Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines.
Methods:
We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg-3 cells with different RA derivates and 2′-deoxy-5-azacytidine (AZA) to induce DNA demethylation.
Results:
RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines.
Discussion:
RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication.
ChenM-CHsuS-LLinHYangT-Y. Retinoic acid and cancer treatment. Biomedicine (Taipei). 2014;4(4):22.
2.
NagpalSPatelSAsanoATJohnsonATDuvicMChandraratnaRA. Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor-responsive gene in skin. J Invest Dermatol. 1996;106(2):269–274.
3.
CunninghamTJDuesterG. Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell biol. 2015;16(2):110–123.
4.
RhinnMDolléP. Retinoic acid signalling during development. Development. 2012;139(5):843–858.
5.
DasBCThapaPKarkiR. Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014;22(2):673–683.
6.
MadenM. Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci. 2002;3(11):843–853.
7.
Merlet-BénichouCVilarJLelièvre-PégorierMGilbertT. Role of retinoids in renal development: pathophysiological implication. Curr Opin Nephrol Hypertens. 1999;8(1):39–43.
8.
NagpalSChandraratnaRA. Recent developments in receptor-selective retinoids. Curr Pharm Des. 2000;6(9):919–931.
9.
AllenbyGBocquelM-TSaundersM. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993;90(1):30–34.
10.
KatoYBraunsteinGD. Retinoic acid stimulates placental hormone secretion by choriocarcinoma cell lines in vitro. Endocrinology. 1991;128(1):401–407.
11.
StephanouAHandwergerS. Retinoic acid and thyroid hormone regulate placental lactogen expression in human trophoblast cells. Endocrinology. 1995;136(3):933–938.
12.
TarradeASchoonjansKGuibourdencheJ. PPARγ/RXRα heterodimers are involved in human CGβ synthesis and human trophoblast differentiation. Endocrinology. 2001;142(10):4504–4514.
13.
TarradeASchoonjansKPavanL. PPARγ/RXRα heterodimers control human trophoblast invasion. J Clin Endocrinol Metab. 2001;86(10):5017–5024.
14.
RuebnerMLangbeinMStrisselPL. Regulation of the human endogenous retroviral Syncytin-1 and cell–cell fusion by the nuclear hormone receptors PPARγ/RXRα in placentogenesis. J Cell Biochem. 2012;113(7):2383–2396.
PengZShenRLiY-WTengK-YShapiroCLLinH-JL. Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. PloS One. 2012;7(5):e36891.
17.
JingCEl-GhanyMABeesleyCFosterCSRudlandPSSmithP. Tazarotene-induced gene 1 (TIG1) expression in prostate carcinomas and its relationship to tumorigenicity. J Natl Cancer Inst. 2002;94(7):482–490.
18.
OldridgeEEWalkerHFStowerMJ. Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN. Oncogenesis. 2013;2:e45.
19.
WuCCTsaiFMShyuRYTsaiYMWangCHJiangSY. G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells. BMC Cancer. 2011;11:175.
20.
OhnishiSOkabeKObataH. Involvement of tazarotene-induced gene 1 in proliferation and differentiation of human adipose tissue-derived mesenchymal stem cells. Cell Prolif. 2009;42(3):309–316.
21.
ZabelBAAllenSJKuligP. Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J Biol Chem. 2005;280(41):34661–34666.
22.
ErnstMCSinalCJ. Chemerin: at the crossroads of inflammation and obesity. Trends Endocrinol Metab. 2010;21(11):660–667.
23.
FerlandDJWattsSW. Chemerin: a comprehensive review elucidating the need for cardiovascular research. Pharmacol Res. 2015;99:351–361.
24.
NagpalSPatelSJacobeH. Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin. J Invest Dermatol. 1997;109(1):91–95.
25.
GarcesMFSanchezERuíz-ParraAI. Serum chemerin levels during normal human pregnancy. Peptides. 2013;42:138–143.
26.
ErdoganSYilmazFMYaziciO. Inflammation and chemerin in colorectal cancer. Tumor Biology. 2016;37(5):6337–6342.
27.
SzydłoBKiczmerPŚwiętochowskaEOstrowskaZ. Role of omentin and chemerin in metabolic syndrome and tumor diseases. Postępy Hig Med Dośw (Online). 2016;70(0):844–849.
MoralesMArenasEJUrosevicJ. RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation. EMBO Mol Med. 2014;6(7):865–881.
30.
WangZWangLHuJ. RARRES3 suppressed metastasis through suppression of MTDH to regulate epithelial-mesenchymal transition in colorectal cancer. Am J Cancer Res. 2015;5(6):1988–1899.
31.
HiguchiEChandraratnaRAHongWKLotanR. Induction of TIG3, a putative class II tumor suppressor gene, by retinoic acid in head and neck and lung carcinoma cells and its association with suppression of the transformed phenotype. Oncogene. 2003;22(30):4627–4635.
32.
ShutohMOueNAungPP. DNA methylation of genes linked with retinoid signaling in gastric carcinoma: expression of the retinoid acid receptor beta, cellular retinol-binding protein 1, and tazarotene-induced gene 1 genes is associated with DNA methylation. Cancer. 2005;104(8):1609–1619.
33.
ZhangJLiuLPfeiferGP. Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene. Oncogene. 2004;23(12):2241–2249.
34.
de TheHdel Mar Vivanco-RuizMTiollaisPStunnenbergHDejeanA. Identification of a retinoic acid responsive element in the retinoic acid receptor & beta; gene. Nature. 1990;343(6254):177–180.
MohammadNYaqinuddinAKakalFSheikhLQureshiRSomaniM. Frequent hypomethylation of PTGS2 gene promoter in human term placenta. Ital J Anat Embryol. 2013;118(2):211–216.
37.
FerrettiCBruniLDangles-MarieVPeckingAPBelletD. Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts. Hum Reprod Update. 2007;13(2):121–141.
38.
HuppertzB. Placental origins of preeclampsia challenging the current hypothesis. Hypertension. 2008;51(4):970–975.
39.
BrackenMBBrintonLAHayashiK. Epidemiology of hydatidiform mole and choriocarcinoma. Epidemiol Rev. 1984;6:52–75.
40.
FahlbuschFBDawoodYHartnerA. Cullin 7 and Fbxw 8 expression in trophoblastic cells is regulated via oxygen tension: implications for intrauterine growth restriction?J Matern Fetal Neonatal Med. 2012;25(11):2209–2215.
41.
RuebnerMStrisselPLEkiciAB. Reduced syncytin-1 expression levels in placental syndromes correlates with epigenetic hypermethylation of the ERVW-1 promoter region. PLoS One. 2013;8(2):e56145.
42.
RuebnerMStrisselPLLangbeinM. Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes. J Mol Med (Berl). 2010;88(11):1143–1156.
43.
Straszewski-ChavezSLAbrahamsVMAlveroAB. The isolation and characterization of a novel telomerase immortalized first trimester trophoblast cell line, Swan 71. Placenta. 2009;30(11):939–948.
44.
YenAFenningRChandraratnaRWalkerPVarvayanisS. A retinoic acid receptor β/γ-selective prodrug (tazarotene) plus a retinoid X receptor ligand induces extracellular signal-regulated kinase activation, retinoblastoma hypophosphorylation, G0 arrest, and cell differentiation. Mol pharmacol. 2004;66(6):1727–1737.
45.
ChandraratnaR. Tazarotene—first of a new generation of receptor-selective retinoids. Br J Dermatol. 1996;135(suppl 49):18–25.
46.
ChandraratnaRA. Tazarotene: the first receptor-selective topical retinoid for the treatment of psoriasis. J Am Acad Dermatol. 1997;37(2 pt 3):S12–S17.
47.
BoschABertranSPLuY. Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis. Breast Cancer Res. 2012;14(4):R121.
48.
AncianPLenoirMMichelS. Effects of CD 2665, a selective RARβ, γ antagonist on the retinoid activity in human keratinocytes and fibroblasts in culture. J Inv Dermatol. 1997;5(108):817.
49.
SomenziGSalaGRossettiSRenMGhidoniRSacchiN. Disruption of retinoic acid receptor alpha reveals the growth promoter face of retinoic acid. PloS one. 2007;2(9):e836.
50.
ShresthaSKimS-YYunY-J. Retinoic acid induces hypersegmentation and enhances cytotoxicity of neutrophils against cancer cells. Immunol Lett. 2017;182:24–29.
51.
LoH-MChenC-LYangC-M. The carotenoid lutein enhances matrix metalloproteinase-9 production and phagocytosis through intracellular ROS generation and ERK1/2, p38 MAPK, and RARβ activation in murine macrophages. J Leukoc Biol. 2013;93(5):723–735.
52.
RoulieraSRochette-EglyCRebut-BonnetonCPorquetDEvain-BrionD. Nuclear retinoic acid receptor characterization in cultured human trophoblast cells: effect of retinoic acid on epidermal growth factor receptor expression. Mol Cell Endocrinol. 1994;105(2):165–173.
53.
TangX-HGudasLJ. Retinoids, retinoic acid receptors, and cancer. Annu Rev Patho. 2011;6:345–364.
54.
JerónimoCHenriqueRHoqueMO. Quantitative RARβ2 Hypermethylation A Promising Prostate Cancer Marker. Clin Cancer Res. 2004;10(12 pt 1):4010–4014.
55.
BastianPJEllingerJHeukampLCKahlPMüllerSCvon RückerA. Prognostic value of CpG island hypermethylation at PTGS2, RAR-beta, EDNRB, and other gene loci in patients undergoing radical prostatectomy. Eur Urol. 2007;51(3):665–674.
56.
JhaANikbakhtMParasharGShrivastavaACapalashNKaurJ. Reversal of Hypermethylation and Reactivation of the RAR [Beta] 2 Gene by Natural Compounds in Cervical Cancer Cell Lines. Folia Biol(Praha). 2010;56(5):195–200.
57.
WangXSasoHIwamotoT. TIG1 Promotes the Development and Progression of Inflammatory Breast Cancer through Activation of Axl Kinase. Cancer Res. 2013;73(21):6516–6525.
58.
WuCCShyuRYChouJM. RARRES1 expression is significantly related to tumour differentiation and staging in colorectal adenocarcinoma. Eur J Cancer. 2006;42(4):557–565.
59.
YanatatsaneejitPChalermchaiTKerekhanjanarongV. Promoter hypermethylation of CCNA1, RARRES1, and HRASLS3 in nasopharyngeal carcinoma. Oral oncology. 2008;44(4):400–406.
60.
CoyleKMurphyJVidovicD. Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1. Oncotarget. 2016;7(28):44098–44112.
61.
LangbeinMStrickRStrisselPL. Impaired cytotrophoblast cell-cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Mol Reprod Dev. 2008;75(1):175–183.
62.
GausterMMoserGOrendiKHuppertzB. Factors involved in regulating trophoblast fusion: potential role in the development of preeclampsia. Placenta. 2009;30(suppl A):S49–S54.
63.
HeazellAMollSJonesCBakerPCrockerI. Formation of syncytial knots is increased by hyperoxia, hypoxia and reactive oxygen species. Placenta. 2007;28(suppl A):S33–S40.
64.
BurtonGJJonesCJ. Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol. 2009;48(1):28–37.
65.
Holdsworth-CarsonSLimRMittonA. Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta. 2010;31(3):222–219.
66.
LongtineMSChenBOdiboAOZhongYNelsonDM. Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR. Placenta. 2012;33(5):352–359.
67.
NewhouseSMDavidgeSTWinkler-LowenBDemianczukNGuilbertLJ. In Vitro Differentiation of Villous Trophoblasts from Pregnancies Complicated by Intrauterine Growth Restriction With and Without Pre-Eclampsia. Placenta. 2007;28(10):999–1003.
68.
FahlbuschFBRuebnerMVolkertG. Corticotropin-releasing hormone stimulates expression of leptin, 11beta-HSD2 and syncytin-1 in primary human trophoblasts. Reprod Biol Endocrinol. 2012;10(1):80.
69.
ShyuRJiangSChouJ. RARRES3 expression positively correlated to tumour differentiation in tissues of colorectal adenocarcinoma. Br J Cancer. 2003;89(1):146–151.
70.
CasanovaBde la FuenteMTGarcia-GilaM. The class II tumor-suppressor gene RARRES3 is expressed in B cell lymphocytic leukemias and down-regulated with disease progression. Leukemia. 2001;15(10):1521–1526.
71.
LiHWCheungANTsaoSWCheungALWSO. Expression of e-cadherin and beta-catenin in trophoblastic tissue in normal and pathological pregnancies. Int J Gynecol Pathol. 2003;22(1):63–70.
72.
Kasher-MeronMMazaki-ToviSBarhodE. Chemerin concentrations in maternal and fetal compartments: implications for metabolic adaptations to normal human pregnancy. J Perinat Med. 2014;42(3):371–378.
73.
StepanHPhilippARothI. Serum levels of the adipokine chemerin are increased in preeclampsia during and 6months after pregnancy. Regul Pept. 2011;168(1):69–72.
74.
DuanDMNiuJMLeiQLinXHChenX. Serum levels of the adipokine chemerin in preeclampsia. J Perinat Med. 2012;40(2):121–127.
75.
VerlindenIGüngörNJanssensJMichielsL. Gene expression profiling to identify parity-induced changes in the human mammary gland. Breast Cancer Res. 2005;7:1.
76.
XuX-C. Tumor-suppressive activity of retinoic acid receptor-β in cancer. Cancer Lett. 2007;253(1):14–24.
77.
GuibourdencheJRoulierSRochette-EglyCEvain-BrionD. High retinoid X receptor expression in JEG-3 choriocarcinoma cells: involvement in cell function modulation by retinoids. J Cell Physiol. 1998;176(3):595–601.
78.
GuibourdencheJAlsatESoncinFRochette-EglyCEvain-BrionD. Retinoid receptors expression in human term placenta: involvement of RXRα in retinoid induced-hCG secretion. J Clin Endocrinol Metab. 1998;83(4):1384–1387.
79.
RodieVAYoungAJordanFSattarNGreerIAFreemanD. Human placental peroxisome proliferator-activated receptor δ and γ expression in healthy pregnancy and in preeclampsia and intrauterine growth restriction. J Soc Gynecol Investig. 2005;12(5):320–329.
80.
TarradeARochette-EglyCGuibourdencheJEvain-BrionD. The expression of nuclear retinoid receptors in human implantation. Placenta. 2000;21(7):703–710.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
