Christian Klausen

University of British Columbia

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Peter C. K. Leung

University of British Columbia

Jung‐Chien Cheng

First Affiliated Hospital of Zhengzhou University

Hsun‐Ming Chang

China Medical University Hospital

Hua Zhu

Affiliated Hospital of Nantong University

Bo Peng

Shenzhen KangNing Hospital

Hamid R. Habibi

University of Calgary

Yan Li

Shandong University

John P. Chang

University of Alberta

Yuyin Yi

British Columbia Children's Hospital

Mohamed A. Bedaiwy

University of British Columbia

Cooperative Institutions

University of British Columbia

Zhejiang University

Shanghai Jiao Tong University

British Columbia Children's Hospital

Women's Hospital, School of Medicine, Zhejiang University

International Peace Maternity & Child Health Hospital

Ministry of Education of the People's Republic of China

Fudan University

Chinese Academy of Medical Sciences & Peking Union Medical College

Child and Family Research Institute

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miR-106a Increases Granulosa Cell Viability and Is Downregulated in Women With Diminished Ovarian Reserve

The Journal of Clinical Endocrinology & Metabolism (2018)

Liming Hong Sha Peng Ying Li Ying Fang Qin Wang

Abstract Context Women with diminished ovarian reserve (DOR) have reduced fertility, cardiovascular events, and osteoporosis. Although differential microRNA (miRNA) expression has been described in several ovarian disorders, little is known about the role of miRNAs in the pathogenesis of DOR. Objective Identify differentially expressed miRNAs in DOR and explore the role of miR-106a in human granulosa cell proliferation. Design miRNA microarray (n = 3) and quantitative reverse transcription polymerase chain reaction (n = 30) were used to examine miRNA expression in serum and granulosa cells from normal-cycling and women with DOR. Primary human granulosa cells were treated alone or in combination with miR-106a mimic, miR-106a inhibitor, apoptosis signal-regulating kinase 1 (ASK1) small interfering RNA (siRNA), or p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) before assessment of cell viability and apoptosis. Western blot was used to measure ASK1 protein and phosphorylation/activation of p38 MAPK. Binding of miR-106a to ASK1 mRNA was examined by 3′ untranslated region (3′UTR) luciferase analysis. Results Fifteen miRNAs were differentially expressed (n = 30), and miR-106a was downregulated in serum and granulosa cells of women with DOR. miR-106a mimic increased cell viability and attenuated apoptosis, whereas the converse occurred following treatment with miR-106a inhibitor. miR-106a suppressed ASK1 expression by directly targeting its 3′UTR. miR-106a inhibitor increased p38 MAPK phosphorylation/activation, and this effect was abolished by treatment with ASK1 siRNA. Whereas knockdown of ASK1 abolished the effects of miR-106a inhibitor on cell viability/apoptosis, pretreatment with SB203580 did not significantly alter the effects of miR-106a inhibitor. Conclusions Downregulation of miR-106a may contribute to the pathogenesis of DOR by reducing granulosa cell viability and promoting apoptosis via enhanced ASK1 signaling.

Viability assay

ASK1

10.1210/jc.2017-02344

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Citations (34)

Recombinant BMP4 and BMP7 Increase Activin A Production by Up-Regulating Inhibin βA Subunit and Furin Expression in Human Granulosa-Lutein Cells

The Journal of Clinical Endocrinology & Metabolism (2015)

Hsun‐Ming Chang Jung‐Chien Cheng Christian Klausen Peter C. K. Leung

Granulosa cell-derived activins play important roles in the regulation of ovarian functions. To date, there is limited information pertaining to the intracellular regulation, assembly, and secretion of endogenous activin A in human granulosa cells.The aim of this study was to examine the effects of BMP4 and BMP7 on furin expression and activin A production as well as the underlying mechanisms of action in human granulosa cells.An established immortalized human granulosa cell line (SVOG) and primary granulosa-lutein cells were used as study models. Expression of inhibin subunits and furin as well as activin A accumulation were examined after exposure to recombinant human BMP4 or BMP7. A BMP type I receptor inhibitor (dorsomorphin), a furin inhibitor (Decanoyl-Arg-Val-Lys-Arg-chloromethylketone), and small interfering RNAs targeting SMAD4 and furin were used to verify the specificity of the effects and investigate potential mechanisms.The study was conducted in an academic center.Specific mRNA and protein levels were examined using real time qPCR and Western blot. Activin A levels were measured using enzyme immunoassay.Treatment with bone morphogenetic protein (BMP) 4 and BMP7 significantly increased furin mRNA and protein, inhibin βA mRNA, and activin A accumulation. Pre-treatment with dorsomorphin or SMAD4 knockdown reversed the stimulatory effects of BMP4 and BMP7 on furin and inhibin βA expression. In addition, furin knockdown or pre-treatment with a furin inhibitor attenuated the BMP4- and BMP7-induced accumulation of activin A.Recombinant BMP4 and BMP7 increase the production of bioactive mature activin A by up-regulating both the production and proteolytic processing of inhibin βA subunit in human granulosa cells. The enhancement of inhibin βA subunit processing is attributable to a SMAD-dependent up-regulation of its proprotein convertase, furin. These findings provide a potential mechanism by which theca cells can regulate neighboring granulosa cells in the ovary.

Furin

ACVR2B

10.1210/jc.2014-3026

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E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

Oncogene (2011)

M-T Lau Christian Klausen Peter C. K. Leung

Tensin

Beta-catenin

10.1038/onc.2011.6

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The Kisspeptin and GPR54 ligand-receptor pair are associated with favorable prognosis and clear cell subtype in human ovarian carcinoma

Clinical Cancer Research (2007)

Leah Prentice Christian Klausen Steve E. Kalloger Martin Köbel Steven McKinney

B73 GPR54 is a G-protein coupled receptor that stimulates release of GnRH upon binding with its secreted ligands, the Kisspeptins. The Kisspeptins have also been credited with inducing an anti-metastatic phenotype in tumor cells in vitro. This study characterizes expression of Kisspeptin and GPR54 in clinical ovarian tumor samples using the immunohistochemical method on a tissue microarray (TMA). The TMA consisted of 518 early stage ovarian carcinomas, all with linked clinical outcome data and was scored using a staining intensity scale of 0 (negative), +1 (mild-moderate), and +2 (strong). For statistical analysis, strong staining cases were considered either Kisspeptin or GPR54 positive and designated as 1, while all other cases were considered negative and designated 0. Kisspeptin positive and GPR54 positive cases show a favorable prognosis in univariable disease specific survival (p=0.0023, p=0.0092), as well as in overall survival (p=0.0006, p=0.0002). Further, Kissspeptin is an independent marker for favorable prognosis is disease specific and overall survival (p=0.0046, p=0.0170), while GPR54 is independent in overall survival only (p=0.0303). Both Kisspeptin and GPR54 positive cases are strongly associated with the ovarian carcinoma clear cell subtype (p

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Tissue microarray

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Growth differentiation factor 8 down-regulates pentraxin 3 in human granulosa cells

Molecular and Cellular Endocrinology (2015)

Hsun‐Ming Chang Lanlan Fang Jung‐Chien Cheng Christian Klausen Yingpu Sun

Granulosa cell

PTX3

ACVR2B

10.1016/j.mce.2015.01.036

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Citations (41)

Gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor are expressed at tubal ectopic pregnancy implantation sites

Fertility and Sterility (2016)

Bo Peng Christian Klausen Lisa Campbell Peter C. K. Leung Andrew W. Horne

GNRHR

Syncytiotrophoblasts

Cytotrophoblast

Human chorionic gonadotropin

Trophoblast

Gonadotropin

Fallopian tube

10.1016/j.fertnstert.2016.02.003

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Interleukin-1β and plasminogen activating system members in endometriotic stromal cell migration/invasion

F&S Science (2022)

Fahad T. Alotaibi Sadaf Sediqi Christian Klausen Mohamed A. Bedaiwy Paul J. Yong

To study the role of interleukin (IL)-1β and the plasminogen activating (PA) system members in endometriotic stromal cell (ESC) migration/invasion.Primary cultures of ESCs.Tertiary referral center for endometriosis and pelvic pain.Patients with surgically excised endometriosis.Interleukin-1β stimulation of primary cultures of ESCs and knockdown of the PA system members urokinase plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-1 (PAI-1).Invasion/migration assays.In primary cultures, IL-1β-stimulated ESC production of the PA system members uPA, uPA receptor, and PAI-1. Interleukin-1β also enhanced ESC migration and invasion, and these effects were inhibited by the IL-1 receptor-1 antagonist anakinra. Knockdown of each of the 3 PA system members also inhibited ESC migration and invasion. Knockdown of these PA system members further attenuated the impact of IL-1β on migration and invasion, suggesting that they mediated the promigration and proinvasion effects of IL-1β. To supplement the cell culture work, immunohistochemistry was performed on tissue sections of endometriotic epithelium/stroma: uPA, PAI-1, and IL-1β histoscores were not found to be correlated with each other.In primary cultures of ESCs, IL-1β induces migration and invasion, which is mediated by PA system members and inhibited by the drug anakinra. However, the immunohistochemistry expression of IL-1β, urokinase plasminogen inhibitor-1, and PAI-1 were not correlated, suggesting other regulatory mechanisms for PA system members. Inhibition of IL-1β (e.g., with anakinra) may have potential as a novel treatment approach for the migration/invasion of endometriosis.

Plasminogen activator inhibitor-1

10.1016/j.xfss.2022.09.004

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Myostatin increases human trophoblast cell invasion by upregulating N-cadherin via SMAD2/3-SMAD4 signaling

Biology of Reproduction (2022)

F. AbdelHafez Christian Klausen Hua Zhu Peter C. K. Leung

Abstract Placental insufficiency disorders are major obstetric complications that share a common phenomenon of poor placental trophoblast cell invasion and remodeling of uterine tissues. Myostatin is a transforming growth factor (TGF)-β superfamily member well known for its important role in muscle growth control. Myostatin is also produced in the placenta and has been shown to regulate some trophoblast functions. However, its roles in placental development are still poorly understood. In this study, we tested the hypothesis that myostatin increases trophoblast cell invasion by upregulating N-cadherin via SMAD2/3-SMAD4 signaling. Primary and immortalized (HTR8/SVneo) trophoblast cells were used as study models. Matrigel-coated transwell invasion assays were used to study the effects of recombinant human myostatin on trophoblast cell invasion. Reverse transcription quantitative real-time polymerase chain reaction and Western blot were used to measure myostatin effects on N-cadherin mRNA and protein levels, respectively. Small inhibitor molecules as well as siRNA-mediated knockdown were used to block myostatin receptor and downstream signaling, respectively. Data were analyzed either by unpaired Student T test or one-way analysis of variance followed by Newman Keuls test for multiple group comparisons. Myostatin significantly increased primary and HTR8/SVneo trophoblast cell invasion. Moreover, myostatin upregulated N-cadherin mRNA and protein levels in a time-dependent manner in both study models. These effects were blocked by inhibition of TGF-β type I receptors as well as siRNA-mediated knockdown of SMAD2/3 combined or common SMAD4. Importantly, myostatin-induced trophoblast cell invasion was abolished by knockdown of N-cadherin, SMAD2/3, or SMAD4. Myostatin may increase human trophoblast cell invasion by upregulating N-cadherin via SMAD2/3-SMAD4 signaling.

Trophoblast

Myostatin

Smad2 Protein

Placentation

10.1093/biolre/ioab238

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Growth Differentiation Factor 9 Reverses Activin A Suppression of Steroidogenic Acute Regulatory Protein Expression and Progesterone Production in Human Granulosa-Lutein Cells

Endocrine Reviews (2010)

Feng-Tao Shi Anthony P. Cheung Christian Klausen Hefeng Huang Peter C. K. Leung

Conclusion:This intracellular mutation can initiate the full spectrum of MEN2a, initiates MTC at an early age, and causes recurrence and death if undertreated.We recommend stringent adherence to established guidance in MEN2a in this rare mutation.

Steroidogenic factor 1

10.1210/edrv.31.4.9972

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SMAD1/5 mediates bone morphogenetic protein 2-induced up-regulation of BAMBI expression in human granulosa-lutein cells

Cellular Signalling (2017)

Long Bai Hsun‐Ming Chang Jung‐Chien Cheng Christian Klausen Guiyan Chu

Smad2 Protein

10.1016/j.cellsig.2017.05.017

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Citations (14)