Details of a Researcher - SAITOU Tsuyoshi

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Overexpression of estrogen receptor-alpha gene suppresses gap junctional intercellular communication in endometrial carcinoma cells

T Saito, R Tanaka, K Wataba, R Kudo, H Yamasaki

ONCOGENE ( NATURE PUBLISHING GROUP ) 23 ( 5 ) 1109 - 1116 2004.02

Stimulation of the endometrium by estrogens without the differentiating effect of progestins is the primary etiological factor associated with the development of endometrial hyperplasia and adenocarcinoma. However, the correlation between sex steroids and gap junctional intercellular communication (GJIC), which is considered to play an important role in the control of cell growth and differentiation, is not well known in endometrial carcinoma. In this study, we focused on the influence of estrogen and its receptor in connexin (Cx) expression and GJIC in endometrial carcinoma cells, established stable clone IK-ER1 overexpressing ER-alpha to transfect the expression vector and analysed them in various hormonal conditions. The growth of IK-ER1 was accelerated by 17beta-estradiol and the acceleration of the 5-bromo-25-deoxyuridine labeling index was observed. GJIC was assayed by scoring the number of dye-coupled cells after microinjecton of single cells with Lucifer-Yellow, and subcellular localization of Cx26 and Cx32 was analysed by immunocytochemistry. In the presence of estradiol, dye-coupled cells of IK-ER1 were significantly reduced compared to those without estradiol and the reduction was completely inhibited by adding ICI182.780, a pure antiestrogen substrate. Cxs were detected as only small spots by immunocytochemistry, and Western blotting showed that the expression was decreased. These results suggest that activation of ER-alpha by estrogen results in tumor progression by stimulating cell growth and suppressing GJIC via suppression of the expression of Cxs in endometrial carcinogenesis.

DOI

Correlation between responsiveness of neoadjuvant chemotherapy and apoptosis-associated proteins for cervical adenocarcinoma

T Saito, M Takehara, R Tanaka, R Lee, M Horie, K Wataba, E Ito, R Kudo

GYNECOLOGIC ONCOLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 92 ( 1 ) 284 - 292 2004.01

Objective. Adenocarcinoma of the uterine cervix appears to be increasing in prevalence and it has been suggested that these tumors tend to be less sensitive to radiation therapy and to chemotherapy than squamous carcinomas. In the present study, 29 patients with locally advanced cervical adenocarcinoma (bulky IB-IVB) were treated with neoadjuvant chemotherapy (NAC) using cisplatin, aclacinomycin-A and mitomycin-C, followed by radical surgery or irradiation. Methods. To predict the prognosis and response to the chemotherapy, the expression of apoptosis associated-proteins, p53, p21WAF1/ CIP1, Bcl-2 and activated caspase-3 was evaluated for tumor samples by immunohistochemistry. Results. Of the analyzed clinicopathological factors, the overexpression of p53 was frequently observed in endocervical-type adenocarcinoma, nonresponders to chemotherapy and the grade 0 histologic effect of the chemotherapy. Positive staining of Bcl-2 was frequently observed in the early stage and had a better prognosis than for patients with the negative staining; however, there was no correlation between responders and nonresponders to chemotherapy. The expression of p21 WAF1/CIP1 and caspase-3 was not correlated to the clinicopathological factors. Conclusion. In this study, the overexpression of p53 was found to be a factor to predict the chemoresistance and positive expression of Bcl-2 indicated as a better prognostic value. For p21WAF1/CIP1 and caspase-3, further analysis is necessary. (C) 2003 Elsevier Inc. All rights reserved.

DOI

[Metastasize mechanism of endometrial cancer]

Nippon Rinsho 62 269 - 72 2004

[A pilot study of combined chemotherapy with paclitaxel, doxorubicin and cisplatin for endometrial cancer]

Gan To Kagaku Ryoho 31 549 - 53 2004

The reproducibility of a binary tumor grading system for uterine endometrial endometrioid carcinoma, compared with FIGO system and nuclear grading

S Sagae, T Saito, M Satoh, T Ikeda, S Kimura, M Mori, N Sato, R Kudo

ONCOLOGY ( KARGER ) 67 ( 5-6 ) 344 - 350 2004

Objective: A binary grading system has been proposed to assess the amount of solid growth, the pattern of invasion, and the presence of necrosis, and thereby divide endometrial endometrioid carcinomas into low- and high-grade tumors. We analyzed this system for predicting the prognosis, with respect to inter- and intraobserver reproducibility and treatment modalities. Methods: A total of 200 endometrial carcinomas, based on hysterectomy specimens, were graded according to the binary grading system, for comparison against The International Federation of Gynecology and Obstetrics (FIGO) system and nuclear grading. Results: Both inter- and intraobserver agreement using the binary grading system (kappa = 0.57; percent agreement: 82% and kappa = 0.62; 84%) were superior compared with the FIGO system (0.50; 60% and 0.62; 73%) and the nuclear grading (0.23; 49% and 0.43; 65%). Patients with early-stage low- grade tumors had a 98% rate for 5-year survival (5YS). Patients with early-stage high-grade tumors, and those with advanced-stage low-grade tumors, had respectively 86% to 87% rates for 5YS. But patients with advanced-stage high-grade tumors had a 49% rate for 5YS. In binary low-grade early-stage tumors, the patient outcome was better with no adjuvant therapy and chemotherapy, compared with other therapies. Conclusion: A binary grading system was superior to others in permitting greater reproducibility and predicting the prognosis of endometrial cancer patients. Copyright (C) 2004 S. Karger AG, Basel.

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Changed expression of heat shock proteins in various pathological findings in placentas with intrauterine fetal growth restriction

Koya Wataba, Tsuyoshi Saito, Makoto Takeuchi, Masahiro Nakayama, Noriyuki Suehara, Ryuichi Kudo

Medical Electron Microscopy 37 ( 3 ) 170 - 176 2004

Heat shock proteins (HSPs) are activated in the cells of most organisms in response to sublethal heat shock and other stressors. It has been reported that HSP27, HSP60, HSP70, and HSP90 are expressed in normal human placenta, and it was thought that these HSPs play a role in the demonstration of cell viability and function. In this study, we performed an immunohistochemical (IHC) study of these HSPs for 27 placentas that had complicated intrauterine fetal growth restriction (IUGR) and compared the IHC findings with the pathological findings. To quantify HSP27, HSP60, HSP70, and HSP90, immunoreacted cells in the chorionic villi, syncytiotrophoblasts (ST), and cytotrophoblasts (CT) were counted. In thrombus, excessive syncytial knots, and avascular villi, the expression of HSPs was higher in the pathological sections compared to control in both ST and CT. In contrast, all HSPs decreased in both ST and CT around the infarction region. The data suggested that chorionic villi cells locally responded to some stresses, e.g., hypoxia and increase or decrease in the expression of HSPs. Although the villous cells around the infarction histologically appear viable, they may have received lethal damage, and as a result the expression of HSPs was decreased. These results are expected to improve our understanding of the pathological findings of IUGR in placentas, including the quality, damage, and function of the chorionic villi. © The Clinical Electron Microscopy Society of Japan 2004.

DOI PubMed

Suppression of gap junctional intercellular communication via 5 ' CpG island methylation in promoter region of E-cadherin gene in endometrial cancer cells

M Nishimura, T Saito, H Yamasaki, R Kudo

CARCINOGENESIS ( OXFORD UNIV PRESS ) 24 ( 10 ) 1615 - 1623 2003.10

Previously, we demonstrated that connexins (Cxs) showed aberrant localization and expression in most endometrial hyperplasia and carcinoma samples, indicating that during endometrial carcinogenesis, loss of gap junctional intercellular communication (GJIC) may occur at relatively early stages. In the present study, we focused on the correlations between GJIC and the expression of the E-cadherin and its 5' CpG island methylation in endometrial cancer cells and tissues to investigate their roles in the carcinogenesis and tumor progression of endometrial cancer. In this study, three of the 10 cell lines investigated, Ishikawa, RL-952 and KLE, in which both Cxs and E-cadherin mRNA were expressed, exhibited GJIC by scrape-loading/dye transfer. On the other hand, the other seven cell lines, in which either or both Cxs and E-cadherin mRNA were negative or weakly expressed, did not show GJIC. HEC-50, HEC-1B and HEC-108, in which Cxs were positively expressed but E-cadherin was negatively expressed, showed cytoplasmic localization of Cxs by immunohistochemistry. All five lines, which showed the weak expression of E-cadherin, had E-cadherin 5' CpG island methylation. By immunohistochemistry of 56 endometrial carcinomas, 13 of 27 methylated samples showed weak expression of Cx26 and the other 14 showed diffuse localization in cytoplasm. On the other hand, of 29 unmethylated samples, two showed cell-cell localization, 25 weak expression and two diffuse localization. Furthermore, E-cadherin expression was revealed to be drastically down-regulated by E-cadherin antisense oligonucleotides that post-transcriptionally down-regulated E-cadherin expression and in the cell, the localization of Cxs were changed from the cell-cell borders to the cytoplasm, and GJIC also decreased. The results indicated that 5' CpG island methylation, which caused loss of E-cadherin expression, indirectly caused the suppression of GJIC by aberrant localization of Cxs in endometrial carcinoma cells.

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Three-dimensional coculture of endometrial cancer cells and fibroblasts in human placenta derived collagen sponges and expression matrix metalloproteinases in these cells

R Tanaka, T Saito, K Ashihara, M Nishimura, H Mizumoto, R Kudo

GYNECOLOGIC ONCOLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 90 ( 2 ) 297 - 304 2003.08

Objective. Collagen gel constitutes a valuable tool for the study of cell-matrix interactions; however, it is sometimes difficult to use the gel, in which tumor and stromal cells are cocultured, for immunohistochemistry, because it is easily broken during the process of fixation and embedding in paraffin, especially after long-term culture. Methods. To examine the interaction between endometrial cancer cells and fibroblasts in tumor invasion, we carried out three-dimensional (3-D) coculture of various endometrial cancer cell lines and fibroblasts in human placenta derived collagen sponges and analyzed the expression and localization of matrix metalloproteinases (NIMP) and plasminogen activators (PA) in these cells by immunohistochemistry. Results. After 4 weeks of culture on the collagen sponges, endometrial cancer cells composed stratiform or glandular structures on the layer of extracellular matrix, which was composed from fibloblasts and extracellular matrix. Compared to Ishikawa cells, which were rarely invasive, HEC-1A and HEC-1BE and cocultured fibroblasts showed high invasiveness and strong expression of some proteins. In cell line HEC-1BE, MMP-1, -7, and -9, MT1-MMP, tissue inhibitors of metalloprotemases 2, and uPA showed intensive staining in both cancer cells and fibroblasts by immunohistochemistry. HEC-1A cells and cocultured fibroblasts showed expression patterns similar to those of HEC-1BE. Conclusion. These results suggested that expression of MMPs and uPA was accelerated in fibroblasts surrounded by cancer cells. We believe that our 3-D coculture system has merit in that the interaction between cancer cells and stromal cells can be visually analyzed by immunohistochemistry and that experiments for a long period, at least 2 weeks, are possible. Furthermore, it is expected that some animal, e.g., nude mouse, experiments can be replaced by experiments using this culture system. (C) 2003 Elsevier Inc. All rights reserved.

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Treatment and prognosis of the invasive cervical cancer with pregnancy

TANAKA Ryoichi, SAITO Tsuyoshi, ITO Eiki, MIZUMOTO Hisanobu, NISHIMURA Makoto, KUDO Ryuichi

日本婦人科腫瘍学会雑誌 = The journal of the Japan Society of Gynecologic Oncology 21 ( 3 ) 245 - 250 2003.06

CiNii

Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferention and myometrial invasion in endometrial carcinoma

T Saito, M Nishimura, H Yamasaki, R Kudo

CANCER ( JOHN WILEY & SONS INC ) 97 ( 4 ) 1002 - 1009 2003.02

BACKGROUND. Loss of E-cadherin expression is associated with aberrant 5' CpG island methylation in various tumors. METODS. The authors analyzed the methylation status and immunohistochemical expression of E-cadherin in 142 endometrial tissues, consisting of 21 normal endometria, 17 endometrial hyperplasias, and 104 endometrial carcinomas. RESULTS. All normal endometria and endometrial hyperplasias showed positive staining of E-cadherin, and methylation of the E-cadherin gene was not detected in any samples. In endometrial carcinoma, the positive ratio of methylation was higher and was associated with tumor dedifferention and myometrial invasion. In G1 endometrial adenocarcinomas, 66.7% showed positive staining and 33.3% showed heterogeneous staining. Methylation of the E-cadherin gene was detected in 15.6%. In G2 tumors, 19.0% showed positive staining, 69.0% showed heterogeneous staining and 11.9% showed negative staining. Methylation of the E-cadherin gene was found in 50.0%. In G3 tumors, 9.1% showed positive staining, 54.5% showed heterogeneous staining and 36.3% showed negative staining. Methylation of the E-cadherin gene was found in 81.8% of the tumors. Of the samples with no-myometrial invasion, 23.1% had methylation. In those with invasion in less than half of the myometrium, 28.6% did and in those with invasion of half or more of the myometrium, 55.6% had methylation. Of samples that did not have lymph node metastasis, 33.7% had methylation, whereas of samples that had lymph node metastasis, 60.0% had methylation. CONCLUSIONS. This is the first report to analyze methylation of the E-cadherin gene promoter of endometrial carcinoma and the evidence suggests that methylation of the E-cadherin gene occurs in association with the acquisition of invasive capacity.

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Usefulness of silver intensification of immunostaining for cytologic diagnosis of primary melanoma of the female genital organs

T Saito, M Takehara, R Tanaka, K Sato, M Fujita, R Kudo

ACTA CYTOLOGICA ( SCI PRINTERS & PUBL INC ) 46 ( 6 ) 1075 - 1080 2002.11

OBJECTIVE: To improve the procedure for diagnosing vaginal melanoma with cytopathologic analysis of HMB-45. STUDY DESIGN: The study examined silver intensification of immunostaining of HMB-45 in nine cases of primary melanoma of the vagina and vulva using archival Papanicolaoustained smears. RESULTS: All nine samples showed positive staining for HMB-45. Five cases showed intensive staining, two moderate and two weak. The positive staining was black in the cytoplasm of melanoma cells but was detected in neither the background nor normal squamous cells. Though destaining of Papanicolaou stain was not performed before immunostaining, the positivity of immunostaining was easily judged. CONCLUSION: After morphologic observation, immunocytochemical study of HMB-45 is possible even though time has passed since the cytologic specimen was obtained. When there is a suspicion of amelanotic melanoma or scantily pigmented melanoma of the vagina and vulva, cytogenesis with HMB-45 is helpful, especially because it involves little invasion.

Imaging studies in patients with malignant melanoma in the female genital tract

M Takehara, T Saito, H Mizumoto, T Baba, R Tanaka, T Fujimoto, K Adachi, R Kudo

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER ( BLACKWELL PUBLISHING INC ) 12 ( 5 ) 506 - 509 2002.09

The purpose of this study was to review magnetic resonance imaging (MRI) and pathologic features of primary malignant melanoma (melanoma) in the female genital tract. We retrospectively evaluated MRI in six women with melanoma of the genital tract. The signal intensity of the tumor on T1-weighted images (WI) was compared with the amount of melanin granules in hematoxylin-eosin stained sections of resected specimen. On T1WI, four melanomas showed a high signal intensity, one intermediate, and one low. The four melanomas with a high signal intensity on T1W1 were rich in melanin granules, while the one intermediate tumor had few granules. The other one was amelanotic. We believe that a high signal on T1WI is characteristic of primary melanotic melanoma of the female genital tract. Our findings suggest that it is strongly influenced by the presence of melanin granules.

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Acceleration of invasive activity via matrix metalloproteinases by transfection of the estrogen receptor-alpha gene in endometrial carcinoma cells

H Mizumoto, T Saito, K Ashihara, M Nishimura, R Tanaka, R Kudo

INTERNATIONAL JOURNAL OF CANCER ( WILEY-LISS ) 100 ( 4 ) 401 - 406 2002.08

It is well known that the functions of reproductive organs are regulated by sex steroids and their receptors and it is hypothesized that the progression of neoplasms that originate from the reproductive organs is influenced by them. However, the correlation between sex steroids and tumor progression, especially tumor invasion, is not well known in endometrial carcinoma. In our study, we focused on the influence of estrogen and its receptor in invasion and matrix metalloproteinases (MMI's), which are known to be important in tumor invasion, as well as on endometrial carcinoma cells. The growth of Ishikawa, cells, to which an estrogen receptor-alpha expressing vector was transfected, was accelerated by 17beta-estradiol as was the acceleration of the expression of cyclin D1. By invasion assay, in conditions with 17beta-estradiol, the invasiveness of Ishikawa cells was enhanced. Furthermore, according to the accelerated invasiveness, the expression of MMP-1, -7 and -9 and Ets-1 was enhanced. These results suggest that activation of ER-alpha by estrogen results in tumor progression by stimulating cell growth and invasiveness via acceleration of the expression of MMPs. (C) 2002 Wiley-Liss, Inc.

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Loss of gamma-catenin expression in squamous differentiation in endometrial carcinomas

K Ashihara, T Saito, H Mizumoto, K Adachi, R Tanaka, M Nishimura, E Ito, R Kudo

INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 21 ( 3 ) 246 - 254 2002.07

Squamous differentiation occurs in 25 to 50% of endometrial endometrioid adenocarcinomas. In this study, we analyzed the immunohistochemical expression and localization of beta- and gamma-catenin, molecular changes in the beta-catenin gene, and the subcellular localization of the desmosomal component protein, desmoplakin, by laser scanning microscopy in 35 endometrial carcinomas with squamous differentiation. In the glandular component, beta-catenin showed nuclear localization in 10 of 35 (28.5%) samples, whereas in the squamous component, nuclear localization was found in 15 of 35 (42.9%). Of the 15 samples that showed nuclear localization of beta-catenin in the squamous component, seven samples (46.7%) did not express gamma-catenin. The phenomenon was not correlated with mutation in exon 3 region of beta-catenin gene. Furthermore. in these samples, there was diffuse cytoplasmic staining for desmoplakin. These observations have not been reported in other tumors. Our results suggest that unique molecular events. i.e., stimulation of beta-catenin and suppression of gamma-catenin expression. occur within endometrial carcinomas with squamous differentiation.

Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study and enzyme immunoassay

H Mizumoto, T Saito, K Ashihara, M Nishimura, M Takehara, R Tanaka, E Ito, R Kudo

LIFE SCIENCES ( PERGAMON-ELSEVIER SCIENCE LTD ) 71 ( 3 ) 259 - 273 2002.06

Like carcinoma, endometriosis has the unique characteristics, of invasion and metastasis, though pathologically, it is a benign tumor. However, the mechanism of destruction of the surrounding tissue in endometriosis is still unclear. In this study, the expression and localization of matrix metalloproteinases (MMP)-1, -2, -3, -7, -9 and tissue inhibitors of metalloprotemases-1 (TIMP-1) were evaluated by immunohistochemistry for 20 cases and the amounts of MMP-1, TIMP-1 and MMP-1/TIMP-1 complex in the fluid of endometrioma, were analyzed by ELISA and western blotting for 20 cases, which were analyzed by immunohistochemical study. MMP-1, -2 and -9 were detected strongly in both stromal and epithelial cells and MMP-7 in the epithelial cells in the menstrual period. MMP-3 was mainly expressed in macrophage containing hemosiderin but the change of expression was not clear. TIMP-1 was intensively detected in both stromal and epithelial cells in the menstrual period but the expression decreased in other stages of the menstrual cycle. ELISA for MMP-1 also showed results similar to immunohistochemistry, suggesting that it was released to the cyst in the menstrual period when it was released to the extracellular space from the cytoplasm. The expression of TIMP-I was not clearly changed during the menstrual cycle. From these results, it was suggested that the destruction of the surrounding matrix by endometriosis might be caused by various MMPs, which are mainly produced in stromal cells. (C) 2002 Elsevier Science Inc. All rights reserved.

DOI PubMed CiNii

Mutation of β-catenin gene in endometrial cancer but not in associated hyperplasia

Koji Ashihara, T. Saito, Hisanobu Mizumoto, Makoto Nishimura, Ryoichi Tanaka, Ryuichi Kudo

Medical Electron Microscopy 35 ( 1 ) 9 - 15 2002

Endometrial hyperplasia is a recognized effect of excessive or unopposed estrogen stimulation and is considered to be a precancerous condition of endometrial adenocarcinoma. We have previously shown that the subcellular localization of β-catenin in the human endometrium is changed according to cell proliferation, suggesting a role of intercellular transduction in cell-growth control in human endometrium, not only in the physiological condition but also in the carcinogenic endometrium. In the present study, to clarify at which stage of endometrial carcinogenesis molecular alteration of the β-catenin gene occurs, we analyzed the subcellular localization of β-catenin by immunohistochemistry, and we analyzed exon 3 of the β-catenin gene, in 25 patients - with endometrial hyperplasia and 20 patients with endometrial cancers associated with endometrial hyperplasia, digesting DNA from the cancer and hyperplasia parts, separately. Fourteen of the 25 (56.0%) endometrial hyperplasia samples, 12 (60.0%) endometrial cancers, and 11 (55.0%) associated hyperplasias of the 20 endometrial cancers associated with hyperplasia showed nuclear localization of β-catenin. Mutation in exon 3 of the β-catenin gene was found in 2 of the 20 endometrial cancer samples however, it was not found in the 25 endometrial hyperplasias or the 20 associated hyperplasias. The results suggest that molecular alteration of the β-catenin gene occurs in atypical hyperplasia or cancer, rather than in simple or complex hyperplasia without atypia, during endometrial carcinogenesis.

DOI PubMed

Hemorrhagic infarction of fibroma: MR imaging appearance

M. Takehara, T. Saito, K. Manase, T. Suzuki, T. Hayashi, R. Kudo

Archives of Gynecology and Obstetrics 266 ( 1 ) 48 - 49 2002

DOI PubMed

Suppressed gap junctional intercellular communication in carcinogenesis of endometrium

T Saito, M Nishimura, R Kudo, H Yamasaki

INTERNATIONAL JOURNAL OF CANCER ( WILEY-LISS ) 93 ( 3 ) 317 - 323 2001.08

To examine whether and at which stage of endometrial carcinogenesis decreased connexin expression occurs, we investigated changes in the expression of the gap junction proteins, connexin 26 (Cx26), Cx32 and Cx43, in human endometrial hyperplasia and cancer samples. Forty-eight endometrial tissue samples (15 endometrial hyperplasias and 33 endometrial cancers) were subjected to immunofluorescence and RT-PCR analysis, In endometrial hyperplasia, Cx26 war aberrantly expressed in all samples as revealed immunohistochemically. There was weak or negative expression in 12 samples (80.0%) and diffuse expression in cytoplasm in 3 samples (20.0%), Cx32 expression in those samples was similar to that of Cx26; there was weak or negative expression in II samples (73.3%) and diffuse expression in 4 samples (26.7%), In endometrial cancer, Cx26 was expressed weakly or negatively in 25 samples (75.8%), diffusely in 6 samples (18.2%) and normally in 2 samples (6.1%), while Cx32 was expressed weakly or negatively in 26 samples (78.8%), diffusely in 5 samples(15.2%) and normally in 2 samples (6.1%). It was confirmed that weak staining of Cx26 and Cx32 was due to poor expression of their mRNA, All samples showed weak Cx43 protein expression as revealed by immunohistochemical analysis, In the majority of samples, concomitant expression levels of Cx26 and Cx32 protein were observed, confirming our long-term hypothesis that Cx26 and Cx32 are both abnormally regulated in a coordinated fashion in the endometrium, Our results indicate that during endometrial carcinogenesis, loss of gap junctional intercellular communication (GJIC) may occur due to the suppressed expression and the aberrant localization of connexin at relatively early stages. (C) 2001 Wiley-Liss, Inc.

DOI PubMed CiNii

Conservative vaginal surgery for cervical pregnancy

N Akutagawa, A Nishikawa, T Saito, S Sagae, R Kudo

BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY ( ELSEVIER SCIENCE BV ) 108 ( 8 ) 888 - 889 2001.08

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Changes in expression and subcellular localization of nuclear retinoic acid receptors in human endometrial epithelium during the menstrual cycle

K Fukunaka, T Saito, K Wataba, K Ashihara, E Ito, R Kudo

MOLECULAR HUMAN REPRODUCTION ( OXFORD UNIV PRESS ) 7 ( 5 ) 437 - 446 2001.05

The endometrium is a uniquely dynamic tissue in that it undergoes monthly cycles of proliferation and secretory activity, and is regulated by ovarian steroid hormones. In this study, we focused on retinoic acid receptors (RAR and RXR) which are ligand-dependent transcription factors belonging to the large family of steroid hormones and are expected to affect to cell growth and differentiation in the endometrium. We analysed the expression and subcellular localization of the RA receptors in 57 samples of human endometrium by immunohistochemistry and Western blotting. In the nuclei of the endometrial epithelium, the RA receptors were expressed strongly in the proliferative phase, However, RAR were drastically reduced in the epithelial nuclei during the secretory phase in association with changes in serum oestradiol and in the expression of the oestrogen receptor. The expression of RXR was localized in the epithelial nuclei throughout the menstrual cycle. Confocal laser scanning microscopical observation clearly showed the difference in the localization between RAR and RXR in the secretory phase. Furthermore the findings of immune-electron microscopy showed pooled RAR around the rough endoplasmic reticulum, suggesting that transport of these receptors to the nuclei is inhibited. These findings suggest that RAR and RXR work mainly in the proliferative phase and that in the endometrium RXR may play a different role to RAR during the secretory phase.

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