Süleyman Cansun DEMİR, Erol ARSLAN, Nermin Seda ILGAZ, Hale ÖKSÜZ, Lütfiye ÖZPAK, Mehmet Bertan YILMAZ, Çiğdem AKCABAY

Preterm erken membran rüptürüne yol açtığı düşünülen mekanizmaların moleküler düzeyde incelenmesi

Amaç: Bu çalışmanın amacı, preterm erken membran rüptürü (PEMR) vakalarında, p16 ile CDK4, CDK6, siklin D, RB1, E2F genlerinin mRNA ekspresyon seviyelerini ve bu genlerin etiyopatogenezdeki rollerini saptamaktır. Gereç ve Yöntem: Çalışmamızda 34. gebelik haftasından önce membran rüptürü olan 21 gebe (çalışma grubu) ile herhangi bir durumla komplike olmamış ve 37. gebelik haftasından sonra doğum yapmış 20 gebenin (kontrol) doğum sonu koryoamniyotik membranları incelendi ve bu iki grubun koryoamniyotik membran örnekleri p16, siklin D, CDK4, CDK6, RB1 ve E2F genlerinin mRNA ekspresyon seviyeleri açısından karşılaştırıldı. Bulgular: Çalışmamızda, kontrol grubu ile kıyaslandığında p16, siklin D, CDK4, CDK6, RB1 ve E2F genlerinin ekspresyon seviyelerinin PEMR grubunda anlamlı derecede azaldığı saptandı. Sonuç: Bulgularımız bu vakalarda oksidatif stresin p16 yolağı üzerinden etki etmeyebileceğini göstermiştir. PEMR’nin moleküler mekanizmasını anlamak için, gelecekteki çalışmalarda oksidatif stres ve yaşlanma biyobelirteçleri ile yaşlanma ve oksidatif streste görevli diğer yolaklar birlikte değerlendirilmelidir.

Anahtar Kelimeler:

PPROM, p16, siklin D, CDK4, CDK6, RB1 ve E2F

Molecular investigation of mechanisms considered to cause preterm premature membrane rupture

Purpose: The aim of this study was to investigate the mRNA expression level of p16, CDK4, CDK6, Cyclin D, RB1, and E2F genes in preterm premature rupture of membrane (PPROM) cases and their roles in etiopathogenesis of PPROM. Materials and Methods: Twenty-one pregnancies with PPROM before 34th gestational weeks (study group) were compared with twenty pregnancies with no complication, who gave birth after 37th gestational-week (control group). Both groups chorioamniotic membranes were compared for mRNA expression of p16, cyclin D, CDK4, CDK6, RB1 and E2F genes. Results: The mRNA expression levels of p16, cyclin D, CDK4, CDK6, RB1and E2F genes decreased in the PPROM group compared to control group at a statistically significant level. Conclusion: Our findings have shown that oxidative stress may not act on the p16 pathway in these cases. In order to understand the molecular mechanism of PPROM, biomarkers of oxidative stress and aging should be evaluated together with other pathways related to aging and oxidative stress in future studies.

Keywords:

PPROM, p16, cyclin D, CDK4, CDK6, RB1 and E2F,

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1. ACOG Practice Bulletin No. 188 Summary: Prelabor Rupture of Membranes. Obstet Gynecol. 2018;131:187-189.
2. Menon R, Richardson LS. Preterm prelabor rupture of the membranes: A disease of the fetal membranes. Semin Perinatol.2017;41:409-419.
3. Tchirikov M, Schlabritz-Loutsevitch N, Maher J, Buchmann J, Naberezhnev Y, Winarno AS, et al. Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome. J Perinat Med. 2018; 26;46:465-488.
4. Practice Bulletin No. 160: Premature Rupture of Membranes. Obstet Gynecol. 2016; 127(1):e39-e51.
5. Medina TM, Hill DA. Preterm premature rupture of membranes: diagnosis and management. Am Fam Physician. 2006;15;73:659-64.
6. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes. Obstet Gynecol. 2018;131:e1-e14.
7. Sultana Z, Maiti K, Dedman L, Smith R. Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction? Am J Obstet Gynecol. 2018;218:S762-S773.
8. Menon R, Boldogh I, Hawkins HK, Woodson M, Polettini J, Syed TA, et al. Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro. Am J Pathol. 2014;184:1740-51.
9. Agarwal P, Kabir F M L, DeInnocentes P and Bird R C. Tumor Suppressor Gene p16/INK4A/CDKN2A and Its Role in Cell Cycle Exit, Differentiation, and Determination of Cell Fate DOI: 10.5772/27882
10. Peurala E, Koivunen P, Haapasaari KM, Bloigu R, Jukkola-Vuorinen A. The prognostic significance and value of cyclin D1, CDK4 and p16 in human breast cancer. Breast Cancer Res. 2013 ; 21;15:R5.
11. Cha JM, Aronoff DM. A role for cellular senescence in birth timing. Cell Cycle. 2017; 16:2023-2031.
12. Sikora E, Bielak-Żmijewska A, Mosieniak G. What is and what is not cell senescence.Postepy Biochem. 2018 ; 15;64:110-118
13. Lanigan F, Geraghty JG, Bracken AP. Transcriptional regulation of cellular senescence.Oncogene. 2011; 30;30:2901-11.
14. Menon R. Oxidative stress damage as a detrimental factor in preterm birth pathology. Front Immunol. 2014 ; 12;5:567.
15. Feng L, Allen TK, Marinello WP, Murtha AP. Roles of Progesterone Receptor Membrane Component 1 in Oxidative Stress-Induced Aging in Chorion Cells. Reprod Sci. 2019;26:394-403.
16. Dutta EH, Behnia F, Boldogh I, Saade GR, Taylor BD, Kacerovský M, et al. Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes. Mol Hum Reprod. 2016;22:143-57.
17. Menon R, Boldogh I, Hawkins HK, Woodson M, Polettini J, Syed TA, et al. Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro. Am J Pathol. 2014;184:1740-51.
18. Lavu N, Richardson L, Radnaa E, Kechichian T, Urrabaz-Garza R, Sheller-Miller S, et al. Oxidative stress-induced downregulation of glycogen synthase kinase 3 beta in fetal membranes promotes cellular senescence†. Biol Reprod. 2019; 21;101:1018-1030.
19. Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15:482-96.
20. Frey N, Venturelli S, Zender L, Bitzer M. Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat Rev Gastroenterol Hepatol. 2018;15:81-95.
21. Broude EV, Swift ME, Vivo C, Chang BD, Davis BM, Kalurupalle S, et al p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation. Oncogene. 2007 ; 18;26:6954-8.
22. Nuzzo AM, Giuffrida D, Masturzo B, Mele P, Piccoli E, Eva C, et al. Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise.Cell Cycle. 2017 ; 17;16:200-212.
23. Tzadikevitch Geffen K, Gal H, Vainer I, Markovitch O, Amiel A, Krizhanovsky V, et al. Senescence and Telomere Homeostasis Might Be Involved in Placenta Percreta-Preliminary Investigation. Reprod Sci. 2018;25:1254-1260.
24. Gal H, Lysenko M, Stroganov S, Vadai E, Youssef SA, Tzadikevitch-Geffen K, et al. Molecular pathways of senescence regulate placental structure and function. EMBO J. 2019 ; 16;38:e100849.
25. Scaife PJ, Simpson A, Kurlak LO, Briggs LV, Gardner DS, Broughton Pipkin F, et al. Increased Placental Cell Senescence and Oxidative Stress in Women with Pre-Eclampsia and Normotensive Post-Term Pregnancies. Int J Mol Sci. 2021; 22: 7295
26. Cindrova-Davies T, Fogarty NME, Jones CJP, Kingdom J, Burton GJ. Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas. Placenta. 2018;68:15-22.