研究者詳細 - 齋藤　豪

論文 - 齋藤　豪

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Significance of matrix metalloproteinases in the pathophysiology of the ovary and uterus.

Toshiaki Endo, Tamotsu Kiya, Taeko Goto, Hirofumi Henmi, Kengo Manase, Hiroyuki Honnma, Tsuyoshi Baba, Shinichi Ishioka, Takuhiro Hayashi, Manabu Chida, Kazuyo Arima, Kiyohiro Yamazaki, Mika Kanaya, Atsushi Azumaguchi, Osamu Moriwaka, Hirofumi Kamiya, Tsuyoshi Saito

Reproductive medicine and biology 5 ( 4 ) 235 - 243 2006年12月 [国内誌]

Matrix metalloproteinases (MMP) are capable of degrading a variety of extracellular matrix (ECM) proteins and are also involved in the processing of a number of bioactive molecules. Our findings indicate that the functions of MMP in the ovary and uterus are organ-specific and time-dependently vary during the reproductive cycle. Prolactin induces structural luteolysis indicated by loss of luteal weight, protein and DNA within 36 h after pretreatment with ergot alkaloid. MMP activation appears crucial for the selective depletion of protein during luteal involution, which entails loss of ECM accompanied by apoptosis. During GnRHagonist-induced luteolysis, this response was also associated with marked increases in MMP-2, which degraded collagen type IV, and MT1-MMP, which in addition to activating MMP-2 also degrades collagen type I, III and V. We also found that the level of MT1-MMP and MMP-2 expression in the human CL is greater during the late luteal phase than during either the early mid luteal phases or during gestation, respectively. That dehydroepiandrosterone (DHEA) treatment caused the formation of cysts from antral follicles in the ovaries of immature rats while depressing MMP-2 collagenolytic activity and enhancing lysyl oxidase expression highlights the importance of collagen degradation in the process of ovulation and suggests that changes in the activities of these enzymes play a key role in ovarian cystogenesis in polycystic ovary syndrome patients. Furthermore, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive apoptotic granulosa cells in rats treated with DHEA, that the Fas/FasL/Caspase-8 (death receptor-dependent) pathway is pivotal for follicular atresia and that increased levels of MT1-MMP likely play an important role in tissue remodeling during follicular atresia. After parturition, the uterus undergoes involution, a conspicuous feature characterized by a rapid reduction in the collagen content mediated by degradation of extracellular collagen bundles. Our findings strongly suggest that MT1-MMP, MMP-2 and MMP-9 are each time-dependently regulated and play important roles in tissue remodeling during postpartum uterine involution. (Reprod Med Biol 2006; 5: 235-243).

DOI PubMed

Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats

Hiroyuki Honnma, Toshiaki Endo, Hirofumi Henmi, Kunihiko Nagasawa, Tsuyoshi Baba, Kiyohiro Yamazaki, Yoshimitsu Kitajima, Takuhiro Hayashi, Kengo Manase, Tsuyoshi Saito

APOPTOSIS ( SPRINGER ) 11 ( 9 ) 1525 - 1533 2006年09月 [査読有り]

One of the characteristics of polycystic ovary syndrome (PCOS) is the presence of cystic follicles in various stages of growth and atresia, the latter of which is known to be the result of apoptosis and tissue remodeling. To further investigate the process of follicular atresia, we compared ovarian expression and localization of Fas, Fas ligand (FasL), casapse-8 and membrane-type1 matrix metalloproteinase (MT1-MMP) in rats treated with dehydroepiandrosterone (DHEA) as a model of PCOS, and in control rats. We found that the numbers of TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive follicles were significantly higher in ovaries from PCOS rats than in those from control rats (P < 0.05), as were ovarian levels of FasL mRNA and protein, processed caspase-8 protein and MT1-MMP mRNA. Correspondingly, we also observed an increase in the level of MTI-MMP catalytic activity and a decrease in the level of pro-caspase-8 protein. In addition, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TUNEL-positive apoptotic granulosa cells within atretic follicles of PCOS ovaries. Our results suggest that under the PCOS-like conditions induced by DHEA, the Fas/FasL/Caspase-8 (death receptor dependent) pathway is pivotal for follicular atresia, and that increased levels of MT1-MMP likely play an important role in tissue remodeling during structural luteolysis.

DOI

Possible involvement of gap junctions in the barrier function of tight junctions of brain and lung endothelial cells

Kunihiko Nagasawa, Hideki Chiba, Hiroki Fujita, Takashi Kojima, Tsuyoshi Saito, Toshiaki Endo, Norimasa Sawada

Journal of Cellular Physiology 208 ( 1 ) 123 - 132 2006年07月

Gap-junction plaques are often observed with tight-junction strands of vascular endothelial cells but the molecular interaction and functional relationships between these two junctions remain obscure. We herein show that gap-junction proteins connexin40 (Cx40) and Cx43 are colocalized and coprecipitated with tight-junction molecules occludin, claudin-5, and ZO-1 in porcine blood-brain barrier (BBB) endothelial cells. Gap junction blockers 18β-glycyrrhetinic acid (18β-GA) and oleamide (OA) did not influence expression of Cx40, Cx43, occludin, claudin-5, junctional adhesion molecule (JAM)-A, JAM-B, JAM-C, or ZO-1, or their subcellular localization in the porcine BBB endothelial cells. In contrast, these gap-junction blocking agents inhibited the barrier function of tight junctions in cells, determined by measurement of transendothelial electrical resistance and paracellular flux of mannitol and inulin. 18β-GA also significantly reduced the barrier property in rat lung endothelial (RLE) cells expressing doxycycline-induced claudin-1, but did not change the interaction between Cx43 and either claudin-1 or ZO-1, nor their expression levels or subcellular distribution. These findings suggest that Cx40- and/or Cx43-based gap junctions might be required to maintain the endothelial barrier function without altering the expression and localization of the tight-junction components analyzed. © 2006 Wiley-Liss, Inc.

DOI PubMed

Coordinated elevation of membrane type I-matrix metalloproteinase and matrix metalloproteinase-2 expression in rat uterus during postpartum involution

Kengo Manase, Toshiaki Endo, Mitunobu Chida, Kunihiko Nagasawa, Hiroyuki Honnma, Kiyohiro Yamazaki, Yoshimitu Kitajima, Taeko Goto, Mika Kanaya, Takuhiro Hayashi, Toshihiro Mitaka, Tsuyoshi Saito

REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY ( BIOMED CENTRAL LTD ) 4 32 2006年06月 [査読有り]

Background: The changes occurring in the rodent uterus after parturition can be used as a model of extensive tissue remodeling. As the uterus returns to its prepregnancy state, the involuting uterus undergoes a rapid reduction in size primarily due to the degradation of the extracellular matrix, particularly collagen. Membrane type-I matrix metalloproteinase (MT1- MMP)is one of the major proteinases that degrades collagen and is the most abundant MMP form in the uterus. Matrix metalloproteinase-2(MMP-2) can degrade type I collagen, although its main function is to degrade type IV collagen found in the basement membrane. To understand the expression patterns of matrix metalloproteinases (MMPs) in the rat uterus, we analyzed their activities in postpartum uterine involution. Methods: We performed gelatin zymography, northern blot analysis and immunohistochemistry to compare the expression levels of MT1- MMP, MMP-2, matrix metalloproteinase-9 (MMP-9) and the tissue inhibitors of MMPs-1 and 2 (TIMP-1 and TIMP-2) in the rat uterus 18 h, 36 h and 5 days after parturition with their expression levels during pregnancy ( day 20). Results: We found that both MT1- MMP and MMP-2 localized mainly in the cytoplasm of uterine interstitial cells. The expression levels of MT1- MMP and MMP-2 mRNAs and the catalytic activities of the expressed proteins significantly increased 18 h and 36 h after parturition, but at postpartum day 5, their mRNA expression levels and catalytic activities decreased markedly. The expression levels of MMP-9 increased 18 h and 36 h after parturition as determined by gelatin zymography including the expression levels of TIMP-1 and TIMP-2. Conclusion: These expression patterns indicate that MT1-MMP, MMP-2, MMP- 9, TIMP-1 and TIMP-2 may play key roles in uterine postpartum involution and subsequent functional regenerative processes.

DOI PubMed

Successful delivery after vaginal radical trachelectomy for invasive uterine cervical cancer.

Ishioka S, Endo T, Hayashi T, Kitajima Y, Sugimura M, Sagae S, Saito T

International journal of clinical oncology 11 ( 2 ) 146 - 149 2006年04月 [査読有り]

DOI PubMed

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines.

Terasawa K, Toyota M, Sagae S, Ogi K, Suzuki H, Sonoda T, Akino K, Maruyama R, Nishikawa N, Imai K, Shinomura Y, Saito T, Tokino T

British journal of cancer ( 6 ) 94 914 - 921 2006年03月 [査読有り]

DOI PubMed

Hyperstimulation and a gonadotropin-releasing hormone agonist modulate ovarian vascular permeability by altering expression of the tight junction protein claudin-5.

Yoshimitsu Kitajima, Toshiaki Endo, Kunihiko Nagasawa, Kengo Manase, Hiroyuki Honnma, Tsuyoshi Baba, Takuhiro Hayashi, Hideki Chiba, Norimasa Sawada, Tsuyoshi Saito

Endocrinology 147 ( 2 ) 694 - 9 2006年02月 [国際誌]

We investigated the mechanism by which a GnRH agonist (GnRHa) affects ovarian vascularity, vascular permeability, and expression of the tight junction protein claudin-5 in a rat model of ovarian hyperstimulation syndrome (OHSS). Hyperstimulated rats received excessive doses of pregnant mare serum gonadotropin (PMSG; 50 IU/d) for 4 consecutive days, from d 25 to 28 of life, followed by 25 IU human chorionic gonadotropin (hCG) on d 29. Control rats received 10 IU PMSG on d 27 of life, followed by 10 IU hCG on d 29. GnRHa (leuprolide 100 microg/kg.d) was administered to some hyperstimulated rats either on d 29 and 30 (short-term GnRHa treatment) or from d 25 to 30 (long-term GnRHa treatment). Ovarian vascular density (vessels per 10 mm(2)) and vessel endothelial area (percent) were assessed by immunohistochemical analysis of the distribution of von Willebrand factor, whereas vascular permeability was evaluated based on leakage of Evans blue. High doses of PMSG and hCG significantly increased ovarian weight, vascular permeability, vascular density, and the vessel endothelial area and significantly reduced expression of claudin-5 protein and mRNA. All of these effects were significantly and dose-dependently inhibited by administration of GnRHa. This suggests that reduced expression of claudin-5 plays a crucial role in the increased ovarian vascular permeability seen in OHSS and that its expression can be modulated by GnRHa treatment. Indeed, preventing redistribution of tight junction proteins in endothelial cells and the resultant loss of endothelial barrier architecture might be the key to protecting patients against massive extravascular fluid accumulation in cases of OHSS.

PubMed

Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers

K Maeno, A Masuda, K Yanagisawa, H Konishi, H Osada, T Saito, R Ueda, T Takahashi

ONCOGENE ( NATURE PUBLISHING GROUP ) 25 ( 2 ) 271 - 277 2006年01月 [査読有り]

The c-jun oncogene is frequently overexpressed in non-small-cell lung cancers (NSCLC), but its functional involvement in lung cancer development has not been clearly elucidated. In this study, we found that among the immediate-early serum responsible genes, exemplified by c-jun, c-fos and c-myc, induction of c-jun in a human bronchial epithelial cell line, BEAS-2B, was dependent on anchorage, in contrast to clear induction of c-fos and c-myc under both anchorage-dependent and - independent conditions. In fact, forced expression of c-jun in BEAS-2B cells significantly increased cell viability and colony formation in soft agar. Furthermore, we also found that such anchorage-dependent regulation of c-jun was lost in a significant fraction of human lung cancer cell lines. Interestingly, suppressed anchorage-independent but not anchorage-dependent growth was noted by constitutive expression of a dominant-negative c-jun mutant in a lung cancer cell line showing dysregulated and sustained c-jun expression in the absence of anchorage. These findings suggest that dysregulated c-jun expression may be involved in the acquisition of anchorage independence in the process of human lung carcinogenesis.

DOI

Accuracy of magnetic resonance imaging for the evaluation of myometrial invasion in endometrial carcinoma

Takashi Fujimoto, Mitsuharu Tamagawa, Miho Kimura, Ryoichi Tanaka, Kota Umemura, Eiki Ito, Takahiro Suzuki, Masato Hareyama, Tsuyoshi Saito

Tumor Research 41 71 - 76 2006年

Endometrial carcinoma is the most common gynecologic malignancy and accounts for 6% of all cancers in women. In patients with endometrial cancer, preoperative knowledge of myometrial tumor extension has important prognostic and therapeutic implications. The aim of this retrospective study is to assess whether magnetic resonance (MR) imaging is useful to assess the depth of myometrial invasion by endometrial carcinoma. Sixty patients between 2003 and 2005 were included in the study. All patients were proven histopathologically endometrial carcinoma and underwent preoperative MR imaging and all data was compared in all cases. The histological results showed no myometrial invasion in 8 cases, myometrial invasion of less than 50% in 35 cases, and myometrial invasion of more than 50% in 17cases. In the cases of no myometrial invasion, MR T2 weighted imaging had a sensitivity of 87.5%, a specificity of 86.5%, a positive predictive Value (PPV) of 50.0% and a negative predictive value (NPV) of 97.8%. In the cases of myometrial invasion of less than 50%, MR T2 weighted imaging had a sensitivity of 82.9%, a specificity of 72.0%, PPV of 80.6% and NPV of 75.0%. By contrast, in the cases of myometrial invasion of more than 50%, the sensitivity, specificity, PPV and NPV of MR T2 weighted imaging were 58.8%, 100%, 100% and 86.0% respectively. Errors in MR findings when determining myometrial tumor spread were more frequently underestimations rather than overestimations. Our results indicate that MR imaging is useful for the preoperative assessment of the depth ofmyometrial invasion in patients with endometrial carcinoma.

Behavior of tight-junction, adherens-junction and cell polarity proteins during HNF-4α-induced epithelial polarization

Seiro Satohisa, Hideki Chiba, Makoto Osanai, Shigeo Ohno, Takashi Kojima, Tsuyoshi Saito, Norimasa Sawada

Experimental Cell Research ( Academic Press Inc. ) 310 ( 1 ) 66 - 78 2005年10月 [査読有り]

We previously reported that expression of tight-junction molecules occludin, claudin-6 and claudin-7, as well as establishment of epithelial polarity, was triggered in mouse F9 cells expressing hepatocyte nuclear factor (HNF)-4α [H. Chiba, T. Gotoh, T. Kojima, S. Satohisa, K. Kikuchi, M. Osanai, N. Sawada. Hepatocyte nuclear factor (HNF)-4α triggers formation of functional tight junctions and establishment of polarized epithelial morphology in F9 embryonal carcinoma cells, Exp. Cell Res. 286 (2003) 288-297]. Using these cells, we examined in the present study behavior of tight-junction, adherens-junction and cell polarity proteins and elucidated the molecular mechanism behind HNF-4α-initiated junction formation and epithelial polarization. We herein show that not only ZO-1 and ZO-2, but also ZO-3, junctional adhesion molecule (JAM)-B, JAM-C and cell polarity proteins PAR-3, PAR-6 and atypical protein kinase C (aPKC) accumulate at primordial adherens junctions in undifferentiated F9 cells. In contrast, CRB3, Pals1 and PATJ appeared to exhibit distinct subcellular localization in immature cells. Induced expression of HNF-4α led to translocation of these tight-junction and cell polarity proteins to beltlike tight junctions, where occludin, claudin-6 and claudin-7 were assembled, in differentiated cells. Interestingly, PAR-6, aPKC, CRB3 and Pals1, but not PAR-3 or PATJ, were also concentrated on the apical membranes in differentiated cells. These findings indicate that HNF-4α provokes not only expression of tight-junction adhesion molecules, but also modulation of subcellular distribution of junction and cell polarity proteins, resulting in junction formation and epithelial polarization. © 2005 Elsevier Inc. All rights reserved.

DOI PubMed

Over-expression of heat shock proteins in carcinogenic endometrium

K Wataba, T Saito, K Fukunaka, K Ashihara, M Nishimura, R Kudo

INTERNATIONAL JOURNAL OF CANCER ( WILEY-LISS ) 91 ( 4 ) 448 - 456 2001年02月 [査読有り]

We have previously shown that the subcellular localization of beta -catenin changes according to the cell proliferation status of the human endometrium, suggesting a role of intercellular transduction in cell growth control in human endometrium not only in the physiological but also in the carcinogenic condition. To further study the possible role of heat shock proteins (HSPs) in growth control, we immunohistochemically analyzed 92 endometrial samples, 30 of normal endometrium, 20 of endometrial hyperplasia and 42 of endometrial cancer, for expression of HSP27, HSP70, HSP90, estrogen receptor (ER) and progesterone receptor. HSP27 and HSP90 were detected in endometrial epithelium strongly in the proliferative phase and weakly in the secretory phase during the menstrual cycle according to the serum estradiol level. However, they were over-expressed in endometrial hyperplasia, especially HSP27. In endometrial cancer, HSP27 expression was heterogenic among the glands and lower than that in the proliferative phase and endometrial hyperplasia. HSP27 over-expression was also observed in samples including endometrial cancer and associated hyperplasia. Results of Western blotting followed those of immunohistochemistry, HSP70 was not changed during the menstrual cycle, as HSP27 and HSP90 were, and was rather stably expressed in endometrial hyperplasia and cancer. Our results suggest that HSP27 and HSP90 contribute to cell proliferation in endometrial epithelium and that over-expression of HSP27 in endometrial hyperplasia occurs as a result of the activated condition of ER, though in cancer it decreases according to the loss of function of ER. (C) 2001 Wiley-Liss, Inc.

Usefulness of enucleation of uterine myoma for patients complicated sterility

H. Mizumoto, T. Saito, T. Endo, A. Nishikawa, K. Ashihara, R. Tanaka, R. Kudo

Japanese Journal of Fertility and Sterility 46 ( 3 ) 13 - 16 2001年

Though it is still unclear about whether uterine myoma is a cause of sterility and whether enucleation of myoma is a successful therapy for sterility, it is believed that the myoma obstructs implantation. In this study, we analyzed the pregnancy rate (%) after enucleation of myoma in 21 women who were suffering from sterility but did not have a clear cause except the myoma. After the enucleation, 12 of the 21 (57%) women became pregnant, These consisted of 9 of the 17 (53%) who had the abdominal enucleation and 3 of the 4 (75%) with vaginal enucleation. We could not find any correlation between the age and the pregnancy rate. As for the correlation between the pregnancy rate and the location of the myoma, 3 patients with subserosal myoma became pregnant as did 9 with intramural myoma, whereas 2 with submucosal myoma did not. Six of the 12 (50%) patients became pregnant within 12 months and within 18 months 9 (75%) had became pregnant. The mean was 14 months. From these results, we concluded that the enucleation of myoma is a useful procedure as a therapy for sterility.

Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers

K Yanagisawa, K Uchida, M Nagatake, A Masuda, M Sugiyama, T Saito, K Yamaki, T Takahashi, H Osada

ONCOGENE ( STOCKTON PRESS ) 19 ( 19 ) 2305 - 2311 2000年05月 [査読有り]

Smad family members are essential intracellular signaling components of the transforming growth factor-beta (TGF-beta) superfamily involved in a range of biological activities. The loss of sensitivity to TGF-beta is frequent in human lung cancers and inactivation of Smad family members are thought to play important roles in disruption of TGF-beta signaling. In the study presented here, we characterized the biological and biochemical functions of six Smad2 and Smad4 mutants, which we previously identified in human lung cancers. All mutant Smad2 and Smad4 were in fact found to be defective in transmitting growth inhibitory signals originating from TGF-beta and incapable of activating Smad/hFAST-1-mediated transcription. Transcriptional activation of plasminogen activator inhibitor type 1 (PAI-1) was impaired in four of the six mutants due to the defects in homo- and/or hetero-oligomerization with wild-type Smads, In contrast, the remaining two Smad mutants showed a modest reduction in the PAI-1 transcriptional activation and apparently retained the ability to oligomerize with wild-type Smads, Significant loss of growth inhibition and Smad/hFAST-1-mediated transcriptional activation by all of the six mutants suggested that Smad mutants are indeed functionally impaired Smad mutations and may play a role in lung tumorigenesis, Moreover, the present findings suggest that in addition to the impairment in the homo- and/or hetero-oligomerization, there may be an alternative mechanism producing disruption of TGF-beta signaling, involving hFAST-1-or possibly other transcriptional cofactor(s)-mediated transcriptional activation.

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