Details of a Researcher - SAITOU Tsuyoshi

Papers - SAITOU Tsuyoshi

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p53 negatively regulates the hepatoma growth factor HDGF.

Yasushi Sasaki, Hideaki Negishi, Masashi Idogawa, Ikuko Yokota, Ryota Koyama, Masanobu Kusano, Hiromu Suzuki, Masahiro Fujita, Reo Maruyama, Minoru Toyota, Tsuyoshi Saito, Takashi Tokino

Cancer research 71 ( 22 ) 7038 - 47 2011.11 [Refereed] [International journal]

Hepatoma-derived growth factor (HDGF) is a secreted heparin-binding growth factor that has been implicated in cancer development and progression. Here, we report that HDGF is a critical target for transcriptional repression by the tumor suppressor p53. Endogenous HDGF expression was decreased in cancer cells with introduction of wild-type p53, which also downregulated HDGF expression after DNA damage. In support of the likelihood that HDGF is a critical driver of cancer cell growth, addition of neutralizing HDGF antibodies to culture media was sufficient to block cell growth, migration, and invasion. Similarly, these effects were elicited by conditioned culture medium from p53-expressing cells, and they could be reversed by the addition of recombinant human HDGF. Interestingly, we found that HDGF was overexpressed also in primary gastric, breast, and lung cancer tissues harboring mutant p53 genes. Mechanistic investigations revealed that p53 repressed HDGF transcription by altering HDAC-dependent chromatin remodeling. Taken together, our results reveal a new pathway in which loss of p53 function contributes to the aggressive pathobiological potential of human cancers by elevating HDGF expression.

DOI PubMed

A Remarkably Easy Knot-Tying Technique for Single-Incision Laparoscopic Surgery with the SILS Port for Gynecologic Diseases

Toshiaki Endo, Kunihiko Nagasawa, Kota Umemura, Tsuyoshi Baba, Hirofumi Henmi, Tsuyoshi Saito

JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY ( ELSEVIER SCIENCE INC ) 18 ( 4 ) 500 - 502 2011.07 [Refereed]

Single-incision laparoscopic surgery (SILS) has been quickly accepted, especially for women, because the cosmetic benefits may be greater than with ordinary laparoscopic surgery. In gynecologic disease, SILS is appropriate for diagnostic laparoscopy, oophorectomy, and salpingectomy, among other conditions. In addition, the knot-tying process for intracorporeal suturing during SILS is a major rate-limiting step and a key determinant of the popularity of SILS. Although a roticulator instrument is useful for creating the needed operative angle, knot tying is still believed to be difficult. We have devised a remarkably simple knot-tying technique that can be applied during SILS with a SILS Port with a Roticulator and a straight-type needle driver. We determined that, after transfixing the needle, the long tail of the thread should be grasped at around 90 degrees relative to the long axis of tip of the Roticulator, which is articulated at 80 degrees. This automatically forms an ideal C-loop because of gravitation. The needle attached to the long tail should face the distal side from the tip of Roticulator (from the surgeon's perspective). The apex of the C-loop is then toward the proximal side from the tip of the Roticulator (from the perspective of the surgeon). This thread position is important during the knot-tying process. The upper arm of the C-loop should then be entwined by applying a series of axial spinning movements to the rod of the needle driver. At this time, the jaws of the needle driver should be kept open so the thread does not slip off of the rod. The benefit of this technique is that it does not require any special skills; any surgeon able to perform intracorporeal suturing should also be able to easily tie knots during SILS. Journal of Minimally Invasive Gynecology (2011) 18, 500-502 (C) 2011 AAGL. All rights reserved.

DOI

Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan.

Tsuyoshi Baba, Toshiaki Endo, Keiko Ikeda, Ayumi Shimizu, Hiroyuki Honnma, Hiroshi Ikeda, Naoya Masumori, Tousei Ohmura, Tamotsu Kiya, Takashi Fujimoto, Motoiki Koizumi, Tsuyoshi Saito

The journal of sexual medicine 8 ( 6 ) 1686 - 93 2011.06 [International journal]

INTRODUCTION: The prevalence of transsexualism is thought to differ among socio-geographic backgrounds, and little is known about its prevalence in Japan. Polycystic ovary syndrome (PCOS), which is known to be associated with insulin resistance and metabolic syndrome, is often seen in female-to-male (FTM) transsexual patients. Consequently, detection of PCOS is an important part of health care for these individuals. AIM: The purpose of this study was to assess the prevalence of transsexuality in Japan, as well as the incidences of PCOS and insulin resistance among Japanese FTM transsexual patients. METHODS: One hundred four male-to-female (MTF) and 238 FTM Japanese transsexual patients were studied. Medical histories, including histories of menstrual cycling and hormone treatment, were taken. To exclude other diseases, such as congenital adrenal hyperplasia and hormone-secreting tumors, thorough medical assessments, including transvaginal or transrectal ultrasonography and measurement of serum hormone levels and insulin resistance indexes, were performed. MAIN OUTCOME MEASURES: The diagnosis of PCOS was based on the Rotterdam 2003 criteria. RESULTS: Based on demographic statistics, the prevalences of MTF and FTM transsexuality are about 3.97 and 8.20 per 100,000 people, respectively, making the MTF-to-FTM ratio about 1:2. Of the FTM transsexual patients studied, 128 had not taken hormones before their initial assessment (untreated group); the remaining 50 self-administered androgen. Among the untreated group, 32.0% were diagnosed with PCOS, 30.1% were insulin-resistant, and 31.1% showed hypoadiponectinemia. CONCLUSIONS: The sex ratio among Japanese transsexuals is different than among Caucasians. PCOS and insulin resistance are common findings in FTM transsexual patients at initial presentation.

DOI PubMed

BAG3 (BCL2-associated athanogene 3) interacts with MMP-2 to positively regulate invasion by ovarian carcinoma cells

Miwa Suzuki, Masahiro Iwasaki, Asuka Sugio, Akinori Hishiya, Ryoichi Tanaka, Toshiaki Endo, Shinichi Takayama, Tsuyoshi Saito

CANCER LETTERS ( ELSEVIER IRELAND LTD ) 303 ( 1 ) 65 - 71 2011.04 [Refereed]

BAG3 (BCL2-associated athanogene 3) is a member of the BAG family proteins, which interact with and regulate Hsp70. Our aim in the present study was to correlate BAG3 expression in ovarian cancer with invasion and progression-free survival. We found that BAG3 interacts with MMP2 in cultured ovarian cancer cells, and that knockdown of BAG3 expression downregulated MMP2 expression and diminished cell motility and invasiveness. The incidence of BAG3 positivity was significantly higher at advanced clinical stages of ovarian cancer than at early stages. We suggest that BAG3 binds to MMP2 to positively regulate the process of cell invasion. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI

Statin-mediated reduction of osteopontin expression induces apoptosis and cell growth arrest in ovarian clear cell carcinoma.

Matsuura M, Suzuki T, Suzuki M, Tanaka R, Ito E, Saito T

Oncology reports 25 ( 1 ) 41 - 47 2011.01 [Refereed]

PubMed

Osteopontin is a new target molecule for ovarian clear cell carcinoma therapy.

Matsuura M, Suzuki T, Saito T

Cancer science 101 ( 8 ) 1828 - 1833 2010.08 [Refereed]

DOI PubMed

Prediction of histologic type and lymph node metastasis for advanced ovarian cancer on uterine cervical and endometrial cytology.

Suzuki M, Suzuki T, Matsuura M, Iwasaki M, Tanaka R, Ito E, Fujii M, Saito T

Acta cytologica 54 ( 4 ) 575 - 581 2010.07 [Refereed]

DOI PubMed

Remarkable features of ovarian morphology and reproductive hormones in insulin-resistant Zucker fatty (fa/fa) rats.

Hiroyuki Honnma, Toshiaki Endo, Tamotsu Kiya, Ayumi Shimizu, Kunihiko Nagasawa, Tsuyoshi Baba, Takashi Fujimoto, Hirofumi Henmi, Yoshimitsu Kitajima, Kengo Manase, Shinichi Ishioka, Eiki Ito, Tsuyoshi Saito

Reproductive biology and endocrinology : RB&E 8 73 - 73 2010.06 [International journal]

BACKGROUND: Zucker fatty (fa/fa) rats are a well-understood model of obesity and hyperinsulinemia. It is now thought that obesity/hyperinsulinemia is an important cause of endocrinological abnormality, but to date there have been no reports on the changes in ovarian morphology or the ovarian androgen profile in rat models of obesity and insulin resistance. METHODS: In this study we investigated the effects of obesity and hyperinsulinemia on ovarian morphology and the hormone profile in insulin-resistant Zucker fatty rats (5, 8, 12 and 16 weeks of age, n = 6-7). RESULTS: Ovaries from 5-week-old fatty rats had significantly greater total and atretic follicle numbers, and higher atretic-to-total follicle ratios than those from lean rats. Ovaries from 12- and 16-week-old fatty rats showed interstitial cell hyperplasia and numerous cysts with features of advanced follicular atresia. In addition, serum testosterone and androstenedione levels significantly declined in fatty rats from age 8 to 16 weeks, so that fatty rats showed significantly lower levels of serum testosterone (12 and 16 weeks) and androstenedione (all weeks) than lean rats. This may reflect a reduction of androgen synthesis during follicular atresia. Serum adiponectin levels were high in immature fatty rats, and although the levels declined significantly as they matured, it remained significantly higher in fatty rats than in lean rats. On the other hand, levels of ovarian adiponectin and its receptors were significantly lower in mature fatty rats than in lean mature rats or immature fatty rats. CONCLUSIONS: Our findings indicate that ovarian morphology and hormone profiles are significantly altered by the continuous insulin resistance in Zucker fatty rats. Simultaneously, abrupt reductions in serum and ovarian adiponectin also likely contribute to the infertility seen in fatty rats.

DOI PubMed

Successful uterus-preserving surgery for treatment of chemotherapy-resistant placenta increta.

Endo T, Hayashi T, Shimizu A, Matsuura M, Mizuuchi M, Nagasawa K, Ezaka Y, Baba T, Ishioka S, Saito T

Gynecologic and obstetric investigation 69 ( 2 ) 112 - 115 2010 [Refereed]

DOI PubMed

Changes of uterine blood flow after vaginal radical trachelectomy (VRT) in patients with early-stage uterine invasive cervical cancer

Kota Umemura, Shin-ichi Ishioka, Toshiaki Endo, Tsuyoshi Baba, Yoshiaki Ezaka, Kunihiko Nagasawa, Madoka Takahashi, Masahito Mizuuchi, Nanako Iwami, Hidefumi Adachi, Noriko Takeda, Mitsuharu Tamagawa, Tsuyoshi Saito

INTERNATIONAL JOURNAL OF MEDICAL SCIENCES ( IVYSPRING INT PUBL ) 7 ( 5 ) 260 - 266 2010 [Refereed]

Background. Vaginal radical trachectomy (RT) ligates and cuts several arteries supplying the uterus. Changes of blood supply to the uterus in two patients who experienced pregnancy and delivery were studied by using 3-D CT scanning. Effects of changes of blood supply to the uterus on the pregnancy courses were also examined. Methods. Vascular distribution in the uterus was studied in two patients who received vaginal RT after delivery. Effects of changes of vascular distribution after vaginal RT were studied with respect to pregnancy courses and cervical functions. Results. New arterial vascularization from the ascending branches of uterine arteries or other arteries occurred, and these new vessels seemed to supply blood to the remaining cervix. Differences of fetal growth and histopathological changes in the placenta between the two patients could not be detected. Conclusion. Ligation and cutting of several supplying arteries by RT induces new areterial vascularization and it does not seem to affect fetal growth and placental function.

Outcomes of planned delivery delay in pregnant patients with invasive gynecologic cancer

Shin-ichi Ishioka, Yoshiaki Ezaka, Toshiaki Endo, Kunihiko Nagasawa, Ayumi Shimizu, Akiyasu Sato, Marie Inoue, Tsuyoshi Saito

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY ( SPRINGER TOKYO ) 14 ( 4 ) 321 - 325 2009.08 [Refereed]

Pregnancy with invasive gynecologic cancer is a rare condition. It is still unclear whether we can choose planned delay in treatment until maturation of the fetus as a treatment modality for this condition. If there are no adverse effects from the cancer and there is improvement of neonatal outcomes, this treatment modality might be an option for patients with this condition. Eight pregnant patients were diagnosed as having invasive gynecologic cancer between January 1998 and December 2007. Five of them, (four with invasive uterine cervical cancer and one with ovarian cancer) chose planned delay in treatment. The pregnancy courses and prognoses of these patients were studied. The period of planned delay in treatment varied from 2 weeks to 19 weeks. The period was shorter for patients who had complications. The pain caused by the cancer was the main obstacle to this treatment modality in two patients (one with advanced ovarian cancer and one with uterine cervical cancer). No apparent tumor growth, elevation of tumor markers, or complications induced by the cancer itself were detected in the remaining three patients. Only the patient with advanced ovarian cancer died of the primary disease after the delivery. Fetal outcome was uniformly good for the delayed-treatment group. All the babies are growing well, and no fetal deaths or neonatal deaths occurred. Planned delay in treatment to allow for fetal maturity is acceptable in pregnant patients with certain types of invasive gynecologic cancers.

DOI

The contributions of resistin and adiponectin gene single nucleotide polymorphisms to the genetic risk for polycystic ovary syndrome in a Japanese population

Tsuyoshi Baba, Toshiaki Endo, Fumihiro Sata, Kunihiko Nagasawa, Hiroyuki Honnma, Yoshimitsu Kitajima, Takuhiro Hayashi, Kengo Manase, Mika Kanaya, Osamu Moriwaka, Hirofumi Kamiya, Hideto Yamada, Hisanori Minakami, Reiko Kishi, Tsuyoshi Saito

GYNECOLOGICAL ENDOCRINOLOGY ( INFORMA HEALTHCARE ) 25 ( 8 ) 498 - 503 2009 [Refereed] [International journal]

Polycystic ovary syndrome (PCOS) is a heterogeneous group of disorders that occur fairly commonly in women of reproductive age and are characterized by a variety of clinical manifestations, including insulin resistance that is independent of obesity. Recent studies suggest that altered adipocytokine gene expression is closely associated with insulin resistance and that single nucleotide polymorphisms (SNPs) modulate the expression and/or function of these genes, thereby affecting insulin sensitivity. With that in mind, we investigated whether SNPs at position 7420 of the resistin gene (RETN) and/or 711377 of the adiponectin gene (ADIPOQ) modulate the susceptibility to PCOS. We evaluated the genotypes of 117 women with PCOS and 380 healthy fertile controls and measured the index of insulin resistance and hormonal profiles in the PCOS women. The RETN 7420G/G homozygous variant genotype occurred significantly more frequently among the PCOS group than among the control group (15.4% vs. 8.4%, p = 0.035). PCOS women with the RETN 7420G/ G genotype also showed significantly higher BMIs and greater insulin resistance than those with RETN 7420 C/C or C/G genotypes. The ADIPOQ SNP at 711377 showed no association with PCOS. We conclude that the RETN G/G at 7420 genotype is associated with PCOS in Japanese women.

DOI PubMed

Analgesic efficacy of controlled-release oxycodone in patients with uterine or ovarian cancer.

Suzuki T, Morishita M, Ito E, Matsuura M, Tanaka R, Saito T

American journal of therapeutics 15 ( 1 ) 31 - 35 2008.01 [Refereed]

DOI PubMed

Advanced epithelial ovarian carcinoma during pregnancy

Shin-ichi Ishioka, Takuhiro Hayashi, Toshiaki Endo, Tsuyoshi Baba, Hiroyuki Honma, Tsuyoshi Saito

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY ( SPRINGER TOKYO ) 12 ( 5 ) 375 - 378 2007.10 [Refereed]

We report a rare case of advanced ovarian mucinous adenocarcinoma in a pregnant woman. A 28-year-old pregnant Japanese woman was diagnosed with an ovarian tumor 8cm in diameter at a local hospital. She was sent to a private hospital at 25 weeks of gestation because of the growing ovarian tumor. Advanced ovarian carcinoma with widespread intraabdominal dissemination was detected by laparotomy at the hospital and she was referred to our hospital for further management. At 27 weeks of gestation, she underwent cesarean section, followed by abdominal total hysterectomy, and bilateral salpingo-oophorectomy. A girl weighing 879 g was delivered, with Apgar scores of 4 and 6 at 1 and 5 min, respectively. The pathological diagnosis of the tumor was mucinous cystadenocarcinoma grade 2. Although chemotherapy was not effective for her and she died of the disease 4 months after the surgery, her baby grew well and weighed 3750g 3 months after delivery. For the treatment of such patients, we believe we should choose operative therapy as early as possible after the maturation of the fetus, although there are several reports of successful treatment with the administration of chemotherapy during pregnancy. To determine a better approach for such patients, multidisciplinary staff meetings, including gynecological oncologists, obstetricians, neonatologists, psychologists, and the patient are important.

DOI

Pregnancy-related complications after vaginal radical trachelectomy for early-stage invasive uterine cervical cancer

Shin-Ichi Ishioka, Toshiaki Endo, Takuhiro Hayashi, Tsuyoshi Baba, Kota Umemura, Tsuyoshi Saito

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY ( SPRINGER TOKYO ) 12 ( 5 ) 350 - 355 2007.10 [Refereed]

Background Pregnancy-related complications after vaginal radical trachelectomy (RT) for early-stage invasive uterine cervical cancer were studied in comparison with those occurring after laser conization. The strategy to reduce vaginal RT-related complications during pregnancy is also discussed. Methods. Pregnancy courses after vaginal RT in two patients and those after laser conization in five patients, whose operations were performed during the same period, were studied with respect to symptoms, cervical length, and infectious signs. Results. The cervix shortened progressively both in patients with laser conization and in those with RT. However, throughout the pregnancy, the remaining cervix after the operation was longer in patients who had undergone conization than in those who had undergone vaginal RT. After laser conization, two of the five patients suffered from preterm rupture of the membrane (PROM) at 36 weeks of gestation, and both patients who had undergone vaginal RT had premature PROM (pPROM), at 32 and 24 weeks of gestation, respectively. Conclusion. Prevention of preterm labor and the following occurrence of pPROM is a significant task to be resolved in order to improve pregnancy outcome after vaginal RT for early-stage invasive uterine cervical cancer. Daily vaginal disinfection with povidone iodine and the administration of a ulinastatin vaginal suppository, bed rest, and the use of ritodrine would be the best approach, and a more conservative approach for stage Ia2 also might be taken into consideration.

DOI

Polycystic ovary syndrome is associated with genetic polymorphism in the insulin signaling gene IRS-1 but not ENPP1 in a Japanese population

Tsuyoshi Baba, Toshiaki Endo, Fumihiro Sata, Hiroyuki Honnma, Yoshimitsu Kitajima, Takuhiro Hayashi, Kengo Manase, Mika Kanaya, Hideto Yamada, Hisanori Minakami, Reiko Kishi, Tsuyoshi Saito

LIFE SCIENCES ( PERGAMON-ELSEVIER SCIENCE LTD ) 81 ( 10 ) 850 - 854 2007.08 [Refereed]

(PCOS). We hypothesized that insulin receptor substrate-1 (IRS-1) Gly972Arg polymorphism and/or ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) Lysl 2 1 Gln polymorphism predisposes women to PCOS and that these polymorphisms also affect anthropometric variables, glucose metabolism and androgen synthesis. To test those ideas, we studied the genotypes, indexes of insulin resistance, and hormone profiles in 123 Japanese women with PCOS and 3 80 healthy Japanese controls. We found that there were significantly more IRS-1 972Arg carriers among the PCOS patients than among the healthy controls (10.6% vs. 4.8%, p=0.029), which is consistent with our finding that women carrying the IRS-1 972Arg allele had a significantly increased risk of developing PCOS (odds ratio: 3.31, 95% confidence interval: 1.49-7.35). By contrast, the ENPPI Lys121Arg polymorphism was distributed equally among PCOS patients and controls. In addition, neither of these polymorphisms studied affected the anthropometric variables, metabolic parameters or androgen levels of women with PCOS. We conclude that the IRS-1 Gly972Arg polymorphism is associated with PCOS in the Japanese population. (c) 2007 Elsevier Inc. All rights reserved.

DOI PubMed

Association between polycystic ovary syndrome and female-to-make transsexuality

Tsuyoshi Baba, Toshiaki Endo, Hiroyuki Honnma, Yoshimitsu Kitajima, Takuhiro Hayashi, Hiroshi Ikeda, Naoya Masumori, Hirofumi Kamiya, Osamu Moriwaka, Tsuyoshi Saito

HUMAN REPRODUCTION ( OXFORD UNIV PRESS ) 22 ( 4 ) 1011 - 1016 2007.04 [Refereed]

The aim of this study is to understand the relationship between polycystic ovary syndrome (PCOS), altered hormonal characteristics and insulin resistance in female-to-male (FTM) transsexual patients. METHODS: We studied 69 Japanese FTM cases, aged 17-47 years, who were seen in the Gender Identity Disorder Clinic of Sapporo Medical University Hospital between December 2003 and May 2006. The subjects had never received hormonal treatment or sex re-assignment surgery. Prior to treatment, they received physical examinations entailing measurement of anthropometric, metabolic and endocrine parameters, after which we compared the values obtained according to the presence or absence of PCOS and/or obesity. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Of the 69 participating FTM cases, 40 (58.0%) were found to have PCOS. Of the 49 for whom HOMA-IR was calculated, 15 (30.6 %) also showed insulin resistance, whereas of the 59 for whom adiponectin was measured, 18 (30.5%) showed hypoadiponectinaemia. Of 69 for whom androgens were measured, 29 (39.1 %) showed hyperandrogenaemia. Insulin resistance was associated with obesity but not with PCOS. In contrast, hyperandrogenaemia was associated with both PCOS and obesity. CONCLUSIONS: FTM transsexual patients have a high prevalence of PCOS and hyperandrogenaemia.

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A successful IVF-pregnancy in a patient who underwent conservative surgery followed by a regimen of cisplatin, vinblastine and peplomycin to treat an advanced ovarian mixed germ cell tumour: A Case Report

Y. Kitajima, T. Endo, T. Hayashi, S. Ishioka, T. Baba, H. Honnma, T. Saito

HUMAN REPRODUCTION ( OXFORD UNIV PRESS ) 22 ( 3 ) 850 - 852 2007.03 [Refereed]

Mixed germ cell tumours of the ovary, one type of malignant ovarian germ cell tumours (MOGCTs), are rare gynaecologic cancers usually affecting young women. We report the case of a patient with an advanced ovarian mixed germ cell tumour who underwent fertility-saving surgery followed by a chemotherapy regimen of cisplatin, vinblastine and peplomycin. The patient was disease-free 8 years after initial presentation. She conceived and gestated dichorionic twins after IVF-embryo transfer. To the best of our knowledge, the patient is the first to be treated successfully with the combination chemotherapy regimen and then conceive safely using assisted reproductive technology (ART).

DOI

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 2006.12 [Domestic journal]

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 2006.09 [Refereed]

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

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Papers - SAITOU Tsuyoshi