CLINICAL RESEARCH
 
KEYWORDS
TOPICS
ABSTRACT
Introduction:
In this study, we investigated the clinical value of using urothelial cancer-associated 1 (UCA1) and microRNA-16 (miR-16) as biomarkers for the diagnosis of pre-eclampsia (PE). Also, we compared the diagnostic values of miR-16, UCA1 and pregnancy-associated plasma protein-A (PAPP-A) in PE. Furthermore, we investigated the interaction between miR-16 and UCA1/PAPP-A.

Material and methods:
128 PE patients and 172 healthy pregnant women were enrolled in this study. Receiver operating characteristic (ROC) analysis was carried out to predict the diagnostic values of UCA1, miR-16 and PAPP-A in PE. Enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR), Western blot analysis, immunohistochemistry (IHC) assay, computational analysis, and luciferase assay were conducted to measure the differential expression of UCA1, miR-16, and PAPP A while establishing a signaling pathway of UCA1/miR-16/PAPP-A.

Results:
Compared with miR-16 and PAPP-A, UCA1 exhibited a better value in the diagnosis of PE. The expression of PAPP-A and UCA1 was down-regulated while the expression of miR-16 was up-regulated in patients with PE, especially in patients with HELLP pregnancies. Moreover, UCA1 was identified as a sponge of miR-16, while PAPP-A mRNA was identified as a virtual target gene of miR-16. Finally, a negative regulatory relationship was observed between the expression of miR-16 and UCA1 or PAPP-A, while the expression of UCA1 and PAPP-A were positively related.

Conclusions:
Taken together, the evidence suggests that UCA1 could be used as a more valuable biomarker in the diagnosis of PE. Meanwhile, the reduced expression of UCA1 could exert a positive effect by reducing the expression of PAPP-A in the pathogenesis of PE.

 
REFERENCES (43)
1.
Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005; 365: 785-99.
 
2.
Moodley J. Maternal deaths due to hypertensive disorders in pregnancy. Best Pract Res Clin Obstet Gynaecol 2008; 22: 559-67.
 
3.
Wright A, Wright D, Syngelaki A, Georgantis A, Nicolaides KH. Two-stage screening for preterm preeclampsia at 11-13 weeks’ gestation. Am J Obstet Gynecol 2019; 220: 197.e1-197.e11.
 
4.
Shennan AH. Recent developments in obstetrics. BMJ 2003; 327: 604-8.
 
5.
Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007; 335: 974.
 
6.
Spencer K, Cowans NJ, Avgidou K, Molina F, Nicolaides KH. First-trimester markers of aneuploidy and the prediction of small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2008; 31: 15-9.
 
7.
Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester using free -hCG and PAPP-A, combined with fetal nuchal translucency thickness. Prenat Diagn 2000; 20: 91-5.
 
8.
Lin TM, Galbert SP, Kiefer D, Spellacy WN, Gall S. Characterization of four human pregnancy-associated plasma proteins. Am J Obstet Gynecol 1974; 118: 223-36.
 
9.
Kristensen T, Oxvig C, Sand O, Moller NP, Sottrup-Jensen L. Amino acid sequence of human pregnancy-associated plasma protein – a derived from cloned cDNA. Biochemi­stry 1994; 33: 1592-8.
 
10.
Stocker W, Grams F, Baumann U, et al. The metzincins – topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci 1995; 4: 823-40.
 
11.
Lawrence JB, Oxvig C, Overgaard MT, et al. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci USA 1999; 96: 3149-53.
 
12.
Pihl K, Larsen T, Krebs L, Christiansen M. First trimester maternal serum PAPP-A, -hCG and ADAM12 in prediction of small-for-gestational-age fetuses. Prenat Diagn 2008; 28: 1131-5.
 
13.
Kuc S, Wortelboer EJ, van Rijn BB, Franx A, Visser GHA, Schielen PCJI. Evaluation of 7 serum biomarkers and uterine artery doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review. Obstet Gynecol Surv 2011; 66: 225-39.
 
14.
Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, van Asshe A. A study of placental bed spiral arteries and trophoblast invasion in normal and severe preeclamptic pregnancies. Br J Obstet Gynaecol 1994; 101: 669-74.
 
15.
Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992; 13: 596-611.
 
16.
Marques AC, Ponting CP. Intergenic lncRNAs and the evolution of gene expression. Curr Opin Genet Dev 2014; 27: 48-53.
 
17.
Chen G, Yin K, Shi L, et al. Comparative analysis of human protein coding and noncoding RNAs between brain and 10 mixed cell lines by RNA-Seq. PLoS One 2011; 6: e28318.
 
18.
Martens-Uzunova ES, Bottcher R, Croce CM, Jenster G, Visakorpi T, Calin GA. Long noncoding RNA in prostate, bladder, and kidney cancer. Eur Urol 2014; 65: 1140-51.
 
19.
Ribeiro AO, Schoof CR, Izzotti A, Pereira LV, Vasques LR. MicroRNAs: modulators of cell identity, and their applications in tissue engineering. Microrna 2014; 3: 45-53.
 
20.
Xiao Y, Jiao C, Lin Y, et al. lncRNA UCA1 contributes to imatinib resistance by acting as a ceRNA against miR-16 in chronic myeloid leukemia cells. DNA Cell Biol 2017; 36: 18-25.
 
21.
Li HJ, Li X, Pang H, Pan JJ, Xie XJ, Chen W. Long non-coding RNA UCA1 promotes glutamine metabolism by targeting miR-16 in human bladder cancer. Jpn J Clin Oncol 2015; 45: 1055-63.
 
22.
De Villiers CP, Hedley PL, Placing S, et al. Placental protein-13 (PP13) in combination with PAPP-A and free leptin index (fLI) in first trimester maternal serum screening for severe and early preeclampsia. Clin Chem Lab Med 2017; 56: 65-74.
 
23.
Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33: 130-7.
 
24.
Spradley FT, Palei AC, Granger JP. Immune mechanisms linking obesity and preeclampsia. Biomolecules 2015; 5: 3142-76.
 
25.
Shaw J, Tang Z, Schneider H, Salje K, Hansson SR, Guller S. Inflammatory processes are specifically enhanced in endothelial cells by placental-derived TNF-alpha: implications in preeclampsia (PE). Placenta 2016; 43: 1-8.
 
26.
Herraiz I, Simon E, Gomez-Arriaga PI, et al. Angiogenesis-related biomarkers (sFlt-1/PLGF) in the prediction and diagnosis of placental dysfunction: an approach for cli­nical integration. Int J Mol Sci 2015; 16: 19009-26.
 
27.
Liu Z, Afink GB, Dijke PT. Soluble fms-like tyrosine kinase 1 and soluble endoglin are elevated circulating anti-angiogenic factors in pre-eclampsia. Pregnancy Hypertens 2012; 2: 358-67.
 
28.
Wang F, Li X, Xie X, Zhao L, Chen W. UCA1, a non-protein-coding RNA up-regulated in bladder carcinoma and embryo, influencing cell growth and promoting invasion. FEBS Lett 2008; 582: 1919-27.
 
29.
Huang J, Zhou N, Watabe K, et al. Long non-coding RNA UCA1 promotes breast tumor growth by suppression of p27 (Kip1). Cell Death Dis 2014; 5: e1008.
 
30.
Fan Y, Shen B, Tan M, et al. Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. FEBS J 2014; 281: 1750-8.
 
31.
Li Z, Li X, Wu S, Xue M, Chen W. Long non-coding RNA UCA1 promotes glycolysis by upregulating hexokinase 2 through the mTOR-STAT3/microRNA143 pathway. Cancer Sci 2014; 105: 951-5.
 
32.
Yang Y, Jiang Y, Wan Y, et al. UCA1 functions as a competing endogenous RNA to suppress epithelial ovarian cancer metastasis. Tumour Biol 2016; 37: 10633-41.
 
33.
Aqeilan RI, Calin GA, Croce CM. miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ 2010; 17: 215-20.
 
34.
Bonci D, Coppola V, Musumeci M, et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 2008; 14: 1271-7.
 
35.
Varol F, Uzunoğlu R, Erbaş H, Süt N, Sayın C. VEGFR-1, Bcl-2, and HO-1 ratios in pregnant women with hypertension. Clin Appl Thromb Hemost 2015; 21: 285-8.
 
36.
Nuzzo AM, Giuffrida D, Zenerino C, et al. JunB/Cyclin-D1 imbalance in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise. Placenta 2014; 35: 483-90.
 
37.
Tan B, Tong C, Yuan Y, et al. The regulation of trophoblastic p53 homeostasis by the p38-Wip1 feedback loop is disturbed in placentas from pregnancies complicated by preeclampsia. Cell Physiol Biochem 2019; 52: 315-35.
 
38.
Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down’s syndrome based on tests performed during the first and second trimesters. N Engl J Med 1999; 341: 461-7.
 
39.
Conover CA, Kiefer MC, Zapf J. Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts. Insulin-like growth factor dependence and biological studies. J Clin Invest 1993; 91: 1129-37.
 
40.
Durham SK, Kiefer MC, Riggs BL, Conover CA. Regulation of insulin-like growth factor binding protein 4 by a specific insulin-like growth factor binding protein 4 proteinase in normal human osteoblast-like cells: implications in bone cell physiology. J Bone Miner Res 1994; 9: 111-7.
 
41.
Parker A, Gockerman A, Busby WH, Clemmons DR. Properties of an insulin-like growth factor-binding protein-4 protease that is secreted by smooth muscle cells. Endocrinology 1995; 136: 2470-6.
 
42.
Canini S, Prefumo F, Pastorino D, et al. Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Fertil Steril 2008; 89: 174-8.
 
43.
Spencer K, Cowans NJ, Avgidou K, Molina F, Nicolaides KH. First-trimester biochemical markers of aneuploidy and the prediction of small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2008; 31: 15-9.
 
eISSN:1896-9151
ISSN:1734-1922
Journals System - logo
Scroll to top