stress, such as mediated by H2O2. They next examined the clinical relevance of RAs by applying these agents to a murine diabetic cataract and observed the development of the disease. RESULTS. F9 cells constitute a well-established autonomous cell model for investigating retinoid signaling, partially representing the lens epithelial phenotype, as determined by the expression of aquaporin 0, a specific differentiation marker for lens cells. Treatment with ATRA and Am580 significantly decreased the influx of Ca2+ into the cells, causally resulting in decreased mRNA expression and inhibited activation of calpains. In addition, RAR alpha agonists significantly abrogated the upregulation of calpain 2 induced by H2O2, which is a potential etiological contributor to the diabetic cataract, whereas H2O2 had no effect on calpain 1. Importantly, this RA-mediated gene-expression alteration was sufficient for dramatically inhibiting the development of lens opacity in mice with diabetes. CONCLUSIONS. Results showed that a certain type of RA inhibits Ca2+ elevation and subsequent overactivation of calpains, suggesting the potential feasibility of calpain-targeting therapies mediated by RA for cataract.

DOI

Oncostatin M induces upregulation of claudin-2 in rodent hepatocytes coinciding with changes in morphology and function of tight junctions.

Imamura M, Kojima T, Lan M, Son S, Murata M, Osanai M, Chiba H, Hirata K, Sawada N

Experimental cell research ( 9 )  313   1951 - 1962  2007年05月  [査読有り]

DOI PubMed

Expression patterns of claudin family of tight-junction proteins in the mouse prostate

Naoyuki Sakai, Hideki Chiba, Hiroki Fujita, Yushi Akashi, Makoto Osanai, Takashi Kojima, Norimasa Sawada

HISTOCHEMISTRY AND CELL BIOLOGY ( SPRINGER )  127 ( 4 ) 457 - 462  2007年04月  [査読有り]

　概要を見る

Claudins are the transmembrane proteins forming the backbone of tight junctions, and consist of over 20 members of a gene family. Claudins are expressed in a tissue- and cell-type specific fashion, and changes in their abundance and/or distribution are proposed to play important roles in the pathophysiology of numerous disorders. In the prostate, claudin-1, -3, -4 and -7 transcripts are known to be expressed, but it is unknown regarding mRNA expression of other claudins or concerning expression and localization of claudin proteins in this organ. We herein show, by RT-PCR and Western blotting analyses, that not only these four claudins but also claudin-5, -8 and -10 are expressed in the normal mouse prostate. Claudin-3, -4, -5, -8 and -10 were primarily localized at the apicalmost sites of lateral membranes of luminal epithelial cells in the prostate gland, whereas claudin-1 and -7 were distributed along the basolateral membranes of the epithelium. These findings provide basic information for elucidating the significance of claudins in prostate diseases, including prostate cancers.

DOI

The nuclear receptor hepatocyte nuclear factor 4alpha acts as a morphogen to induce the formation of microvilli.

Chiba H, Sakai N, Murata M, Osanai M, Ninomiya T, Kojima T, Sawada N

The Journal of cell biology ( 6 )  175   971 - 980  2006年12月  [査読有り]

DOI PubMed

Connexin 26 expression prevents down-regulation of barrier and fence functions of tight junctions by Na+/K+-ATPase inhibitor ouabain in human airway epithelial cell line Calu-3.

Go M, Kojima T, Takano K, Murata M, Koizumi J, Kurose M, Kamekura R, Osanai M, Chiba H, Spray DC, Himi T, Sawada N

Experimental cell research ( 19 )  312   3847 - 3856  2006年11月  [査読有り]

DOI PubMed

タイト結合による上皮細胞極性維持にはoccludinの細胞外第2ループが重要である

徳永 祐一, 小島 隆, 飛岡 弘敏, 村田 雅樹, 小山内 誠, 千葉 英樹, 澤田 典均

日本癌学会総会記事 ( (一社)日本癌学会 )  65回   242 - 242  2006年09月

病態発生とタイト結合とギャップ結合の役割 黄疸と血液胆汁関門

小島 隆, 村田 雅樹, 小山内 誠, 千葉 英樹, 澤田 典均

日本病理学会会誌 ( (一社)日本病理学会 )  95 ( 1 ) 155 - 155  2006年04月

肝細胞のバリア機能におけるタイト結合蛋白claudin-2の役割

今村 将史, 小島 隆, 孫 誠一, 村田 雅樹, 小山内 誠, 千葉 英樹, 平田 公一, 澤田 典均

日本病理学会会誌 ( (一社)日本病理学会 )  95 ( 1 ) 191 - 191  2006年04月

Glial cell line-derived neurotrophic factor in the vitreous of patients with proliferative diabetic retinopathy

N Nishikiori, Y Mitamura, A Tashimo, Y Nakamura, T Harada, M Osanai, N Sawada, K Ohtsuka

DIABETES CARE ( AMER DIABETES ASSOC )  28 ( 10 ) 2588 - 2588  2005年10月  [査読有り]

DOI PubMed

タイト結合蛋白occludinは肝細胞において生存シグナルの伝達に重要な役割を有する

村田 雅樹, 小島 隆, 高野 賢一, 畠山 尚子, 小山内 誠, 千葉 英樹, 澤田 典均

日本癌学会総会記事 ( (一社)日本癌学会 )  64回   368 - 368  2005年09月