研究者詳細 - 小山内　誠

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子宮頸部腺癌におけるタイト結合関連たんぱく質の免疫組織化学的検討

高澤啓, 秋元太志, 村田雅樹, 青山智志, 田中敏, 小山内誠, 長谷川匡, 澤田典均

日本病理学会会誌 ( (一社)日本病理学会 ) 105 ( 1 ) 478 - 478 2016年04月

子宮頸部腺癌における受容体型チロシンキナーゼの発現解析

上田朝子, 高澤啓, 秋元太志, 中西敬太郎, 村田雅樹, 青山智志, 田中敏, 小山内誠, 長谷川匡, 澤田典均

日本病理学会会誌 ( (一社)日本病理学会 ) 105 ( 1 ) 602 - 602 2016年04月

Elevated expression of the retinoic acid-metabolizing enzyme CYP26C1 in primary breast carcinomas

Makoto Osanai, Gang-Hong Lee

MEDICAL MOLECULAR MORPHOLOGY ( SPRINGER JAPAN KK ) 49 ( 1 ) 22 - 27 2016年03月

Retinoic acid (RA)-metabolizing enzyme CYP26A1 has been shown to have increased expression levels in breast cancers and to effectively promote the survival of breast carcinoma cells, implying a potential oncogenic function. However, the expression of CYP26C1, another CYP26 family member, in primary breast carcinoma remains to be clarified. In the present study, we examined the expression of CYP26C1 by immunohistochemistry, using three different types of microarray, and observed strong cytoplasmic staining of CYP26C1 in 73 of the 219 (33.3 %) breast carcinomas. In contrast, CYP26C1 was not expressed in normal ductal and lobular cells in non-neoplastic tissue. Interestingly, increased expression of CYP26C1 was significantly associated with a high Ki-67 labeling index and a grade of tumor. However, CYP26C1 immunoreactivity was not associated with clinicopathological variables, including primary tumor status, lymph node involvement, distant metastasis, and tumor stage. In addition, CYP26C1 positivity was independent of the expression status of the hormone receptors and immunohistochemical surrogates for the intrinsic subtypes of breast cancer. This report is the first to demonstrate elevated expression of CYP26C1 in primary breast carcinomas. Based on the RA-catabolizing activity of CYP26C1, our data suggest that CYP26C1 expression may contribute to neoplasia in the breast.

DOI

Vasculogenic mimicry in gastrointestinal stromal tumor of the stomach; A case report

Osanai M, Takasawa A, Murata M, Tanaka S, Miura H, Hata F, Sawada N

Case Rep Clin Pathol 3 50 - 54 2016年 [査読有り]

タイト結合蛋白occludinの低酸素下でのジスルフィド結合とユビキチン化を介した細胞内分布調節

田中敏, 小野佑輔, 高澤啓, 村田雅樹, 高澤久美, 小山内誠, 澤田典均

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 [2P0424] - [2P0424] 2015年12月

The retinoic acid-metabolizing enzyme CYP26A1 upregulates fascin and promotes the malignant behavior of breast carcinoma cells

Makoto Osanai, Gang-Hong Lee

ONCOLOGY REPORTS ( SPANDIDOS PUBL LTD ) 34 ( 2 ) 850 - 858 2015年08月 [査読有り]

The retinoic acid (RA)-metabolizing enzyme CYP26A1 has been shown to efficiently enhance the oncogenic potential of breast cancer, suggesting a potential oncogenic function. We previously demonstrated that CYP26A1 confers unique cell survival properties by modulating the expression of a variety of genes and identified a number of genes that drive the cells into the oncogenic state. Accumulating evidence suggested that fascin is overexpressed in various types of cancer, primarily leading to increased cell motility. Therefore, in the present study, we examined fascin, an actin-bundling protein, using immunohistochemical and SA-P-gal staining as well as TUNEL and colony forming assays. The results of the present study showed that the expression levels of fascin increased significantly in response to CYP26A1 overexpression and, conversely, treatment with all-trans RA downregulated the expression of fascin. In addition, primary breast carcinoma samples, particularly hormone receptor-negative carcinomas and CYP26A1-overexpressing cancers, expressed elevated levels of fascin. Notably, fascin contributed to the ability of breast carcinoma cells to escape premature senescence and exhibit enhanced cell apoptotic resistance, promoting anchorage-independent growth properties. Fascin also promoted cell motility and the invasiveness of CYP26A1-expressing breast carcinoma cells. These data suggest that fascin expression is modulated by the intracellular RA status regulated by the expression of CYP26A1 and plays a significant role in the malignant behavior of CYP26A1-expressing breast carcinoma cells. CYP26A1 exerts oncogenic functions during breast carcinogenesis. Therefore, CYP26A1-mediated oncogenic characteristics may be partially responsible for the elevated expression of fascin.

DOI

Increased expression of the retinoic acid-metabolizing enzyme CYP26A1 during the progression of cervical squamous neoplasia and head and neck cancer

Makoto Osanai, Gang-Hong Lee

BMC Research Notes ( BioMed Central Ltd. ) 7 ( 1 ) 697 - 697 2014年10月 [査読有り]

Background: Retinoic acid (RA) is a critical regulator of cell differentiation, proliferation, and apoptosis in various cell types. Recently, the RA-metabolizing enzyme CYP26A1 (cytochrome P450, family 26, subfamily A, polypeptide 1) has been shown to have an oncogenic function in breast carcinogenesis. However, the relevance of elevated CYP26A1 expression in human cancers remains to be clarified. Methods. We immunohistochemically examined the expression of CYP26A1 in cervical squamous cell carcinoma (SCC) and its precursors, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as head and neck cancer (HNC). The association between CYP26A1 expression and a number of clinicopathological parameters was also evaluated. Results: CYP26A1 was not expressed in normal cervical epithelium. CYP26A1 expression was present in LSIL but limited to basal and parabasal cells. HSIL cases exhibited strong nuclear expression of CYP26A1 and mixed cytoplasmic expression patterns with widely distributed expression toward the epithelial surface. Importantly, strong cytoplasmic staining of CYP26A1 was observed in 19 of 50 (38%) patients with cervical SCC. Elevated expression of CYP26A1 was significantly associated with younger age (< 50 years) and lymph node involvement (pN). Similarly, CYP26A1 was not expressed in non-neoplastic tissues of the head and neck, but strong cytoplasmic staining of CYP26A1 was observed in 52 of 128 (41%) HNC cases. Such strong CYP26A1 expression was significantly associated with the primary tumor stage of carcinomas (pT) and the pathological tumor-node-metastasis (pTNM) stage in HNC. Conclusion: Our results indicated an elevated CYP26A1 expression in malignant and precancerous dysplastic lesions of the human cervix, which also increased with the progression of cervical squamous neoplasia. In addition, this report is the first to demonstrate the increased expression of CYP26A1 in HNC and its significant correlation with primary tumor growth. These data suggested that CYP26A1 overexpression might contribute to the development and progression of cervical malignancies and squamous neoplasia of the head and neck.

DOI PubMed

Enhanced expression of retinoic acid-metabolizing enzyme CYP26A1 in sunlight-damaged human skin

Makoto Osanai, Gang-Hong Lee

MEDICAL MOLECULAR MORPHOLOGY ( SPRINGER TOKYO ) 44 ( 4 ) 200 - 206 2011年12月

Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis. CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, has been shown to result in a state of functional VAD of the cell. Recently, we demonstrated that CYP26A1 efficiently promotes cell survival properties and eventually contributes to the carcinogenic process, implying roles as an oncogene. To clarify the possible association between VAD caused by CYP26A1 expression and the development of human epithelial neoplasia, we examined whether enhanced expression of CYP26A1 might be observed in various lesions of human skin. We report here that basal keratinocytes showed only weak positivity of CYP26A1 in sunlight-nonexposed areas, whereas strong positive staining was observed in skin from chronically sunexposed body areas and in epidermis that had the dysplastic changes known as actinic keratosis. However, we found no expression of constitutive CYP26A1 in skin malignancies such as squamous cell carcinomas. Our observation suggests an involvement of enhanced CYP26A1 expression causing a functional VAD state in skin that can potentially lead to neoplastic transformation of keratinocytes in an early phase during skin carcinogenesis.

DOI

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

M. Osanai, N. Sawada, G-H Lee

ONCOGENE ( NATURE PUBLISHING GROUP ) 29 ( 8 ) 1135 - 1144 2010年02月

Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis in animal models and elevated risk for a number of human cancers. Here, we found that CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, is highly expressed in 42% (27/65) of primary breast cancers. We also showed that enhanced expression of CYP26A1 suppresses cellular responses to anoikis and consequently promotes anchorage-independent growth. This transformed phenotype was sufficient to markedly increase tumorigenic and metastatic potential. Suppression of CYP26A1 significantly reversed the CYP26A1-mediated oncogenic characteristics, suggesting a direct link between intracellular RA status and tumorigenicity. Our observations provide strong evidence for oncogenic and cell survival properties of CYP26A1 in carcinogenesis, and suggest mechanisms whereby VAD might promote cancer development. Oncogene (2010) 29, 1135-1144; doi: 10.1038/onc.2009.414; published online 23 November 2009

DOI

Emerging novel treatment strategies for diabetic eye diseases

Makoto Osanai, Nami Nishikiori, Gang-Hong Lee, Norimasa Sawada

Current Diabetes Reviews 6 ( 1 ) 35 - 41 2010年01月

書評論文，書評，文献紹介等

Endothelial tight junctions (TJs) in the retina are potential therapeutic targets for diabetic complications such as retinopathy. TJs primarily determine the endothelial barrier, regulating vascular permeability to maintain tightly closed circulating homeostasis. Our recent study has demonstrated that glial cell-derived cytokines limit vascular permeability by modulating the TJ function of retinal capillary endothelium and eventually attenuate the breakdown of vascular integrity in diabetic microangiopathy. In addition, suppression of deregulated protease activity in lens cells results in dramatic inhibition of the development of murine diabetic cataracts. We believe that pharmacological modulation of the ocular tissue microenvironment such as that regulated by endothelial TJs may be a feasible strategy for reducing the development of diabetic complications in the eye. © 2010 Bentham Science Publishers Ltd.

DOI PubMed

Transmembrane proteins of tight junctions

Hideki Chiba, Makoto Osanai, Masaki Murata, Takashi Kojima, Norimasa Sawada

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES ( ELSEVIER SCIENCE BV ) 1778 ( 3 ) 588 - 600 2008年03月

書評論文，書評，文献紹介等

Tight junctions contribute to the paracellular barrier, the fence dividing plasma membranes, and signal transduction, acting as a multifunctional complex in vertebrate epithelial and endothelial cells. The identification and characterization of the transmembrane proteins of tight junctions, claudins, junctional adhesion molecules (JAMs), occludin and tricellulin, have led to insights into the molecular nature of tight junctions. We provide an overview of recent progress in studies on these proteins and highlight their roles and regulation, as well as their functional significance in human diseases. (C) 2007 Elsevier B.V. All rights reserved.

DOI

Epigenetic silencing of claudin-6 promotes anchorage-independent growth of breast carcinoma cells

Makoto Osanai, Masaki Murata, Hideki Chiba, Takashi Kojima, Norimasa Sawada

CANCER SCIENCE ( BLACKWELL PUBLISHING ) 98 ( 10 ) 1557 - 1562 2007年10月

Cancer cells often exhibit loss of functional tight junctions (TJ), and disruption of the TJ structure is associated with cancer development. However, whether loss of a certain type of claudin, an integral membrane protein of TJ, is involved in malignant phenotypes remains to be clarified. Based on a report that claudin-6 functions as a tumor suppressor for breast cancer, the authors show here that suppression of claudin-6 expression results in increased resistance to various apoptogens, and causally enhances anchorage-independent growth properties. Because claudin-6 expression is partially silenced by promoter CpG island hypermethylation in MCF7 breast carcinoma cells, a synergistic effect of a demethylator and histone deacetylase inhibitor up-regulates the expression of endogenous claudin-6, which is sufficient for apoptotic sensitization and abrogation of colony-forming efficacy. In addition, decreased expression of claudin-6 promotes cellular invasiveness and transendothelial migration, accompanied by an increase in matrix metalloproteinase activity. These data suggest that the methylator phenotype of claudin-6 may at least partially contribute to enhanced tumorigenic and invasive properties of breast carcinoma cells.

DOI

Occludin-mediated premature senescence is a fail-safe mechanism against tumorigenesis in breast carcinoma cells

Makoto Osanai, Masaki Murata, Nami Nishikiori, Hideki Chiba, Takashi Kojima, Norimasa Sawada

CANCER SCIENCE ( BLACKWELL PUBLISHING ) 98 ( 7 ) 1027 - 1034 2007年07月

We have previously demonstrated that epigenetic silencing of occludin, a tight junction-associated membrane protein, results in the acquisition of apoptotic resistance to various apoptogenic stimuli, causally contributing to the enhanced tumorigenicity of cancer cells. However, it remains to be examined whether occludin expression in transformed cells has an alternative impact that is important for cancer progression. Here we show that forced expression of occludin induces anoikis and promotes oxidative stress-induced premature senescence in breast carcinoma cells, which is accompanied by upregulation of negative cell cycle regulators such as p16(INK4A), p21(Waf1/Cip1) and p27(Kip1) but not p53. The senescent phenotype is reversed by specific inhibition of mitogen-activated protein kinase. Endogenous reexpression of occludin mediated by a synergistic effect with a demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor alpha is also sufficient for provoking the senescent phenotype. In addition, tumors that developed from occludin-expressing cells in mice showed a feature of cellular senescence that has not been described as a consequence of occludin signaling. These findings suggest that the loss of occludin expression is at least partially involved in the senescence-escape program during mammary tumorigenesis.

DOI

HNF4αによる上皮極性形成におけるタイト結合膜裏打ち分子cingulinの機能

杉本幸太郎, 千葉英樹, 酒井直行, 小山内誠, 小島隆, 澤田典均

日本病理学会会誌 ( (一社)日本病理学会 ) 96 ( 1 ) 358 - 358 2007年02月

Cellular retinoic acid bioavailability determines epithelial integrity: Role of retinoic acid receptor alpha agonists in colitis

Makoto Osanai, Nami Nishikiori, Masaki Murata, Hideki Chiba, Takashi Kojima, Norimasa Sawada

MOLECULAR PHARMACOLOGY ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 71 ( 1 ) 250 - 258 2007年01月

The epithelial barrier is determined primarily by intercellular tight junctions (TJs). We have demonstrated previously that all-trans retinoic acid (atRA) plays an important role in forming functional TJs through a specific retinoic acid receptor (RAR)/retinoid X receptor heterodimer in epithelial cells. However, the physiological relevance of retinoic acids (RAs) in maintaining the epithelial integrity remains to be examined. Here, we show that several types of RA, including atRA, promote the barrier function of epithelial TJs. Conversely, RA depletion in the cells by overexpressing CYP26s, cytochrome P450 enzymes specifically involved in the metabolic inactivation of RAs, induces an increase of permeability as measured by two differently sized tracer molecules, inulin and mannitol. This RA-mediated enhancement of barrier function is potentially associated with the increased expression of TJ-associated genes such as occludin, claudin-1, claudin-4, and zonula occludens-1. We also found that RAR alpha is a preferential regulator of the epithelial barrier in vitro. Studies of murine experimental colitis, which is characterized by increased gut permeability, reveal that RAR alpha stimulation significantly attenuates the loss of the epithelial barrier during colitis in vivo. Our results suggest that cellular RA bioavailability determines the epithelial integrity, because it is a critical regulator for barrier protection during mucosal injuries.

DOI

Epigenetic silencing of occludin promotes tumorigenic and metastatic properties of cancer cells via modulations of unique sets of apoptosis-associated genes

Makoto Osanai, Masaki Murata, Nami Nishikiori, Hideki Chiba, Takashi Kojima, Norimasa Sawada

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 66 ( 18 ) 9125 - 9133 2006年09月

Occludin is the first identified integral protein for the tight junction (TJ), and its long COOH-terminal domain is considered to have functions in receiving and transmitting cell survival signals. Loss of TJ-associated molecules, such as occludin, has been correlated with tumor progression in carcinogenesis; however, the precise molecular mechanisms explaining its loss of expression and whether occludin expression has any effects on cancer phenotypes remain to be clarified. Here, we show that forced expression of occludin in cancer cells exhibits enhanced sensitivity to differently acting apoptogenic factors, and thus inhibits the tumorigenicity of transformed cells, via modulation of unique sets of apoptosis-associated genes. In addition, studies using deletion mutants of occludin constructs show that 44 amino acids at the COOH-terminal end play a critical role in modifying the cellular phenotypes. Interestingly, occludin decreases cellular invasiveness and motility, thereby abrogating metastatic potencies of cancer cells. We also found that occludin expression is silenced by CpG island hypermethylation on its promoter region. Synergy with a demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor alpha induces endogenous occludin, which is sufficient for apoptotic sensitization. Our results show the functional diversity of occludin and suggest that methylator phenotype of occludin provides enhanced tumorigenic, invasive, and metastatic properties of cancer cells, identifying occludin as a likely candidate for a tumor-suppressor gene in certain types of cancer.

DOI

HNF-4αはタイト結合膜裏打ち分子cingulinの発現を誘導する

杉本幸太郎, 千葉英樹, 藤田裕樹, 小山内誠, 小島隆, 澤田典均

日本病理学会会誌 ( (一社)日本病理学会 ) 95 ( 1 ) 390 - 390 2006年04月

Occludin expression inhibits tumorigenicity and metastasis

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

FASEB JOURNAL ( FEDERATION AMER SOC EXP BIOL ) 20 ( 4 ) A223 - A223 2006年03月

研究発表ペーパー・要旨（国際会議）

Glial cell line-derived neurotrophic factor (GDNF) regulates the vascular permeability of the blood-retinal barrier (BRB)

N Nishikiori, M Osanai, H Miyajima, H Chiba, T Kojima, N Sawada

FASEB JOURNAL ( FEDERATION AMER SOC EXP BIOL ) 20 ( 4 ) A636 - A637 2006年03月

研究発表ペーパー・要旨（国際会議）

The significance of interferon-gamma-triggered internalization of tight-junction proteins in inflammatory bowel disease.

Hideki Chiba, Takashi Kojima, Makoto Osanai, Norimasa Sawada

Science's STKE : signal transduction knowledge environment 2006 ( 316 ) pe1 2006年

書評論文，書評，文献紹介等

Disruption of the epithelial barrier function of tight junctions by the proinflammatory cytokine interferon (IFN)-gamma plays a fundamental role in the pathogenesis of inflammatory bowel disease and other gastrointestinal disorders, but its precise mechanism has not been established. This Perspective provides an overview of how IFN-gamma triggers barrier dysfunction and bacterial translocation in intestinal epithelial cells, and highlights the roles of internalization of tight-junction transmembrane proteins, as well as rearrangements of the cortical actin cytoskeleton, in intestinal inflammation.

DOI PubMed

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