25 results found
Raglan O, Kalliala I, Markozannes G, et al., 2019, Risk factors for endometrial cancer: An umbrella review of the literature, International Journal of Cancer, Vol: 145, Pages: 1719-1730, ISSN: 0020-7136
Although many risk factors could have causal association with endometrial cancer, they are also prone to residual confounding or other biases which could lead to over‐ or underestimation. This umbrella review evaluates the strength and validity of evidence pertaining risk factors for endometrial cancer.Systematic reviews or meta‐analyses of observational studies evaluating the association between non‐genetic risk factors and risk of developing or dying from endometrial cancer were identified from inception to April 2018 using PubMed, the Cochrane database and manual reference screening. Evidence was graded strong, highly suggestive, suggestive or weak based on statistical significance of random‐effects summary estimate, largest study included, number of cases, between‐study heterogeneity, 95% prediction intervals, small study effects, excess significance bias and sensitivity analysis with credibility ceilings.We identified 171 meta‐analyses investigating associations between 53 risk factors and endometrial cancer incidence and mortality. Risk factors were categorised: anthropometric indices, dietary intake, physical activity, medical conditions, hormonal therapy use, biochemical markers, gynaecological history and smoking. Of 127 meta‐analyses including cohort studies, three associations were graded with strong evidence. Body mass index and waist‐to‐hip ratio were associated with increased cancer risk in premenopausal women (RR per 5 kg/m2 1.49; CI 1.39–1.61) and for total endometrial cancer (RR per 0.1unit 1.21; CI 1.13–1.29), respectively. Parity reduced risk of disease (RR 0.66, CI 0.60–0.74).Of many proposed risk factors, only three had strong association without hints of bias. Identification of genuine risk factors associated with endometrial cancer may assist in developing targeted prevention strategies for women at high risk.
Salker MS, Singh Y, Durairaj RRP, et al., 2018, LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca²+ entry, JOURNAL OF MOLECULAR MEDICINE-JMM, Vol: 96, Pages: 173-182, ISSN: 0946-2716
Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-β family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes.
Raglan O, Kalliala I, Markozannes G, et al., 2017, RISK FACTORS ASSOCIATED WITH ENDOMETRIAL CANCER: AN UMBRELLA REVIEW, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 570-570, ISSN: 1048-891X
Janczar S, Nautiyal J, Xiao Y, et al., 2017, WWOX sensitizes ovarian cancer cells to paclitaxel via modulation of the ER stress response, Cell Death & Disease, Vol: 8, ISSN: 2041-4889
There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel also activates endoplasmic reticulum (ER) stress. Here, we examine the role of WWOX (WW domain containing oxidoreductase), a gene frequently lost in several cancers, in mediating paclitaxel response. We examine the ER stress-mediated apoptotic response to paclitaxel in WWOX-transfected epithelial ovarian cancer (EOC) cells and following siRNA knockdown of WWOX. We show that WWOX-induced apoptosis following exposure of EOC cells to paclitaxel is related to ER stress and independent of the antimitotic action of taxanes. The apoptotic response to ER stress induced by WWOX re-expression could be reversed by WWOX siRNA in EOC cells. We report that paclitaxel treatment activates both the IRE-1 and PERK kinases and that the increase in paclitaxel-mediated cell death through WWOX is dependent on active ER stress pathway. Log-rank analysis of overall survival (OS) and progression-free survival (PFS) in two prominent EOC microarray data sets (Tothill and The Cancer Genome Atlas), encompassing ~800 patients in total, confirmed clinical relevance to our findings. High WWOX mRNA expression predicted longer OS and PFS in patients treated with paclitaxel, but not in patients who were treated with only cisplatin. The association of WWOX and survival was dependent on the expression level of glucose-related protein 78 (GRP78), a key ER stress marker in paclitaxel-treated patients. We conclude that WWOX sensitises EOC to paclitaxel via ER stress-induced apoptosis, and predicts clinical outcome in patients. Thus, ER stress response mechanisms could be targeted to overcome chemoresistance in cancer.
Nautiyal J, 2017, Transcriptional coregulator RIP140: an essential regulator of physiology, Journal of Molecular Endocrinology, Vol: 58, Pages: R147-R158, ISSN: 1479-6813
Transcriptional coregulators drive gene regulatory decisions in the transcriptional space. While transcription factors including all nuclear receptors provide a docking platform for coregulators to bind, these proteins bring enzymatic capabilities to the gene regulatory sites. RIP140 is a transcriptional coregulator essential for several physiological processes and aberrations in its function may lead to diseased states. Unlike several other coregulators which are either known for their coactivating or corepressing roles, in gene regulation, RIP140 is capable of acting both as a coactivator and a corepressor. The role of RIP140 in female reproductive axis and recent findings of its role in carcinogenesis and adipose biology have been summarized.
Salker MS, Steel JH, Hosseinzadeh Z, et al., 2016, Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation, Cellular Physiology and Biochemistry, Vol: 39, Pages: 2077-2087, ISSN: 1421-9778
Background: Serum & Glucocorticoid Regulated Kinase 1 (SGK1) plays a fundamental role in ion and solute transport processes in epithelia. In the endometrium, down-regulation of SGK1 during the window of receptivity facilitates embryo implantation whereas expression of a constitutively active mutant in the murine uterus blocks implantation. Methods/Results: Here, we report that treatment of endometrial epithelial cells with specific inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT activity pathway results in reciprocal activation of SGK1. Flushing of the uterine lumen of mice with a cell permeable, substrate competitive phosphatidylinositol analogue that inhibits AKT activation (AKT inhibitor III) resulted in Sgk1 phosphorylation, down-regulation of the E3 ubiquitin-protein ligase Nedd4-2, and increased expression of epithelial Na+ channels (ENaC). Furthermore, exposure of the uterine lumen to AKT inhibitor III prior to embryo transfer induced a spectrum of early pregnancy defects, ranging from implantation failure to aberrant spacing of implantation sites. Conclusion: Taken together, our data indicate that the balanced activities of two related serine/threonine kinases, AKT and SGK1, critically govern the implantation process.
Reiss LK, Fragoulis A, Siegl S, et al., 2014, Interplay between Nuclear Factor Erythroid 2-Related Factor 2 and Amphiregulin during Mechanical Ventilation, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 51, Pages: 668-677, ISSN: 1044-1549
Rosell M, Nevedomskaya E, Stelloo S, et al., 2014, Complex Formation and Function of Estrogen Receptor alpha in Transcription Requires RIP140, CANCER RESEARCH, Vol: 74, Pages: 5469-5479, ISSN: 0008-5472
Brosens JJ, Salker MS, Teklenburg G, et al., 2014, Uterine Selection of Human Embryos at Implantation, SCIENTIFIC REPORTS, Vol: 4, ISSN: 2045-2322
Nautiyal J, Christian M, Parker M, 2013, Distinct functions of RIP140 in Development, Inflammation and Metabolism, Trends in Endocrinology and Metabolism
Nautiyal J, Steel JH, Mane MR, et al., 2013, The transcriptional co-factor RIP140 regulates mammary gland development by promoting the generation of key mitogenic signals, Development, Vol: 140, Pages: 1079-1089, ISSN: 0950-1991
Salker MS, Nautiyal J, Steel JH, et al., 2012, Disordered IL-33/ST2 Activation in Decidualizing Stromal Cells Prolongs Uterine Receptivity in Women with Recurrent Pregnancy Loss, PLOS ONE, Vol: 7, ISSN: 1932-6203
Rong Y, Meng Q, Nautiyal J, et al., 2012, Genetic co-regulation of age of female sexual maturation and life span through circulating IGF-1 among inbred mouse strains, Proceedings of the National Academy of Sciences
Salker MS, Christian M, Steel JH, et al., 2011, Deregulation of serum-and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure, Nature Medicine, Vol: 17, Pages: 1509-1513, ISSN: 1546-170X
Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations1, 2. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival3, 4, 5, 6, is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional importance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling and abolished embryo implantation. By contrast, implantation was unhindered in Sgk1−/− mice, but pregnancy was often complicated by bleeding at the decidual-placental interface and fetal growth retardation and subsequent demise. Compared to wild-type mice, Sgk1−/− mice had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with RPL and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.
Rosell M, Wilbert Z, Nautiyal J, et al., 2011, Genome-wide characterization of RIP140 binding events in breast cancer cells, EMBO Conference on Nuclear Receptors
Nautiyal J, Steel JH, Rosell M, et al., 2011, The transcriptional regulator RIP140 regulates ductal morphogenesis in the mammary gland by regulating key mitogenic signals, EMBO Conference on Nuclear Receptors
Salker MS, Christian M, Steel JH, et al., 2011, Deregulation of the serum and glucocorticoid regulated Kinase SGK1 in the endometrium causes reproductive failure, 27th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology, Publisher: OXFORD UNIV PRESS, Pages: I99-I99, ISSN: 0268-1161
Salker MS, Christian M, Steel JH, et al., 2011, Deregulated Activity of the Serum and Glucocorticoid-Inducible Kinase (SGK1) in the Endometrium Causes Reproductive Failure, Publisher: SAGE PUBLICATIONS INC, Pages: 272A-272A, ISSN: 1933-7191
Nautiyal J, Steel JH, Rosell MM, et al., 2010, The Nuclear Receptor Cofactor Receptor-Interacting Protein 140 Is a Positive Regulator of Amphiregulin Expression and Cumulus Cell-Oocyte Complex Expansion in the Mouse Ovary, ENDOCRINOLOGY, Vol: 151, Pages: 2923-2932, ISSN: 0013-7227
Nautiyal J, Steel JH, Wood N, et al., 2010, The transcriptional regulator RIP140 is a mediator of hormonal signalling and ductal morphogenesis in the mammary gland, 14th International Congress on Hormonal Steroids and Hormones and Cancer
Kumar V, Hassan I, Tomar AK, et al., 2009, Proteomic analysis of heparin-binding proteins from human seminal plasma: a step towards identification of molecular markers of male fertility, J.Biosci, Vol: 34(6), Pages: 899-908
Nautiyal J, Nikolopoulou E, Steel J, et al., 2008, Ups and downs of nuclear receptor action in the ovary, World Congress on Reproductive Biology, Publisher: SOC STUDY REPRODUCTION, Pages: 271-271, ISSN: 0006-3363
Nautiyal J, Kumar PG, Laloraya M, 2004, Mifepristone (Ru486)antagonizes monocyte chemotactic protein-3 down-regulation at early mouse pregnancy revealing immunomodulatory events in Ru486 induced abortion., Am J Reprod Immunol., Vol: 52(1), Pages: 8-18
Nautiyal J, Kumar PG, Laloraya M, 2004, 17 Beta-estradiol induces nuclear translocation of CrkL at the Window of Embryo Implantation, Biochem Biophys Res Commun., Vol: 318(1), Pages: 103-112
Nautiyal J, Steel JH, Nikolopoulou E, et al., RIP140: A key regulator of Ovulation, Keystone Meeting on Frontiers in Reproductive Biology and Regulation of Fertility
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