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Takeshi Hisamatsu,
Seiji Mabuchi,
Yuri Matsumoto,
Mahiru Kawano,
Tomoyuki Sasano,
Ryoko Takahashi, Kenjiro Sawada,
Kimihiko Ito,
Hirohisa Kurachi,
Russell J Schilder,
Joseph R Testa,
Tadashi Kimura
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ABSTRACT: The goal of this study was to examine the role of mTORC2 as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histological subtype. Using tissue microarrays of 98 primary ovarian cancers (52 CCCs and 46 serous adenocarcinomas (SACs)), activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTORC1 inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and RAD001-resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared to the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the anti-tumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a front-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.
Molecular Cancer Therapeutics 04/2013; · 5.23 Impact Factor
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Chifumi Ohyagi-Hara, Kenjiro Sawada,
Shoji Kamiura,
Yasuhiko Tomita,
Aki Isobe,
Kae Hashimoto,
Yasuto Kinose,
Seiji Mabuchi,
Takeshi Hisamatsu,
Toshifumi Takahashi,
Keiichi Kumasawa,
Shigenori Nagata,
Ken-Ichiroiu Morishige,
Ernst Lengyel,
Hirohisa Kurachi,
Tadashi Kimura
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ABSTRACT: Ovarian cancer is characterized by widespread peritoneal dissemination and ascites and has a cure rate of only 30%. As has been previously reported, integrin α5 plays a key role in the peritoneal dissemination of ovarian cancer. Our aim was to identify a new miRNA that regulates integrin α5 expression and analyze the therapeutic potential of targeting this miRNA. By using an IHC analysis, we proved that high integrin α5 expression correlates with a poor prognosis in Japanese patients with International Federation of Gynecology and Obstetrics stage III ovarian cancer. Based on an miRNA algorithm search, we identified hsa-mir-92a (miR-92a) as a candidate. The level of miR-92a expression was significantly inversely correlated with ITGA5 expression in various cancer cells. Transfection of precursor miR-92a reduced integrin α5 expression in ovarian cancer cells, which was accompanied by the inhibition of cancer cell adhesion, invasion, and proliferation. miR-92a overexpression reduced the luciferase activity of the ITGA5 3'-untranslated region, suggesting that ITGA5 mRNA is a direct target of miR-92a. In in vivo ovarian cancer xenografts, the enforced expression of miR-92a in HeyA-8 cells suppressed peritoneal dissemination. Although we still have a long way to go before an effective and nontoxic miRNA-based cancer therapy can be introduced into the clinic, the inhibition of integrin α5 expression by targeting miR-92a needs to be explored further for future applications in ovarian cancer treatment.
American Journal Of Pathology 03/2013; · 4.89 Impact Factor
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Lina Chen,
Sun-Mi Park,
Alexei V Tumanov,
Annika Hau, Kenjiro Sawada,
Christine Feig,
Jerrold R Turner,
Yang-Xin Fu,
Iris L Romero,
Ernst Lengyel,
Marcus E Peter
Nature 11/2012; · 36.28 Impact Factor
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ABSTRACT: Ovarian cancer is a deadly disease, with a cure rate of only 30%. Despite aggressive treatments, relapse remains almost inevitable in patients with advanced-stage disease. In recent years, great progress has been made towards targeting integrins in cancer treatment, and clinical studies with various integrin inhibitors have demonstrated their effectiveness in blocking cancer progression. Given that the initial critical step of ovarian cancer metastasis is the attachment of cancer cells onto the peritoneum or omentum, in addition to the proven positive clinical results of anti-angiogenic therapy, targeting integrins is likely to be one of the most feasible approaches. This paper summarizes the current understanding of the integrin biology in ovarian cancer metastasis and the various therapeutic approaches attempted with integrin inhibitors. Although no integrin inhibitors have shown favorable results so far, integrin-targeted therapies continue to be a promising approach to be explored for further clinical investigation.
Journal of Oncology 01/2012; 2012:915140.
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ABSTRACT: Severe post-partum hemorrhage during cesarean section due to placenta previa is still one of the leading causes of maternal mortality. The aim of this study was to evaluate the efficiency of intrauterine tamponade with a Sengstaken-Blakemore tube (SB-tube) for the treatment of severe post-partum hemorrhage in cases of placenta previa.
Data were collected from our departmental clinical records on all patients who underwent caesarian section due to placenta previa between 2007 and 2009.
During the period analyzed, 37 patients underwent caesarian section due to placenta previa/low-lying placenta. Four (11%) underwent hysterectomy due to placenta accreta and 33 (89%) were treated conservatively. Of the 33 patients with conserved uterus, 10 (28%) patients required a SB-tube during the cesarean section because of continuous post-partum hemorrhage despite appropriate medical treatment. The median bleeding during the operation was 2030±860mL in the patients who used SB-tube. None of them presented severe complications related to these procedures or required any further invasive surgery.
Intrauterine balloon-tamponade could successfully control severe hemorrhage from a lower uterine segment of a patient with placenta previa. This technique is simple to use, scarcely invasive, and available at a low cost to all maternity wards, and should be considered as one of the first management options to reduce the risk of undesirable hysterectomy.
Journal of Obstetrics and Gynaecology Research 08/2011; 38(1):102-7. · 0.94 Impact Factor
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Lina Chen,
Sun-Mi Park,
Alexei V Tumanov,
Annika Hau, Kenjiro Sawada,
Christine Feig,
Jerrold R Turner,
Yang-Xin Fu,
Iris L Romero,
Ernst Lengyel,
Marcus E Peter
Nature 06/2011; · 36.28 Impact Factor
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ABSTRACT: The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype.
Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo.
Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin.
Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC.
Clinical Cancer Research 06/2011; 17(13):4462-73. · 7.74 Impact Factor
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ABSTRACT: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth.
The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum.
In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G(2)-M cell-cycle arrest, and (e) induction of anoikis.
This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer.
Clinical Cancer Research 06/2011; 17(12):4042-51. · 7.74 Impact Factor
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Lina Chen,
Sun-Mi Park,
Alexei V Tumanov,
Annika Hau, Kenjiro Sawada,
Christine Feig,
Jerrold R Turner,
Yang-Xin Fu,
Iris L Romero,
Ernst Lengyel,
Marcus E Peter
Nature 03/2011; 471(7337):254. · 36.28 Impact Factor
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ABSTRACT: Pseudomyxoma peritonei is an extremely rare condition characterized by the presence of gelatinous ascites and disseminated intra-peritoneal mucinous tumors. To our knowledge, there have been only two case reports of pseudomyxoma peritonei during pregnancy in 2009, both of which originated from the appendix. We present the first case of pseudomyxoma peritonei originating from colorectal cancer during pregnancy. Prenatal ultrasound examination of a 34-year-old, asymptomatic woman revealed characteristic features of pseudomyxoma peritonei at 24 weeks gestation. At laparotomy, both ovaries were involved with copious amounts of mucinous tumors and fluid, an advanced colorectal cancer had invaded the peritoneal cavity and multiple disseminated tumors were noted around the intraperitoneal cavity. All clinicians practicing obstetrics and gynecology must consider the possibility of a malignant neoplasm presenting in a pregnant woman and should recognize the highly characteristic features of pseudomyxoma peritonei to enable detection of this rare condition incidentally during routine screening ultrasound examinations.
Journal of Obstetrics and Gynaecology Research 11/2010; 37(3):254-8. · 0.94 Impact Factor
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Seiji Mabuchi,
Chiaki Kawase,
Deborah A Altomare,
Kenichirou Morishige,
Masami Hayashi, Kenjiro Sawada,
Kimihiko Ito,
Yoshito Terai,
Yukihiro Nishio,
Andres J Klein-Szanto,
Robert A Burger,
Masahide Ohmichi,
Joseph R Testa,
Tadashi Kimura
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ABSTRACT: This study examines the role of vascular endothelial growth factor (VEGF) as a therapeutic target in clear cell carcinoma (CCC) of the ovary, which has been regarded as a chemoresistant histologic subtype. Immunohistochemical analysis using tissue microarrays of 98 primary ovarian cancers revealed that VEGF was strongly expressed both in early-stage and advanced-stage CCC of the ovary. In early-stage CCCs, patients who had tumors with high levels of VEGF had significantly shorter survival than those with low levels of VEGF. In vitro experiments revealed that VEGF expression was significantly higher in cisplatin-refractory human CCC cells (RMG1-CR and KOC7C-CR), compared with the respective parental cells (RMG1 and KOC7C) in the presence of cisplatin. In vivo treatment with bevacizumab markedly inhibited the growth of both parental CCC cell-derived (RMG1 and KOC7C) and cisplatin-refractory CCC cell-derived (RMG1-CR and KOC7C-CR) tumors as a result of inhibition of tumor angiogenesis. The results of the current study indicate that VEGF is frequently expressed and can be a promising therapeutic target in the management of CCC. Bevacizumab may be efficacious not only as a first-line treatment but also as a second-line treatment of recurrent disease in patients previously treated with cisplatin.
Molecular Cancer Therapeutics 08/2010; 9(8):2411-22. · 5.23 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 07/2010; 68 Suppl 7:220-2.
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Shinsuke Koyama,
Takuji Tomimatsu, Kenjiro Sawada,
Takeshi Kanagawa,
Aki Isobe,
Yukiko Taniguchi,
Tomo Wada,
Tadashi Kimura,
Hitomi Arahori,
Yasuji Kitabatake,
Kazuko Wada
Prenatal Diagnosis 05/2010; 30(5):489-91. · 2.11 Impact Factor
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ABSTRACT: Cervical insufficiency is a known risk factor for preterm birth and miscarriage. The etiology of cervical insufficiency has not been fully recognized and the association between it and prior cesarean delivery is unknown. We experienced two similar characteristic cases of cervical insufficiency following term cesarean delivery. Interestingly, both cesarean sections were uneventfully performed after the prolonged second stage of labor. Our experience and recent literature strongly support the idea that an unintentional incision into the uterine cervix during a previous cesarean section may cause cervical insufficiency in subsequent pregnancies. It is important for obstetricians to take into account the possible occurrence of cervical insufficiency depending on the circumstances of previous deliveries. Our report highlights the need to alert obstetricians to take more care with their cesarean section technique.
Journal of Obstetrics and Gynaecology Research 04/2010; 36(2):411-3. · 0.94 Impact Factor
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ABSTRACT: Ovarian cancer is known to be highly invasive. The poor prognosis of advanced ovarian cancer comes from increased invasiveness of human ovarian cancer cells. The lysophosphatidic acid (LPA)/Rho/Rho-associated kinase (ROCK) pathway is intimately involved in the course of ovarian cancer progression, and the inhibition of this pathway attenuates ovarian cancer invasiveness. Fasudil (1-[5-isoquinolinesulfonyl]-homopiperazine; HA-1077) is a drug that has been in clinical use in Japan for the prevention of vasospasm after subarachnoid hemorrhage and is known to be a potent ROCK-specific inhibitor. In this study, we examined the effect of fasudil on LPA-induced invasiveness of human ovarian cancer cells to explore the potential of fasudil as an anticancer agent against ovarian cancer. Fasudil induced changes in cell morphology but not in cell viability. Fasudil significantly inhibited LPA-induced invasion and motility of human ovarian cancer cells in a dose-dependent manner. Furthermore, fasudil caused the loss of intracellular cytoskeletal rearrangement, which is necessary for cell motility, such as stress fiber formation and focal adhesion assembly. Fasudil suppressed LPA-induced tyrosine phosphorylation of paxillin, a representative focal adhesion protein, and serine phosphorylation of myosin light chain, which are essential for the process for cell migration. These findings showed that fasudil attenuated the invasiveness of human ovarian cancer cells via inhibition of the LPA/Rho/ROCK pathway. In SKOV-3ip1 ovarian cancer xenografts, intraperitoneal treatment with fasudil significantly reduced tumor burden and ascites formation. Our findings suggest that fasudil might be useful to prevent the progression of ovarian cancer in clinical settings.
International Journal of Gynecological Cancer 12/2009; 19(9):1473-80. · 1.65 Impact Factor
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Seiji Mabuchi,
Chiaki Kawase,
Deborah A Altomare,
Kenichirou Morishige, Kenjiro Sawada,
Masami Hayashi,
Masahiko Tsujimoto,
Mareo Yamoto,
Andres J Klein-Szanto,
Russell J Schilder,
Masahide Ohmichi,
Joseph R Testa,
Tadashi Kimura
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ABSTRACT: Mammalian target of rapamycin (mTOR) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear cell carcinoma of the ovary, which is regarded as an aggressive, chemoresistant histologic subtype.
Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus) was examined using two pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo.
Immunohistochemical analysis showed that mTOR was more frequently activated in clear cell carcinomas than in serous adenocarcinomas (86.6% versus 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo. Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared with the respective parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than did parental RMG1 and KOC7C cells, respectively, in vitro and in vivo.
mTOR is frequently activated in clear cell carcinoma and can be a promising therapeutic target in the management of clear cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in patients previously treated with cisplatin.
Clinical Cancer Research 09/2009; 15(17):5404-13. · 7.74 Impact Factor
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Emi Arimoto-Ishida,
Masahiro Sakata, Kenjiro Sawada,
Masahiro Nakayama,
Fumihito Nishimoto,
Seiji Mabuchi,
Takashi Takeda,
Toshiya Yamamoto,
Aki Isobe,
Yoko Okamoto,
Ernst Lengyel,
Noriyuki Suehara,
Ken-Ichirou Morishige,
Tadashi Kimura
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ABSTRACT: During early pregnancy, cytotrophoblast cells differentiate into extravillous trophoblast (EVT) cells and invade the uterine spiral arteries. This physiological process is essential for the development of maternal-fetal circulation. Because EVT cells are exposed to a low-oxygen environment during this process, we investigated the role of hypoxia in the mechanism that regulates the invasive behavior of EVT cells. Real-time PCR and immunofluorescent analysis were performed to investigate how hypoxia influences the expression of E-cadherin in villous explants cultures and in trophoblast-derived BeWo cells. We determined that hypoxia induced E-cadherin down-regulation through Snail up-regulation in villous explant cultures. The influence of E-cadherin loss was examined by analyzing the expression of alpha(5)-integrin and phosphorylated focal adhesion kinase (FAK) by Western blot and evaluating trophoblast invasion using a matrigel invasion assay. E-cadherin loss induced the up-regulation of alpha(5)-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An alpha(5)-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that alpha(5)-integrin was up-regulated and FAK tyrosine phosphorylated (Try(861)) as EVT cells invade the uterine myometrium, whereas E-cadherin expression was down-regulated. These results suggest that alpha(5)-integrin up-regulation induced by E-cadherin loss under hypoxia has a crucial role in regulating the migration of EVT cells. This finding should help us reach a better understanding of the pathogenesis of critical gestational diseases, such as preeclampsia.
Endocrinology 07/2009; 150(9):4306-15. · 4.46 Impact Factor
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ABSTRACT: A twin pregnancy consisting of complete hydatidiform mole with coexisting fetus is an extremely rare condition. Recent advances in obstetric ultrasonography and cytogenetic analysis have made the prenatal diagnosis of this rare pregnancy possible. Recent literature advocating DNA polymorphism analysis being required for the accurate diagnosis of complete hydatidiform mole with coexisting fetus is discussed. We present a case of complete hydatidiform mole with coexisting fetus terminated at 16 weeks' gestation. After successful termination of the pregnancy with intravaginal gemeprost, androgenesis of the molar placenta was proven by karyotyping analysis only, without DNA polymorphism analysis, because the short arm of chromosome 21 of the paternal allele had the normal variant satellite. To our knowledge, this is the first case report of complete hydatidiform mole with coexisting fetus diagnosed by variation of the acrocentric short arms, followed by termination with intravaginal gemeprost. We describe the clinical course of our case and review some literature concerning complete hydatidiform mole with coexisting fetus.
American Journal of Perinatology 07/2009; 27(2):143-9. · 1.32 Impact Factor
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ABSTRACT: A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and may suggest underlying skeletal fragility. Therefore, establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for patients who suffer from osteoporosis. The objective of this study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to monitor the response to alendronate therapy at the distal radius in early postmenopausal Japanese women. Thirty-two early postmenopausal women who were diagnosed with osteoporosis or osteopenia were randomized to either alendronate or control treatment. We analyzed the BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turnover (deoxypyridinoline) at baseline, 3, 6 and 12 months. The control group showed a significant decrease from baseline in the trabecular BMD of the radius at 12 months (3.5 +/- 3.7%; p < 0.01), whereas the alendronate group showed a significant increase (4.3 +/- 8.1%). The changes in the trabecular BMD of the radius between the alendronate and control groups were statistically different at 6 and 12 months (p < 0.01). However, in the total BMD at the diaphysis of the radius, no significant differences were seen in the changes in bone densities between the alendronate and control groups after 1 year of treatment. pQCT detected significant differences in BMD of the radius in early postmenopausal women after 1 year of treatment with alendronate. Collectively, our preliminary clinical trial showed that pQCT might be useful to monitor response to alendronate therapy, especially at the radius, and it might explain why alendronate prevents Colles' fracture.
Journal of Bone and Mineral Metabolism 01/2009; 27(2):175-81. · 2.27 Impact Factor
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Fumihito Nishimoto,
Masahiro Sakata,
Ryoko Minekawa,
Yoko Okamoto,
Asako Miyake,
Aki Isobe,
Toshiya Yamamoto,
Takashi Takeda,
Emi Ishida, Kenjiro Sawada,
Ken-Ichiro Morishige,
Tadashi Kimura
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ABSTRACT: Placenta growth factor (PlGF) is a placental angiogenic factor. Metal-responsive transcription factor (MTF)-1 was reported to take part in the hypoxic induction of PlGF in RAS-transformed mouse fibroblasts. We contrarily showed that PlGF mRNA and protein levels decreased under hypoxia in a choriocarcinoma BeWo cell line derived from trophoblast. In this report, we examined whether hypoxia-dependent regulation of the PlGF gene in these cells also depends on MTF-1. We analyzed the effect of hypoxia on MTF-1 expression, and it was revealed to be decreased. Moreover, MTF-1 small interfering RNA treatment decreased PlGF mRNA level. To investigate the transcription of PlGF under hypoxia, we cloned promoter region of the human PlGF. Promoter deletion analysis suggested that triple repeats of metal-responsive element located between -511 and -468 bp in the promoter are important for the hypoxic regulation of PlGF. Treatment with MTF-1 small interfering RNA resulted in the significant decreased luciferase activity in PlGF reporter constructs. Chromatin immunoprecipitation showed the binding of the MTF-1 protein to the promoter region. We examined MTF-1 immunoreactivity in trophoblasts of term placental tissue from patients with normal pregnancies and preeclampsia, which represents a condition of placental hypoxia. Immunoreactivity of the MTF-1 protein was decreased in placentas from pregnant women with preeclampsia when compared with those from normal pregnant women. Taken together, these findings suggest that MTF-1 is involved in hypoxia-dependent regulation of PlGF in trophoblast-derived cells.
Endocrinology 12/2008; 150(4):1801-8. · 4.46 Impact Factor
