Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2019

Open Access 01-12-2019 | Research

HAS2-AS1 is a novel LH/hCG target gene regulating HAS2 expression and enhancing cumulus cells migration

Authors: Yuval Yung, Libby Ophir, Gil M. Yerushalmi, Micha Baum, Ariel Hourvitz, Ettie Maman

Published in: Journal of Ovarian Research | Issue 1/2019

Login to get access

Abstract

Background

The cumulus expansion process is one of the LH mediated ovulatory processes. Hyaluronan synthase 2 (HAS2) regulates the synthesis of hyaluronic acid, the main component of the cumulus expansion process. Recently, the lncRNA HAS2 antisense RNA 1 (HAS2-AS1) was identified in our global transcriptome RNA-sequencing of novel ovulation associated genes. The role of HAS2-AS1 in HAS2 regulation w.as studied previously with contradictive results in different models but not in the ovary. Taken together the induction of HAS2-AS1 and the important role of HAS2 in the cumulus expansion process, we hypothesize that HAS2-AS1 regulate HAS2 expression and function in the ovary. Therefore we undertook to study the expression, regulation, and possible functional role of HAS2-AS1 in the human ovary.

Results

HAS2-AS1, located within the HAS2 gene that was highly regulated in our library. We found that HAS2-AS1 express mainly in cumulus cells (CCs). Furthermore, HAS2-AS1 showed low expression in immature CCs and a significant increase expression in mature CCs. Functional studies reveal that inhibition of HAS2-AS1 by siRNA caused decrease expression of HAS2. Furthermore, inhibition of HAS2-AS1 by siRNA results in decrease migration of granulosa cells.

Conclusions

Our results suggest that HAS2-AS1 is an LH/hCG target gene that plays a positive role in HAS2 expression and thus might play a role in regulating cumulus expansion and migration.
Literature
1.
Hizaki H, Segi E, Sugimoto Y, Hirose M, Saji T, Ushikubi F, et al. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP(2). Proc Natl Acad Sci U S A. 1999;96(18):10501–6 PubMed PMID: 10468638. Epub 1999/09/01. eng.CrossRef
2.
Richards JS, Pangas SA. The ovary: basic biology and clinical implications. J Clin Invest. 2010;120(4):963–72 PubMed PMID: 20364094. Epub 2010/04/07. eng.CrossRef
3.
Russell DL, Robker RL. Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update. 2007;13(3):289–312 PubMed PMID: 17242016. Epub 2007/01/24. eng.CrossRef
4.
Hess KA, Chen L, Larsen WJ. Inter-alpha-inhibitor binding to hyaluronan in the cumulus extracellular matrix is required for optimal ovulation and development of mouse oocytes. Biol Reprod. 1999;61(2):436–43. PubMed PMID: 10411524. Epub 1999/07/20. eng.CrossRef
5.
Fulop C, Szanto S, Mukhopadhyay D, Bardos T, Kamath RV, Rugg MS, et al. Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice. Development. 2003;130(10):2253–61 PubMed PMID: 12668637. Epub 2003/04/02. eng.CrossRef
6.
Richards JS. Ovulation: new factors that prepare the oocyte for fertilization. Mol Cell Endocrinol. 2005;234(1–2):75–9 PubMed PMID: 15836955. Epub 2005/04/20. eng.CrossRef
7.
Shepel EA, Voznesenskaya TY, Blashkiv TV, Yanchii RI. CUMULUS CELL GENES AS POTENTIAL BIOMARKERS OF OOCYTE AND EMBRYO DEVELOPMENTAL COMPETENCE. Fiziolohichnyi zhurnal (Kiev, Ukraine : 1994). 2016;62(1):107–13 PubMed PMID: 29537212. Epub 2016/01/01. eng.CrossRef
8.
Kurokawa R. Long noncoding RNA as a regulator for transcription. Prog Mol Subcell Biol. 2011;51:29–41 PubMed PMID: 21287132.CrossRef
9.
Yan B, Wang Z. Long noncoding RNA: its physiological and pathological roles. DNA Cell Biol. 2012;31(Suppl 1):S34–41 PubMed PMID: 22612272.CrossRef
10.
Kim ED, Sung S. Long noncoding RNA: unveiling hidden layer of gene regulatory networks. Trends Plant Sci. 2012;17(1):16–21 PubMed PMID: 22104407.CrossRef
11.
Yerushalmi GM, Salmon-Divon M, Yung Y, Maman E, Kedem A, Ophir L, et al. Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation. Mol Hum Reprod. 2014;20(8):719–35 PubMed PMID: 24770949. Epub 2014/04/29. eng.CrossRef
12.
Chao H, Spicer AP. Natural antisense mRNAs to hyaluronan synthase 2 inhibit hyaluronan biosynthesis and cell proliferation. J Biol Chem. 2005;280(30):27513–22 PubMed PMID: 15843373. Epub 2005/04/22. eng.CrossRef
13.
Michael DR, Phillips AO, Krupa A, Martin J, Redman JE, Altaher A, et al. The human hyaluronan synthase 2 (HAS2) gene and its natural antisense RNA exhibit coordinated expression in the renal proximal tubular epithelial cell. J Biol Chem. 2011;286(22):19523–32 PubMed PMID: 21357421. Pubmed Central PMCID: PMC3103331. Epub 2011/03/02. eng.CrossRef
14.
Vigetti D, Deleonibus S, Moretto P, Bowen T, Fischer JW, Grandoch M, et al. Natural antisense transcript for hyaluronan synthase 2 (HAS2-AS1) induces transcription of HAS2 via protein O-GlcNAcylation. J Biol Chem. 2014;289(42):28816–26 PubMed PMID: 25183006. Pubmed Central PMCID: PMC4200242. Epub 2014/09/04. eng.CrossRef
15.
Akison LK, Alvino ER, Dunning KR, Robker RL, Russell DL. Transient invasive migration in mouse cumulus oocyte complexes induced at ovulation by luteinizing hormone. Biol Reprod. 2012;86(4):125 PubMed PMID: 22238281. Epub 2012/01/13. eng.CrossRef
16.
Jandura A, Krause HM. The New RNA World: Growing Evidence for Long Noncoding RNA Functionality. Trends Genet. 2017;33(10). Epub 2017 Sep 1.
17.
18.
Long Y, Wang X, Youmans DT, Cech TR. How do lncRNAs regulate transcription? Sci Adv. 2017;3(9) Epub 2017 Sep 27.
19.
Men Y, Fan Y, Shen Y, Lu L, Kallen AN. The steroidogenic acute regulatory protein (StAR) is regulated by the H19/let-7 Axis. Endocrinology. 2017;158(2):402–9 PubMed PMID: 27813675. Pubmed Central PMCID: 5413078.PubMed
20.
Nakagawa S, Shimada M, Yanaka K, Mito M, Arai T, Takahashi E, et al. The lncRNA Neat1 is required for corpus luteum formation and the establishment of pregnancy in a subpopulation of mice. Development. 2014;141(23):4618–27 PubMed PMID: 25359727. Pubmed Central PMCID: 4302932.CrossRef
21.
Kedem A, Yung Y, Yerushalmi GM, Haas J, Maman E, Hanochi M, et al. Anti Mullerian hormone (AMH) level and expression in mural and cumulus cells in relation to age. J Ovarian Res. 2014;7:113 PubMed PMID: 25500128. Pubmed Central PMCID: 4269874.CrossRef
22.
Yung Y, Aviel-Ronen S, Maman E, Rubinstein N, Avivi C, Orvieto R, et al. Localization of luteinizing hormone receptor protein in the human ovary. Mol Hum Reprod. 2014;20(9):844–9 PubMed PMID: 24874553. Epub 2014/05/31. eng.CrossRef
23.
Haas J, Ophir L, Barzilay E, Machtinger R, Yung Y, Orvieto R, et al. Standard human chorionic gonadotropin versus double trigger for final oocyte maturation results in different granulosa cells gene expressions: a pilot study. Fertil Steril. 2016;106(3):653–9 e1. PubMed PMID: 27341989. Epub 2016/06/28. eng.CrossRef
24.
Stock AE, Bouchard N, Brown K, Spicer AP, Underhill CB, Dore M, et al. Induction of hyaluronan synthase 2 by human chorionic gonadotropin in mural granulosa cells of equine preovulatory follicles. Endocrinology. 2002;143(11):4375–84 PubMed PMID: 12399434. Epub 2002/10/26. eng.CrossRef
25.
Kawashima I, Liu Z, Mullany LK, Mihara T, Richards JS, Shimada M. EGF-like factors induce expansion of the cumulus cell-oocyte complexes by activating calpain-mediated cell movement. Endocrinology. 2012;153(8):3949–59 PubMed PMID: 22673225. Pubmed Central PMCID: 3404342.CrossRef
26.
Shi H, Asher C, Yung Y, Kligman L, Reuveny E, Seger R, et al. Casein kinase 2 specifically binds to and phosphorylates the carboxy termini of ENaC subunits. Eur J Biochem. 2002;269(18):4551–8 PubMed PMID: 12230567. Epub 2002/09/17. eng.CrossRef
27.
Shi H, Asher C, Chigaev A, Yung Y, Reuveny E, Seger R, et al. Interactions of beta and gamma ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation. J Biol Chem. 2002;277(16):13539–47 PubMed PMID: 11805112. Epub 2002/01/24. eng.CrossRef
28.
Yao Z, Flash I, Raviv Z, Yung Y, Asscher Y, Pleban S, et al. Non-regulated and stimulated mechanisms cooperate in the nuclear accumulation of MEK1. Oncogene. 2001;20(52):7588–96 PubMed PMID: 11753637. Epub 2001/12/26. eng.CrossRef
29.
Yung Y, Yao Z, Aebersold DM, Hanoch T, Seger R. Altered regulation of ERK1b by MEK1 and PTP-SL and modified Elk1 phosphorylation by ERK1b are caused by abrogation of the regulatory C-terminal sequence of ERKs. J Biol Chem. 2001;276(38):35280–9 PubMed PMID: 11463794. Epub 2001/07/21. eng.CrossRef
30.
Van Soom A, Tanghe S, De Pauw I, Maes D, de Kruif A. Function of the cumulus oophorus before and during mammalian fertilization. Reprod Domest Anim. 2002;37(3):144–51 PubMed PMID: 12071888. Epub 2002/06/20. eng.CrossRef
31.
Yokoo M, Sato E. Cumulus-oocyte complex interactions during oocyte maturation. Int Rev Cytol 2004;235:251–291. PubMed PMID: 15219785. Epub 2004/06/29. eng.
32.
Hourvitz A, Lerner-Geva L, Elizur SE, Baum M, Levron J, David B, et al. Role of embryo quality in predicting early pregnancy loss following assisted reproductive technology. Reprod BioMed Online. 2006;13(4):504–9 PubMed PMID: 17007670. Epub 2006/09/30. eng.CrossRef
33.
Nishi Y, Yanase T, Mu Y, Oba K, Ichino I, Saito M, et al. Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor. Endocrinology. 2001;142(1):437–45 PubMed PMID: 11145608.CrossRef
Metadata
Title
HAS2-AS1 is a novel LH/hCG target gene regulating HAS2 expression and enhancing cumulus cells migration
Authors
Yuval Yung
Libby Ophir
Gil M. Yerushalmi
Micha Baum
Ariel Hourvitz
Ettie Maman
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2019
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-019-0495-3

Other articles of this Issue 1/2019

Journal of Ovarian Research 1/2019 Go to the issue

Research

Effect of BRCA mutational status on survival outcome in advanced-stage high-grade serous ovarian cancer

Review

Biomarkers and algorithms for diagnosis of ovarian cancer: CA125, HE4, RMI and ROMA, a review

Research

Low dose human chorionic gonadotropin administration at the time of gonadotropin releasing-hormone agonist trigger versus 35 h later in women at high risk of developing ovarian hyperstimulation syndrome – a prospective randomized double-blind clinical trial

Correction

Correction to: Nanog interaction with the androgen receptor signaling axis induce ovarian cancer stem cell regulation: studies based on the CRISPR/Cas9 system

Research

Decellularization of the mouse ovary: comparison of different scaffold generation protocols for future ovarian bioengineering

Research

Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer