نقش مسیرهای سیگنال‌دهی، microRNAها و lncRNAها در پاتوفیزیولوژی اندومتریوز
محورهای موضوعی : زیست شناسی سلولی تکوینی گیاهی و جانوری ، تکوین و تمایز ، زیست شناسی میکروارگانیسم
رضا فانی کیسمی
1
,
فاطمه قاسمیان
2
*
1 - گروه زیست شناسی، دانشکده علوم پایه، دانشگاه گیلان، رشت، ایران
2 - گروه زیست شناسی-دانشکده علوم پایه- دانشگاه گیلان- رشت- ایران
کلید واژه: اندومتریوز, مسیرهای سیگنال‌دهی, micRNAs, LncRNAs.,
چکیده مقاله :
اندومتریوز یک بیماری مزمن وابسته به استروژن در زنان است که با رشد بافت مشابه آندومتر در خارج از رحم مشخص می‌شود و باعث درد لگن، ناباروری و التهاب می‌شود. با وجود تحقیقات گسترده، علت دقیق این بیماری همچنان نامشخص است. این مرور به بررسی جامع مکانیسم‌های مولکولی اندومتریوز می‌پردازد و بر عوامل ژنتیکی، مسیرهای سیگنال‌دهی، میکروRNAها (miRNAها) و RNAهای بلند غیرکدکننده (lncRNA) تمرکز دارد. استعداد ژنتیکی نقش مهمی ایفا می‌کند و پلی‌مورفیسم‌ها و جهش در ژن‌هایی مانند PTEN، TP53، KRAS و گیرنده‌های هورمونی با افزایش خطر ابتلا به بیماری مرتبط هستند. مسیرهای سیگنال‌دهی مختل‌شده از جمله MAPK، PI3K/Akt، Wnt/β-catenin و TGF-β منجر به تکثیر سلولی غیرطبیعی، تهاجم و مقاومت در برابر آپوپتوز می‌شوند. میکروRNAها با هدف‌گیری ژن‌های کلیدی دخیل در چسبندگی و مهاجرت، پاسخ‌های التهابی و فرآیندهای سلولی را تعدیل می‌کنند، در حالی که lncRNAها از طریق تعامل با RNA رقابتی (ceRNA)، بازسازی کروماتین و اتصال به پروتئین‌ها بیان ژن را تنظیم کرده و بر مسیرهایی مانند p38-MAPK و NF-κB تأثیر می‌گذارند. lncRNAهایی مانند MEG3-210 و MALAT1 نشان می‌دهند که چگونه عوامل ژنتیکی و اپی‌ژنتیکی بر رفتار سلولی در اندومتریوز تأثیر می‌گذارند. درک این شبکه‌های مولکولی پیچیده بینشی عمیق‌تر از پاتوژنز ارائه داده و اهداف درمانی بالقوه‌ای را برجسته می‌کند که نویدبخش درمان‌های مؤثرتر هستند.
Endometriosis is a chronic, estrogen-dependent gynecological disorder characterized by the growth of endometrial-like tissue outside the uterus, causing pelvic pain, infertility, and inflammation. Despite significant research, the exact etiology remains unclear. This review provides a comprehensive exploration of the molecular mechanisms underlying endometriosis, focusing on genetic factors, signaling pathways, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). Genetic predisposition plays a pivotal role, with polymorphisms and mutations in genes such as PTEN, TP53, KRAS, and hormone receptors linked to disease susceptibility. Dysregulated signaling pathways, including MAPK, PI3K/Akt, Wnt/β-catenin, and TGF-β, drive aberrant cellular proliferation, invasion, and resistance to apoptosis. miRNAs modulate inflammatory responses and cellular processes by targeting key genes involved in adhesion and migration, while lncRNAs regulate gene expression through competing endogenous RNA (ceRNA) interactions, chromatin remodeling, and protein binding, impacting pathways such as p38-MAPK and NF-κB. Specific lncRNAs like MEG3-210 and MALAT1 illustrate how genetic and epigenetic factors influence cellular behavior in endometriosis. Understanding these complex molecular networks enhances insights into pathogenesis and highlights potential therapeutic targets, offering hope for more effective treatment approaches.
[1] Ghasemian F, S Esmaeilnezhad S. Metformin, clomiphene citrate and flutamide effects on oocyte ultrastructure status and quality in PCOS mouse model. Reproductive BioMedicine Online, 2022; 2022;45(2):191-201.
[2] Ghasemian F, Faraji R, Asgharnia M, Zahiri Z, Bahadori MH. The impact of different time intervals between hCG priming and oocyte retrieval on ART outcomes. Iran J Reprod Med, 2013;11(7):559-564.
[3] Aghajani S, Salehzadeh A, Ghasemian F, Mehrafza M. The impact of maternal age on chromosomal aneuploidy, blastocyst quality, and pregnancy outcomes during intracytoplasmic sperm injection cycles. J Advanc Biomed Sci, 2021; 11: 4107-4117.
[4] Rohloff N, Götte M, Kiesel L. Regulation of proliferation and invasion in endometriosis. menstrual cycle related disorders. ISGE Series. Springer, Cham, 2019; 167-175.
[5] Leyland N, Estes SJ, Lessey BA, Advincula AP, Taylor HSA. Clinician’s guide to the treatment of endometriosis. J Women Health, 2020; 30: 569–578.
[6] Sridhar S, Gallant T, Brunn E. Overview of pathogenesis, symptoms, diagnosis, management, and prognosis of endometriosis and its role in infertility. J Gynecol Surgery, 2022; 38:3-6.
[7] Bora G, Yaba A. The role of mitogen-activated protein kinase signaling pathway in endometriosis. J Obstet Gynaecol Res, 2021;47(5):1610-1623.
[8] Santulli P, Marcellin L, Tosti C, Chouzenoux S, Cerles O, Borghese B, et al. MAP kinases and the inflammatory signaling cascade as targets for the treatment of endometriosis? Expert Opin Ther Targets, 2015;19(11):1465-83.
[9] Cho YJ, Lee SH, Park JW, Han M, Park MJ, Han SJ. Dysfunctional signaling underlying endometriosis: current state of knowledge. J Mol Endocrinol, 2018;60(3): R97-R113.
[10] Langan KL, Farrell ME, Keyser EA, Salyer BA, Burney RO. Endometriosis: translation of molecular insights to management. Minerva Endocrinol, 2014;39(3):141-54.
[11] Begum T, Chowdhury SR. Etiology and pathogenesis of endometriosis - a review. Mymensingh Med J, 2013;22(1):218-21.
[12] Rosales AAL, Rodríguez JAL, Mendoza AA, Medina AL, González EM, Rodríguez RA. Factors causing infertility in women diagnosed with endometriosis. Int J Med Scie Clinic Res Stud, 2022; 2(10),1099–1103.
[13] Saunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell, 2021; 184(11): 2807-2824.
[14] Painter J, Zondervan K, Montgomery G. Understanding the pathogenesis of endometriosis: Gene map stud, 2012; 54–64.
[15] Dun EC, Taylor RN, Wieser F. Advances in the genetics of endometriosis. Genome Med, 2010;2(10):75.
[16] Garai J, Molnar V, Varga T, Koppan M, Torok A, Bodis J. Endometriosis: harmful survival of an ectopic tissue. Front Biosci. 2006;11:595-619.
[17] Greene AD, Lang SA, Kendziorski JA, Sroga-Rios JM, Herzog TJ, Burns KA. Endometriosis: where are we and where are we going? Reproduction. 2016;152(3):R63-78.
[18] Wagstaff D, Becker CM. Do we know what causes endometriosis? British J Hospital Medicine, 2008; 69: 314-315.
[19] Králíčková M, Vetvicka V. Immunological aspects of endometriosis: a review. Ann Transl Med,. 2015;3(11):153.
[20] Izumi G, Koga K, Takamura M, Makabe T, Satake E, Takeuchi A, et al. Involvement of immune cells in the pathogenesis of endometriosis. J Obstet Gynaecol Res, 2018;44(2):191-198.
[21] Hoorsan H, Mirmiran P, Chaichian S, Chaichian S, Moradi Y, Akhlaghdoust M, et al. Diet and Risk of Endometriosis: A Systematic Review and Meta-Analysis Study. Iran Red Crescent Med J, 2017; 19(9):e41248.
[22] Signorile PG, Viceconte R, Baldi A. New Insights in Pathogenesis of Endometriosis. Front Med, 2022; 9:879015
[23] Lamceva J, Uljanovs R, Strumfa I. The Main Theories on the Pathogenesis of Endometriosis. Int J Mol Sci, 2023;24(5):4254.
[24] Fung J, Sapkota Y, Nyholt D, Montgomery G. Genetic risk factors for endometriosis. Journal of Endometriosis and Pelvic Pain Disorders, 2017;9(2):69-76.
[25] Saha R, Pettersson H, Svedberg P, Olovsson M, Bergqvist A, Marions L, et al. Heritability of endometriosis. Fertil Steril, 2015; 104:947-952.
[26] Hansen KA, Eyster KM. Genetics and genomics of endometriosis. Clin Obstet Gynecol, 2010;53(2):403-412.
[27] Rahmioglu N, Montgomery GW, Zondervan KT. Genetics of endometriosis. Womens Health (Lond). 2015;11(5):577-86.
[28] Krishnamoorthy K, Decherney AH. Genetics of Endometriosis. Clin Obstet Gynecol, 2017;60(3):531-538.
[29] Fung JN, Montgomery GW. Genetics of endometriosis: State of the art on genetic risk factors for endometriosis. Best Pract Res Clin Obstet Gynaecol. 2018;50:61-71.
[30] Bischoff F, Simpson JL. Genetic basis of endometriosis. Ann N Y Acad Sci, 2004;1034:284-99.
[31] Simpson JL, Bischoff FZ. Heritability and molecular genetic studies of endometriosis. Ann N Y Acad Sci, 2002;955:239-51; discussion 293-5, 396-406
[32] Matalliotakis M, Zervou MI, Matalliotaki C, Rahmioglu N, Koumantakis G, Kalogiannidis I, et al. The role of gene polymorphisms in endometriosis. Mol Med Rep, 2017;16(5):5881-5886.
[33] Lalami I, Abo C, Borghese B, Chapron C, Vaiman D. Genomics of Endometriosis: From Genome Wide Association Studies to Exome Sequencing. Int J Mol Sci, 2021;22(14):7297.
[34] Aghajani S, Salehzadeh A, Ghasemian F, Mehrafza M. Evaluating the expression of miRNAs in the culture medium of human embryos with normal sex chromosomes and embryos with an X sex chromosome (Turner syndrome). J Ilam University Medical Sciences, 2023; 4:68-78.
[35] Ghasemi F, Alemzadeh E, Allahqoli L, Alemzadeh E, Mazidimoradi A, Salehiniya H, et al. MicroRNAs dysregulation as potential biomarkers for early diagnosis of endometriosis. biomedicines, 2022; 10(10):2558.
[36] Dabi Y, Suisse S, Jornea L, Bouteiller D, Touboul C, Puchar A, et al. Clues for improving the pathophysiology knowledge for endometriosis using plasma micro-RNA expression. diagnostics (Basel), 2022;12(1):175.
[37] Raja MHR, Farooqui N, Zuberi N, Ashraf M, Azhar A, Baig R, et al. Endometriosis, infertility and microRNA's: A review. J Gynecol Obstet Hum Reprod, 2021;50(9):102157.
[38] Fazaeli H, Sheikholeslami A, Ghasemian F, Amini E. The emerging role of LncRNA FENDRR in multiple cancers: a review. Current Molecular Medicine, 2023; 23: 606-629.
[39] Wang Y, Li Y, Yang Z, Liu K, Wang D. Genome-wide microarray analysis of long non-coding RNAs in eutopic secretory endometrium with endometriosis. Cell Physiol Biochem, 2015;37(6):2231-2245.
[40] Panir K, Schjenken JE, Robertson SA, Hull ML. Non-coding RNAs in endometriosis: a narrative review. Hum Reprod Update, 2018;24(4):497-515.
[41] Yin M, Zhai L, Wang J, Yu Q, Li T, Xu X, et al. Comprehensive analysis of RNA-Seq in endometriosis reveals competing endogenous RNA network composed of circRNA, lncRNA and mRNA. Front Genet, 2022;13:828238.
[42] Liu Y, Huang X, Lu D, Feng Y, Xu R, Li X, Yin C, Xue B, Zhao H, Wang S, Ma Y, Jia C. LncRNA SNHG4 promotes the increased growth of endometrial tissue outside the uterine cavity via regulating c-Met mediated by miR-148a-3p. Mol Cell Endocrinol, 2020;514:110887.
[43] Yu J, Chen LH, Zhang B, Zheng QM. The modulation of endometriosis by lncRNA MALAT1 via NF-κB/iNOS. Eur Rev Med Pharmacol Sci, 2019;23(10):4073-4080.
[44] Li Y, Liu YD, Chen SL, Chen X, Ye DS, Zhou XY, et al. Down-regulation of long non-coding RNA MALAT1 inhibits granulosa cell proliferation in endometriosis by up-regulating P21 via activation of the ERK/MAPK pathway. Mol Hum Reprod, 2019;25(1):17-29.
[45] Liu J, Wang Y, Chen P, Ma Y, Wang S, Tian Y, et al. AC002454.1 and CDK6 synergistically promote endometrial cell migration and invasion in endometriosis. Reproduction, 2019;157(6), 535–543.
[46] Zhang M, Xu T, Tong D, Li S, Yu X, Liu B, et al. Research advances in endometriosis-related signaling pathways: A review. Biomed Pharmacother, 2023;164:114909.
[47] Ghafouri-Fard S, Shoorei H, Taheri M. Role of non-coding RNAs in the pathogenesis of endometriosis. Front Oncol. 2020 Aug 4;10:1370.
[48] Alkan AH, Akgül B. Endogenous miRNA sponges. Methods Mol Biol, 2022;2257:91-104.
[49] Figueroa-Bossi N, Bossi L. Sponges and predators in the small RNA world. Microbiol Spectr, 2018;6(4).
[50] Migault M, Donnou-Fournet E, Galibert MD, Gilot D. Definition and identification of small RNA sponges: Focus on miRNA sequestration. Methods, 2017;117:35-47.
[51] Ebert MS, Sharp PA. MicroRNA sponges: progress and possibilities. RNA, 2010;16(11):2043-50.
[52] Azam INA, Wahab NA, Mokhtar MH, Shafiee MN, Mokhtar NM. Roles of microRNAs in regulating apoptosis in the pathogenesis of endometriosis. Life (Basel), 2022;12(9):1321.
[53] Markowska A, Pawałowska M, Lubin J, Markowska J. Signalling pathways in endometrial cancer. Contemp Oncol (Pozn), 2014;18(3):143-148.
[54] Marí-Alexandre J, Sánchez-Izquierdo D, Gilabert-Estellés J, Barceló-Molina M, Braza-Boïls A, Sandoval J. miRNAs regulation and its role as biomarkers in endometriosis. Int J Mol Sci, 2016;17(1):93.
[55] Seifati SM, Parivar K, Aflatoonian A, Dehghani Firouzabadi R, Sheikhha MH. No association of GSTM1 null polymorphism with endometriosis in women from central and southern Iran. Iran J Reprod Med, 2012;10(1):23-28.
[56] Nothnick WB. MicroRNAs and progesterone receptor signaling in endometriosis pathophysiology. Cells, 2022;11(7):1096.
[57] Smolarz B, Szyłło K, Romanowicz H. The genetic background of endometriosis: can ESR2 and CYP19A1 genes be a potential risk factor for its development? Int J Mol Sci, 2020;21(21):8235.
[58] Sapkota Y, Low SK, Attia J, Gordon SD, Henders AK, Holliday EG, et al. Association between endometriosis and the interleukin 1A (IL1A) locus. Hum Reprod, 2015;30(1):239-48.
[59] Rabajdová M, Špaková I, Klepcová Z, Smolko L, Abrahamovská M, Urdzík P, et al. Zinc (II) niflumato complex effects on MMP activity and gene expression in human endometrial cell lines. Sci Rep. 2021;11(1):19086.
[60] Duan YW, Chen SX, Li QY, Zang Y. Neuroimmune mechanisms underlying neuropathic pain: The potential role of TNF-α-necroptosis pathway. Int J Mol Sci, 2022; 23(13):7191.
[61] Mai H, Wei Y, Yin Y, Huang S, Lin H, Liao Y, et al. LINC01541 overexpression attenuates the 17β-Estradiol-induced migration and invasion capabilities of endometrial stromal cells. Syst Biol Reprod Med, 2019;65(3):214-222.
[62] Qiu JJ, Lin XJ, Zheng TT, Tang XY, Zhang Y, Hua KQ. The Exosomal long noncoding RNA aHIF is upregulated in serum from patients with endometriosis and promotes angiogenesis in endometriosis. Reprod Sci, 2019;26(12):1590-1602.
[63] Hudson QJ, Proestling K, Perricos A, Kuessel L, Husslein H, Wenzl R, et al. The role of long non-coding RNAs in endometriosis. Int J Mol Sci, 2021; 22(21):11425.
[64] Wang H, Sha L, Huang L, Yang S, Zhou Q, Luo X, et al. LINC00261 functions as a competing endogenous RNA to regulate BCL2L11 expression by sponging miR-132-3p in endometriosis. Am J Transl Res, 2019;11(4):2269-2279.
[65] Liu H, Zhang Z, Xiong W, Zhang L, Du Y, Liu Y, et al. Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis. J Cell Mol Med, 2019;23(1):439-452.
[66] Feng Y, Tan BZ. LncRNA MALAT1 inhibits apoptosis of endometrial stromal cells through miR-126-5p-CREB1 axis by activating PI3K-AKT pathway. Mol Cell Biochem, 2020;475(1-2):185-194.
[67] Jiang L, Zhang M, Wang S, Xiao Y, Wu J, Zhou Y, et al. LINC01018 and SMIM25 sponged miR-182-5p in endometriosis revealed by the ceRNA network construction. Int J Immunopathol Pharmacol, 2020;34:2058738420976309.