Decreased Endometrial Expression of Leukemia Inhibitory Factor Receptor Disrupts the STAT3 Signaling in Adenomyosis During the Implantation Window

Yen, Chih-Feng; Liao, Shuen‐Kuei; Huang, S. Joseph; Tabak, Selcuk; Arcuri, Felice; Lee, Chyi‐Long; Arıcı, Aydın; Wang, Hsin-Shih; Kayisli, Umit A.

doi:10.1177/1933719116681515

Cited by 50 publications

(33 citation statements)

References 55 publications

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“…Immunohistochemistry was performed on placental sections as previously described (27) using the primary antibody (rabbit anti-LIN28B, 40 mg/ml, ab71415, RRID:AB_2135050; Abcam, Cambridge, United Kingdom) and detected using a biotinylated goat anti-rabbit secondary antibody (BA-1000, RRID:AB _2313606; Vector Laboratories, Burlingame, CA, USA) together with the avidin-biotin-peroxidase complex (Vectastain ABC Kit, pk6200, RRID:AB_2336826; Vector Laboratories) followed by 3,39diaminobezidine (sk-4100, RRID:AB_2336382; Vector Laboratories) incubation as a substrate and counterstained with hematoxylin (H3404, RRID:AB_2336843; Vector Laboratories).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration

Canfield¹,

Arlıer²,

Mong³

et al. 2018

FASEB j.

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Preeclampsia (PE) is a common cause of maternal morbidity, characterized by impaired trophoblast invasion and spiral artery transformation resulting in progressive uteroplacental hypoxia. Given the primary role of LIN28A and LIN28B in modulating cell metabolism, differentiation, and invasion, we hypothesized that LIN28A and/or LIN28B regulates trophoblast differentiation and invasion, and that its dysregulation may contribute to PE. Here we show that LIN28B is expressed ∼1300‐fold higher than LIN28A in human term placenta and is the predominant paralog expressed in primary human trophoblast cultures. The expression of LIN28B mRNA and protein levels are significantly reduced in gestational age–matched preeclamptic vs. normal placentas, whereas LIN28A expression is not different. First trimester human placental sections displayed stronger LIN28B immunoreactivity in extravillous (invasive) cytotrophoblasts and syncytial sprouts vs. villous trophoblasts. LIN28B overexpression increased HTR8 cell proliferation, migration, and invasion, whereas LIN28B knockdown in JEG3 cells reduced cell proliferation. Moreover, LIN28B knockdown in JEG3 cells suppressed syncytin 1 (SYN‐1), apelin receptor early endogenous ligand (ELABELA), and the chromosome 19 microRNA cluster, and increased mRNA expression of ITGp4and TNF‐α. Incubation of BeWo and JEG3 cells under hypoxia significantly decreased expression of LIN28B and LIN28A, SYN‐1, and ELABELA, whereas TNF‐α is increased. These results provide the first evidence that LIN28B is the predominant paralog in human placenta and that decreased LIN28B may play a role in PE by reducing trophoblast invasion and syncytialization, and by promoting inflammation.—Canfield, J., Arlier, S., Mong, E. F., Lockhart, J., Vanwye, J., Guzeloglu‐Kayisli, O., Schatz, F., Magness, R. R., Lockwood, C. J., Tsibris, J. C. M., Kayisli, U. A., Totary‐Jain, H. Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration. FASEB J. 33, 2759–2769 (2019). http://www.fasebj.org

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Section: Immunohistochemistrymentioning

confidence: 99%

Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration

Canfield¹,

Arlıer²,

Mong³

et al. 2018

FASEB j.

Self Cite

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“…Adenomyosis is a common and chronic gynaecological disease that affects 10%‐80% of women of reproductive age worldwide . It is characterized by the presence of endometrial stroma and glands within the myometrium and its main clinical features include chronic pelvic pain, abnormal uterine bleeding, menorrhagia, dysmenorrhea, dyspareunia and infertility . In recent years, due to the advancement of imaging techniques such as transvaginal ultrasound scan (TVUS) and magnetic resonance imaging (MRI), substantial evidences suggest that adenomyosis may develop more often among younger women .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 It is characterized by the presence of endometrial stroma and glands within the myometrium and its main clinical features include chronic pelvic pain, abnormal uterine bleeding, menorrhagia, dysmenorrhea, dyspareunia and infertility. 1,[3][4][5] In recent years, due to the advancement of imaging techniques such as transvaginal ultrasound scan (TVUS) and magnetic resonance imaging (MRI), substantial evidences suggest that adenomyosis may develop more often among younger women. 6,7 To date, no novel compound is reported to develop for adenomyosis and clinical studies on the well-conducted pharmacologic treatment are seldom reported.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome sequencing of adenomyosis eutopic endometrium: A new insight into its pathophysiology

Ying

Sun

Yang

et al. 2019

J Cellular Molecular Medi

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The eutopic endometrium has been suggested to play a crucial role in the pathogenesis of adenomyosis. However, the specific genes in eutopic endometrium responsible for the pathogenesis of adenomyosis still remain to be elucidated. We aim to identify differentially expressed genes (DEGs) and molecular pathways/networks in eutopic endometrium from adenomyosis patients and provide a new insight into disease mechanisms at transcriptome level. RNA sequencing (RNA‐Seq) was performed with 12 eutopic endometrium from adenomyosis and control groups. Differentially expressed genes in adenomyosis were validated by quantitative real‐time PCR (qPCR) and immunochemistry. Functional annotations of the DEGs were analysed with Ingenuity Pathway Analysis (IPA). Quantitative DNA methylation analysis of CEBPB was performed with MassArray system. A total of 373 differentially expressed genes were identified in the adenomyosis eutopic endometrium compared to matched controls. Bioinformatic analysis predicted that IL‐6 signalling and ERK/MAPK signalling were activated in adenomyosis endometrium. We also found that the increased expression and DNA hypomethylation of CEBPB were associated with adenomyosis. Our results revealed key pathways and networks in eutopic endometrium of adenomyosis. The study is the first to propose the association between C/EBPβ and adenomyosis and can improve the understanding of the pathogenesis of adenomyosis.

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“…In the endometrium, LIF and LIFR expression are particularly prominent in the secretory phase of the menstrual cycle, indicating a potential role in embryo implantation . Indeed, expression of LIFR, LIF, and its coreceptor gp130 is reduced in subfertile endometriosis patients compared with healthy controls, and a reduction of LIFR expression is associated with reduced downstream signaling via signal transducer and activator of transcription 3 in women with adenomyosis during the window of implantation . Therefore, although GSI‐induced inhibition of LIFR expression can be expected to aid in targeting stem cell properties in endometriotic lesions, it may cause unwanted fertility‐related side effects.…”

Section: Discussionmentioning

confidence: 99%

γ‐Secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells

Williams

Brüggemann

Hubert

et al. 2019

Acta Obstet Gynecol Scand

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Introduction Stem cells mediate cyclic regeneration of the endometrium. The upregulated expression of receptors and modulators of the notch signaling pathway in endometriosis suggests an involvement in the pathogenetic process. Here, we investigated the effects of notch pathway inhibition by a γ‐secretase inhibitor (GSI) on stemness‐associated properties of the epithelial endometriotic cell line 12Z and of primary endometriotic stroma cells. Material and methods 12Z cells and primary endometriotic stroma cells of 7 patients were treated with or without GSI, and analyzed for changes in gene expression by TaqMan low‐density arrays, quantitative PCR, and flow cytometry. The functional impact of GSI treatment was studied by MTT assay, cell cycle analysis, colony formation assay, annexin V apoptosis assay, and aldehyde dehydrogenase activity assays. Results In 12Z cells, GSI treatment reduced aldehyde dehydrogenase activity and colony formation, and induced a shift to the G2/M phase of the cell cycle. Cell viability was decreased and apoptosis was increased in both cell models. GSI further induced transcriptional downregulation of the stemness‐associated factors leukemia inhibitory factor receptor (LIFR), sex‐determining region Y (SRY)‐ box 2, interferon‐induced transmembrane protein 1, and hes‐related family bHLH transcription factor with YRPW motif 1, in 12Z cells and in primary cell cultures. Downregulation of LIFR expression by GSI was confirmed at the protein level by flow cytometry. Conclusions Our in vitro data suggest that application of GSI may be a worthwhile approach in the treatment of endometriosis that warrants further investigation.

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Decreased Endometrial Expression of Leukemia Inhibitory Factor Receptor Disrupts the STAT3 Signaling in Adenomyosis During the Implantation Window

Cited by 50 publications

References 55 publications

Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration

Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration

Transcriptome sequencing of adenomyosis eutopic endometrium: A new insight into its pathophysiology

γ‐Secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells

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