Differential glucocorticoid effects on proliferation and invasion of human trophoblast cell lines

Several clinical situations require continuous glucocorticoid (GC) treatment during pregnancy. A well-known deleterious side effect of such treatment is the higher incidence of growth-restricted fetuses, for which a too shallow trophoblast invasion is presently hypothesised as the underlying cause. This study investigated whether the synthetic GC triamcinolone acetonide (TA) influences proliferation, invasion and endocrine activity of human trophoblast. BeWo and JEG-3 choriocarcinoma cell lines both express GC receptors (western blotting) and were used as models for human trophoblast. JAR devoid cells of GC receptor were used as negative control. The cells were cultured for 48 h without (control) or with 0.5, 5 and 50 μM TA. In the presence and absence of serum, proliferation was determined by cell counting and measuring the cell cycle regulating protein cyclin B1 (Western blotting); invasion was determined by a conventional Matrigel invasion assay and by measuring the secretion (ELISA) of matrix-metalloproteinases (MMP-2, MMP-9) into the culture medium; endocrine activity was assessed by measuring the levels of human chorionic gonadotropin (ELISA) into the culture medium. TA altered the number of viable and dead cells as well as cyclin B1 levels and, to a lesser extent, invasion of BeWo and JEG-3, with a strong influence of serum. BeWo and JEG-3 cells reacted differently and in most instances reverse. In the cell lines used as models of human trophoblast, TA alter some functions relevant to proliferation and invasion, and suggest that caution should be exercised when treating women with GCs during pregnancy.

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ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia

AJP Cell Physiology ◽

10.1152/ajpcell.00404.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. C481-C491 ◽

Cited By ~ 4

Author(s):

Yalan Xu ◽

Lili Sui ◽

Bintao Qiu ◽

Xiuju Yin ◽

Juntao Liu ◽

...

Keyword(s):

Cell Proliferation ◽

Western Blotting ◽

Underlying Mechanism ◽

Trophoblast Invasion ◽

Pathological Examination ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Annexin A4 ◽

Extravillous Cytotrophoblasts ◽

Phosphoinositide 3 Kinase

The inadequate trophoblast invasion is associated with the development of preeclampsia (PE). Considering that annexin A4 (ANXA4) enhances tumor invasion, we aimed to explore the functional role of ANXA4 in trophoblast cells and to examine the underlying mechanism. ANXA4 expression in PE placentas was analyzed using immunohistochemistry and Western blotting. Cell proliferation, invasion, and apoptosis were determined using a MTT assay, Transwell assay, and flow cytometry, respectively. The expression levels of matrix metalloproteinase (MMP)-2, MMP-9, phosphoinositide 3-kinase (PI3K), Akt, phosphorylated (p)-Akt, and phosphorylated endothelial nitric oxide synthase (p-eNOS) were detected by Western blotting. Placentas were prepared for pathological examination using hematoxylin and eosin staining and apoptosis determination using the TUNEL method. Expression of ANXA4, PI3K, p-Akt and p-eNOS was downregulated in human PE placentas and PE placenta-derived extravillous cytotrophoblasts (EVCTs). Furthermore, ANXA4 overexpression promoted cell proliferation and invasion, inhibited cell apoptosis, and upregulated protein expression of PI3K, p-Akt, and p-eNOS in human trophoblast cells HTR-8/SVneo and JEG-3. By contrast, ANXA4 knockdown exerted the opposite effects. Furthermore, inhibition of the PI3K/Akt pathway by LY294002 abrogated the ANXA4 overexpression-mediated effects on trophoblast behavior. Furthermore, eNOS knockdown abrogated the ANXA4 overexpression-induced promotion of cell invasion and MMP2/9 expression. Additionally, in N-nitro-l-arginine methyl ester (l-NAME)-induced PE rats, ANXA4 overexpression alleviated PE progression, accompanied by an increase in expression of PI3K, p-Akt, and p-eNOS in rat placentas. Our findings demonstrate that ANXA4 expression is downregulated in PE. ANXA4 may promote trophoblast invasion via the PI3K/Akt/eNOS pathway.

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Silencing of the TROP2 gene suppresses proliferation and invasion of hepatocellular carcinoma HepG2 cells

Journal of International Medical Research ◽

10.1177/0300060518822913 ◽

2019 ◽

Vol 47 (3) ◽

pp. 1319-1329 ◽

Cited By ~ 3

Author(s):

Jian Zhang ◽

Hai Ma ◽

Liu Yang ◽

Hongchun Yang ◽

Zhenxing He

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Protein Expression ◽

Cell Lines ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Human Trophoblast ◽

Mesenchymal Transition ◽

Expression Levels ◽

Proliferation And Invasion

Objectives Overexpression of human trophoblast cell surface antigen 2 (Trop2) has been observed in many cancers; however, its roles in proliferation, apoptosis, migration, and invasion of hepatocellular carcinoma (HCC) remain unclear. Thus, this study aimed to characterize the function of Trop2 in HCC. Methods Trop2 protein expression was detected by immunohistochemistry in HCC tissues. Cell proliferation, apoptosis, and invasion were respectively measured by CCK-8, flow cytometry, Transwell, and wound healing assays. Expression levels of epithelial–mesenchymal transition-related proteins and Trop2 protein in HCC cell lines were detected by western blotting after silencing of the TROP2 gene. Results Trop2 protein was highly expressed in HCC tissues and HCC cell lines. Trop2 mRNA and protein expression levels decreased in HepG2 and HCCLM3 cells after transfection with Trop2 siRNA. Silencing of the TROP2 gene in HepG2 and HCCLM3 cells strongly inhibited cell proliferation and migration, while enhancing cell apoptosis. Investigation of the molecular mechanism revealed that silencing of the TROP2 gene suppressed epithelial–mesenchymal transition of HepG2 and HCCLM3 cells. Conclusions The results of the present study may improve understanding of the role of Trop2 in regulation of cell proliferation and invasion, and may aid in development of novel therapy for HCC.

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Inhibition of PLOD3 Suppresses Proliferation, Invasion and Migration of Breast Cancer Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2171 ◽

2019 ◽

Vol 9 (11) ◽

pp. 1528-1534

Author(s):

Shiqiong Su ◽

Qing Ni ◽

Jing Hou

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Western Blotting ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Cell Counting ◽

Matrix Metalloproteinase 2 ◽

Invasion And Migration ◽

And Migration ◽

Interfering Rna

Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) has been reported to be involved in various human cancers. However, the function of PLOD3 in breast cancer (BC) has not been addressed. This research attempted to probe the effects and molecular mechanisms of PLOD3 in BC. The expression of PLOD3 was examined by Western blotting and RT-qPCR in several BC cell lines and nontumorigenic breast MCF-10A cells. Then, PLOD3 was silenced by transfecting with small interfering RNA (siRNA). Cell proliferation was measured by Cell Counting Kit-8 assay and cell cycle was evaluated by flow cytometry assay after transfection. Subsequently, wound healing assay and Transwell assay were exploited for detecting the abilities of cell invasion and migration, respectively. In addition, the expression of proliferation- and migration-related genes were examined by Western blotting. The results revealed that the expression of PLOD3 was upregulated in BC cell lines compared with MCF-10A cells. PLOD3 silencing suppressed the proliferative ability of BC cells, enhanced the ratio of cells in the G1 and G2 phases and reduced those in the S phase. Moreover, the expression of Ki67 and cyclinD1 were significantly downregulated, accompanied by an upregulation in p27 expression after transfection with PLOD3 siRNA. Furthermore, inhibition of PLOD3 restrained invasion and migration of BC cells coupled with a reduced expression of matrix metalloproteinase 2 (MMP2) and MMP9. The explorations unveiled that PLOD3 silencing restrained proliferation, invasion and migration of BC cells, which provides theoretical basis and treatment strategies for the treatment of BC.

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Investigation of human trophoblast invasion in vitro

Human Reproduction Update ◽

10.1093/humupd/dmaa017 ◽

2020 ◽

Vol 26 (4) ◽

pp. 501-513 ◽

Cited By ~ 4

Author(s):

Yassen Abbas ◽

Margherita Y Turco ◽

Graham J Burton ◽

Ashley Moffett

Keyword(s):

Cell Lines ◽

First Trimester ◽

Trophoblast Cell ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Human Trophoblast ◽

Uterine Environment ◽

Microfluidic Assays ◽

Invasion Assays

Abstract BACKGROUND In humans, inadequate trophoblast invasion into the decidua is associated with the ‘great obstetrical syndromes’ which include pre-eclampsia, foetal growth restriction (FGR) and stillbirth. The mechanisms regulating invasion remain poorly understood, although interactions with the uterine environment are clearly of central importance. Extravillous trophoblast (EVT) cells invade the uterus and transform the spiral arteries. Progress in understanding how they invade has been limited due to the lack of good in vitro models. Firstly, there are no non-malignant cell lines that have an EVT phenotype. Secondly, the invasion assays used are of limited use for the small numbers of primary EVT available from first-trimester placentas. We discuss recent progress in this field with the generation of new EVT lines and invasion assays using microfluidic technology. OBJECTIVE AND RATIONALE Our aim is to describe the established models used to study human trophoblast invasion in vivo and in vitro. The difficulties of obtaining primary cells and cell lines that recapitulate the phenotype of EVT are discussed together with the advantages and pitfalls of the different invasion assays. We compare these traditional end point assays to microfluidic assays where the dynamics of migration can be measured. SEARCH METHODS Relevant studies were identified by PubMed search, last updated on February 2020. A search was conducted to determine the number of journal articles published using the cell lines JEG-3, BeWo, JAR, HTR-8/Svneo, Swan-71 and primary human extravillous trophoblast in the last 5 years. OUTCOMES Deep trophoblast invasion into the maternal decidua is a particular feature of human pregnancy. This invasion needs to be finely regulated to allocate resources between mother and baby. A reliable source of EVT is needed to study in vitro how the uterine environment regulates this process. First, we critically discuss the issues with the trophoblast cell lines currently used; for example, most of them lack expression of the defining marker of EVT, HLA-G. Recently, advances in human stem cell and organoid technology have been applied to extraembryonic tissues to develop trophoblast cell lines that can grow in two (2D) and three dimensions (3D) and differentiate to EVT. This means that the ‘trophoblast’ cell lines currently in use should rapidly become obsolete. Second, we critically discuss the problems with assays to study trophoblast invasion. These lack physiological relevance and have simplified migration dynamics. Microfluidic assays are a powerful tool to study cell invasion because they require only a few cells, which are embedded in 3D in an extracellular matrix. Their major advantage is real-time monitoring of cell movement, enabling detailed analysis of the dynamics of trophoblast migration. WIDER IMPLICATIONS Trophoblast invasion in the first trimester of pregnancy remains poorly understood despite the importance of this process in the pathogenesis of pre-eclampsia, FGR, stillbirth and recurrent miscarriage. The new technologies described here will allow investigation into this critical process.

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miR-148a-3p inhibits DNMT1-mediated methylation of VEGF and promotes proliferation and invasion in glioma cells via the PI3K/Akt/eNOS signaling pathway

10.21203/rs.3.rs-18747/v1 ◽

2020 ◽

Author(s):

Jun-feng Huo ◽

Xiao-bing Chen

Keyword(s):

Cell Lines ◽

Methylation Level ◽

Promoter Region ◽

Dna Methyltransferase ◽

Cell Counting ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Protein Levels ◽

U87 Cells ◽

Proliferation And Invasion

Abstract Background: Abnormal DNA methylation in the promoter region of vascular endothelial growth factor (VEGF) has been observed in multiple types of cancer. Increasing evidence shows that miR-148a-3p is involved in the regulation of methylation. However, it is unclear how miR-148a-3p regulates VEGF methylation.Methods: Methylation-specific polymerase chain reaction (MSP) and bisulfate-sequencing PCR (BSP) were performed to detect the methylation level of the VEGF promoter region in glioma tissues and cell lines. Then, we used RT-qPCR to detect the expression of miR-148a-3p and VEGF in glioma tissues and cell lines. Human glioma U87 cells were transfected with miR-148a-3p mimic or a pcDNA3.1 overexpression vector of VEGF, and then, the proliferation, invasion and apoptosis of U87 cells were examined with cell counting kit-8 (CCK-8), Transwell assay and Flow cytometry, respectively. We next examined the relationship between DNA methyltransferase 1 (DNMT1) and miR-148a-3p with online prediction and luciferase reporter gene experiments. Furthermore, we also used Western blotting to detect the protein levels of VEGF, DNMT1, PI3K, Akt and eNOS.Results: Both miR-148a-3p and VEGF were significantly up-regulated, and the promoter methylation of VEGF was hypomethylation in glioma. Overexpression miR-148a-3p or VEGF promoted the proliferation and invasion of U87 cells and inhibited the apoptosis. Silencing VEGF inhibited U87 cells proliferation and invasion and induced the apoptosis. Furthermore, miR-148a-3p regulated DNMT1 at the post-transcriptional. Overexpression of DNMT1 mediated an increase in the methylation level of VEGF, which reduced the expression of VEGF in U87 cells. The opposite was exact when DNMT1 was silenced. We also observed that silencing VEGF inhibited the activation of the PI3K/Akt/eNOS pathway and induced U87 cell apoptosis.Conclusion: These results indicated that miR-148a-3p down-regulates VEGF methylation by targeting DNMT1 and promotes the proliferation, invasion of the glioma cell through the PI3K/Akt/eNOS pathway.

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Knockdown of nrf2 Exacerbates TNF-α-Induced Proliferation and Invasion of Rheumatoid Arthritis Fibroblast-Like Synoviocytes through Activating JNK Pathway

Journal of Immunology Research ◽

10.1155/2020/6670464 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Yu Du ◽

Qian Wang ◽

Na Tian ◽

Meng Lu ◽

Xian-Long Zhang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Western Blotting ◽

Nuclear Translocation ◽

Cell Counting ◽

Related Factor ◽

Jnk Pathway ◽

Tnf Α ◽

Synovial Tissues ◽

Proliferation And Invasion ◽

Fibroblast Like Synoviocytes

Fibroblast-like synoviocytes (FLS) in the synovial tissue of rheumatoid arthritis (RA) exhibit over-proliferative and aggressive phenotypes, which participate in the pathophysiology of RA. In RA, little is known about the nonantioxidant effect of nuclear factor erythroid 2-related factor 2 (nrf2), the master regulator of redox homeostasis. In this study, we aimed to explore the expression and upstream regulatory factors of nrf2 and revealed its functions in modulating the proliferation and invasion in RA-FLS. FLS were isolated from RA and osteoarthritis patients. Expression of nrf2 in the synovial tissues and FLS was analyzed by immunohistochemistry, real-time PCR, Western blotting, and immunofluorescence staining. Cell proliferation was examined by Cell Counting Kit-8. Cell invasion was tested by transwell assay. Phosphorylation of JNK was determined by Western blotting. The results showed that nrf2 expression in the RA synovial tissues was upregulated. TNF-α promoted expression and nuclear translocation of nrf2 in RA-FLS and increased the intracellular reactive oxygen species (ROS) level. Nrf2 nuclear translocation was blocked by ROS inhibitor N-acetylcysteine. Both knockdown of nrf2 by siRNA and inhibition of nrf2 by ML385 significantly promoted the TNF-α-induced proliferation and invasion of RA-FLS. Activation of nrf2 by sulforaphane (SFN) profoundly inhibited the TNF-α-induced proliferation and invasion of RA-FLS. Knockdown of nrf2 also enhanced the TNF-α-induced matrix metalloproteinases (MMPs) expression and phosphorylation of JNK in RA-FLS. Proliferation and invasion of RA-FLS incubated with TNF-α and nrf2 siRNA were inhibited by pretreatment with JNK inhibitor SP600125. In conclusion, nrf2 is overexpressed in synovial tissues of RA patients, which may be promoted by TNF-α and ROS levels. Activation of nrf2 may suppress TNF-α-induced proliferation, invasion, and MMPs expression in RA-FLS by inhibiting JNK activation, indicating that nrf2 plays a protective role in relieving the severity of synovitis in RA. Our results might provide novel insights into the treatment of RA.

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ALKBH2 inhibition alleviates malignancy in colorectal cancer by regulating BMI1-mediated activation of NF-κB pathway

World Journal of Surgical Oncology ◽

10.1186/s12957-020-02106-0 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Bingxin Ke ◽

Kejun Ye ◽

Shaobing Cheng

Keyword(s):

Cell Proliferation ◽

Western Blotting ◽

Integration Site ◽

Cell Counting ◽

Nuclear Accumulation ◽

Luciferase Reporter ◽

Lovo Cell ◽

Mesenchymal Transition ◽

Proliferation And Invasion

Abstract Background The alkB homolog 2, alpha-ketoglutarate-dependent dioxygenase (ALKBH2) gene is involved in DNA repair and is expressed in different types of malignancies. However, the role of ALKBH2 in colorectal carcinoma (CRC) remains unclear. This study aimed to explore the potential mechanism of ALKBH2 and its function in CRC. Methods The expression levels of ALKBH2 in CRC tissues and cells were determined by qRT-PCR. Following that, the role of ALKBH2 in cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in CRC cells (Caco-2 and LOVO) were assessed by Cell Counting Kit-8 (CCK-8), transwell assays, and Western blotting, respectively. The effect of ALKBH2 on B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and downstream NF-κB pathway was determined by Western blotting and luciferase reporter assay. Results The expression of ALKBH2 was significantly upregulated both in CRC tissues and cells. Further experiments demonstrated that reduction of ALKBH2 suppressed Caco-2 and LOVO cell proliferation and invasion. Moreover, ALKBH2 knockdown also suppressed EMT, which increased E-cadherin expression and reduced N-cadherin expression. Besides, ALKBH2 silencing inhibited BMI1 expression and reduced nuclear accumulation of the NF-κB p65 protein, as well as the luciferase activity of NF-κB p65. Upregulation of BMI1 reversed the effect of ALKBH2 knockdown on the proliferation and invasion in CRC cells. Conclusions Our findings suggest that suppression of ALKBH2 alleviates malignancy in CRC by regulating BMI1-mediated activation of NF-κB pathway. ALKBH2 may serve as a potential treatment target for human CRC.

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Exosome-Carried microRNA-375 Inhibits Cell Progression and Dissemination via Bcl-2 Blocking in Colon Cancer

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.244.375 ◽

2015 ◽

Vol 24 (4) ◽

pp. 435-443 ◽

Cited By ~ 44

Author(s):

Florin Zaharie ◽

Mihai-Stefan Muresan ◽

Bobe Petrushev ◽

Cristian Berce ◽

Grigore-Aristide Gafencu ◽

...

Keyword(s):

Colorectal Cancer ◽

Electron Microscopy ◽

Growth Factor ◽

Western Blotting ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Mitogen Activated Protein Kinase ◽

Cell Counting ◽

Rt Pcr ◽

Matrigel Invasion

Background: Worldwide, colorectal cancer (CRC) is the third most common cancer in men and second in women. The aim of the current study was to identify whether the miR-375 is indeed down-regulated in metastatic CRC and if it could be considered as a potential minimally invasive prognostic biomarker for CRC. Methods. Exosomes were isolated and characterized from patients with liver metastasis from CCR. The characterization of exosome was performed using TEM/SEM. HCT116 cells were treated with miR-375 mimic, NSM and miR-375 inhibitor. Functional assays included cell counting assay for 14 days, Matrigel invasion assay, apoptosis assay by flow cytometry using Annexin V-FITC, RT-PCR and Western blotting. Results. Increased proliferation potential was proven for the cells transfected with miR-375 inhibitor, while the miR-375 mimic decreased the cell number. The cells transfected with the miR-375 inhibitor are aggressive and cross the membrane; 3.84% of the cells transfected with the miR-375 inhibitor entered apoptosis, while 6.45% of those transfected with the non-specific mimic were in programmed cell death, less than those transfected with the microRNA. RT-PCR for Bcl-2 expression showed that Bcl-2 is down-regulated for miR-375 inhibitor and up-regulated for the miR-375 mimic, a result confirmed by Western blotting. Conclusion: The present study brings to the forefront new data that suggest miR-375 as a new player in controlling the pathways responsible for inhibiting the natural history of CRC tumor cells, via the Bcl-2 pathway. Abbreviations: APC: adenomatous polyposis coli; CRC: colorectal cancer; EGFR: epidermal growth factor receptor; ERB: Erythroblastic Leukemia Viral Oncogene Homolog; FITC: Fluorescein isothiocyanate; MAPK: mitogen-activated protein-kinase; miR: microRNA; mTOR: mammalian target of rapamycin; NSM: non specific mimic; qRT-PCR: quantitative real time polymerase chain reaction; SEM: scanning electron microscopy; TEM: transmission electron microscopy; TGF-beta: transforming growth factor beta.

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223. Interleukin-11 inhibits human trophoblast invasion via STAT-3 and not MAPK, indicating a likely role in the decidual restraint of trophoblast invasion during placentation

Reproduction Fertility and Development ◽

10.1071/srb08abs223 ◽

2008 ◽

Vol 20 (9) ◽

pp. 23

Author(s):

P. Paiva ◽

L. A. Salamonsen ◽

U. Manuelpillai ◽

E. Dimitriadis

Keyword(s):

Western Blot ◽

Plasminogen Activator ◽

Mitogen Activated Protein Kinase ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Integrin Expression ◽

Human Trophoblast ◽

Matrigel Invasion ◽

Pai 1

Successful pregnancy depends on the precise regulation of extravillous trophoblast (EVT) invasion into the uterine decidua, primarily by decidua-derived factors. In humans, during early pregnancy, interleukin (IL)-11 is maximally expressed in the decidua1, with its receptor, IL-11-receptor α (Rα) also identified on invasive EVT in vivo2. While a role for IL-11 in EVT migration has been established2, whether it also plays a role in regulating EVT invasion is unknown. We investigated whether IL-11 influences human EVT invasion and the signalling pathways and underlying mechanisms involved using the HTR-8/SVneo immortalised EVT cell-line and primary EVT as models for EVT. The effect of IL-11 on tyrosine phosphorylation (p) of signal transducer and activator of transcription (STAT)-3 was determined by Western Blot. EVT invasion was assessed using in vitro Matrigel invasion assays. To elucidate the mechanisms by which IL-11 may influence EVT invasion, matrix metalloproteinase (MMP) and urokinase plasminogen activator (uPA) activity were assessed by gelatin and plasminogen zymography / uPA activity assay respectively. Tissue inhibitor of MMPs (TIMPs)-1 and –2, plasminogen activator inhibitor (PAI)-1 and –2 and uPA receptor (uPAR) were assessed by ELISA whereas TIMP-3 was assessed by Western Blot. EVT adhesive properties and integrin expression were assessed by in vitro adhesion assays. IL-11 (100 ng/mL) significantly inhibited invasion of EVT cells by 40–60% (P < 0.001). This effect was abolished by inhibitors of STAT-3 but not of mitogen-activated protein kinase pathways. IL-11 (100 ng/mL) had no effect on MMP-2 and –9, TIMP 1–3, uPA, uPAR, PAI-1 and –2 in EVT conditioned media and / or cell lysates. IL-11 (100 ng/mL) also did not regulate EVT cell adhesion or integrin expression. These data demonstrate that IL-11 inhibits human EVT invasion via STAT-3 indicating an important role for IL-11 in the decidual restraint of EVT invasion during normal pregnancy. (1) Dimitriadis et al. (2003) Reprod Biol Endocrinol. 1, 34–38 (2) Paiva et al. (2007) Endocrinol. 148, 5566–72

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