Analýza imunohistochemického a genetického vzorce exprese kisspeptinu v endometriálních polypech

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Autoři: Şeyma İlayda Paltacı ¹ ; Özlem Kayacık Günday ¹ ; Müjgan Özdemir Erdoğan ² ; Fatma Fırat ³ ; Gülsüm Şeyma Yalçın ⁴ ; Nermin Akçalı ²
Působiště autorů: Department of Obstetrics and Gynecology, Faculty of Medicine, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Turkey ¹; Department of Genetics, Faculty of Medicine, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Turkey ²; Department of Histology and Embryology, Faculty of Medicine, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Turkey ³; Department of Pathology, Faculty of Medicine, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Turkey ⁴
Vyšlo v časopise: Ceska Gynekol 2024; 89(4): 269-277
Kategorie: Původní práce
doi: https://doi.org/10.48095/cccg2024269

Souhrn

Cíl: Endometriální polypy (EP) představují patologii, která je v klinické praxi běžná. Ačkoli jejich přesná etiologie není úplně známá, existují důkazy o tom, že jsou citlivé vůči hormonální stimulaci. Naším cílem bylo prozkoumat vztah mezi kisspeptinem (KP) a EP pomocí srovnání míry genetické exprese (tkáň–krev) a imunohistochemické (IHC) exprese KP v lézích EP u pacientek s normálním endometriálním nálezem. Materiál a metody: Byla provedena retrospektivní případová studie u 50 pacientek s EP (n = 25) a normálním endometriálním nálezem (n = 25) z biopsie a/nebo materiálu z excize. Krev a vzorky z biopsie od všech pacientek byly uchovávány při –80 °C. Exprese genů KP byla stanovena v parafinových blocích a vzorcích periferní žilní krve získaných z bioptických vzorků a analýza skóre IHC-H byla provedena na parafinových blocích. EP a příslušné kontroly byly srovnány z hlediska KP. Výsledky: Po IHC bylo KP-H skóre v kontrolní skupině vyšší než ve skupině s EP a tento rozdíl byl statisticky významný; H skóre: kontroly: 5 (++; 1–15); polypy: 1 (+; 0–12) (p < 0,05). Ačkoli byla exprese KP jak v tkáni, tak v krvi vyšší v kontrolní skupině oproti skupině s EP, tento rozdíl nebyl statisticky významný (p > 0,05). V krvi ani tkáni nebyla zjištěna významná korelace mezi IHC-H skóre a expresí KP. Podle analýzy ROC cut-off hodnoty exprese KP v tkáni a krvi a plocha pod křivkou (AUC), která predikuje pravděpodobnost vzniku EP, nebyly významné (KP v tkáni: 1,04; AUC: 0,570; p = 0,388; senzitivita 56 %, specificita 60 % / KP v krvi: 1,06; AUC: 0,569; p = 0,401; senzitivita 80 %, specificita 40 %). Závěry: Snížená míra exprese KP v lézích EP může predikovat diagnózu EP a v budoucnu může mít KP při benigních gynekologických patologiích, jako jsou polypy, terapeutický potenciál.

Klíčová slova:

imunohistochemie – endometrium – endometriální polypy – kisspeptin – PCR s reverzní transkripcí (RT-PCR)

Zdroje

1. Salim S, Won H, Nesbitt-Hawes E et al. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol 2011; 18 (5): 569–581. doi: 10.1016/j.jmig.2011.05.018.

2. Lee SC, Kaunitz AM, Sanchez-Ramos L et al. The oncogenic potential of endometrial polyps: a systematic review and meta-analysis. Obstet Gynecol 2010; 116 (5): 1197–1205. doi: 10.1097/ AOG.0b013e3181f4864.

3. Kim KR, Peng R, Ro JY et al. A diagnostically useful histopathologic feature of endometrial polyp: the long axis of endometrial glands arranged parallel to surface epithelium. Am J Surg Pathol 2004; 28 (8): 1057–1062. doi: 10.1097/01.pas.0000128659.73944.f3.

4. Lieng M, Istre O, Qvigstad E. Treatment of endometrial polyps: a systematic review. Acta Obstet Gynecol Scand 2010; 89 (8): 992–1002. doi: 10.3109/00016349.2010.493196.

5. Inceboz US, Nese N, Uyar Y et al. Hormone receptor expressions and proliferation markers in postmenopausal endometrial polyps. Gynecol Obstet Invest 2006; 61 (1): 24–28. doi: 10.1159/000088018.

6. Peng X, Li T, Xia E et al. A comparison of oestrogen receptor and progesterone receptor expression in endometrial polyps and endometrium of premenopausal women. J Obstet Gynaecol 2009; 29 (4): 340–346. doi: 10.1080/01443610902878775.

7. Dal Cin P, Vanni R, Marras S et al. Four cytogenetic subgroups can be identified in endometrial polyps. Cancer Res 1995; 55 (7): 1565–1568.

8. Jovanovic AS, Boynton KA, Mutter GL. Uteri of women with endometrial carcinoma contain a histopathological spectrum of monoclonal putative precancers, some with microsatellite instability. Cancer Res 1996; 56 (8): 1917–1921.

9. Pal L, Niklaus AL, Kim M et al. Heterogeneity in endometrial expression of aromatase in polyp-bearing uteri. Hum Reprod 2008; 23 (1): 80–84. doi: 10.1093/humrep/dem346.

10. Taylor LJ, Jackson TL, Reid JG et al. The differential expression of oestrogen receptors, progesterone receptors, Bcl-2 and Ki67 in endometrial polyps. BJOG 2003; 110 (9): 794–798.

11. Erdemoglu E, Güney M, Karahan N et al. Expression of cyclooxygenase-2, matrix metalloproteinase-2 and matrix metalloproteinase-9 in premenopausal and postmenopausal endometrial polyps. Maturitas 2008; 59 (3): 268–274. doi: 10.1016/j.maturitas.2008.02.007.

12. Nijkang NP, Anderson L, Markham R et al. Endometrial polyps: pathogenesis, sequelae and treatment. SAGE Open Med 2019; 7 : 2050312119848247. doi: 10.1177/20503121198 48247.

13. Ferrazzi E, Zupi E, Leone FP et al. How often are endometrial polyps malignant in asymptomatic postmenopausal women? A multicenter study. Am J Obstet Gynecol 2009; 200 (3): 235.e1 –⁠ –235.e6. doi: 10.1016/j.ajog.2008.09.876.

14. Elyashiv O, Sagiv R, Kerner R et al. Hysterscopic resection of premalignant and malignant endometrial polyps: is it a safe alternative to hysterectomy? J Minim Invasive Gynecol 2017; 24 (7): 1200–1203. doi: 10.1016/j.jmig.2017. 08.002.

15. Kotani M, Detheux M, Vandenbogaerde A et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001; 276 (37): 34631–34636. doi: 10.1074/jbc.M104847200.

16. Trevisan CM, Montagna E, de Oliveira R et al. Kisspeptin/GPR54 system: what do we know about its role in human reproduction? Cell Physiol Biochem 2018; 49 (4): 1259–1276. doi: 10.1159/000493406.

17. Cejudo Roman A, Pinto FM, Dorta I et al. Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract. Fertil Steril 2012; 97 (5): 1213–1219. doi: 10.1016/j.fertnstert.2012.02.021.

18. Casañ EM, Raga F, Bonilla-Musoles F et al. Human oviductal gonadotropin-releasing hormone: possible implications in fertilization, early embryonic development, and implantation. J Clin Endocrinol Metab 2000; 85 (4): 1377–1381. doi: 10.1210/jcem.85.4.6503.

19. Baba T, Kang HS, Hosoe Y et al. Menstrual cyclic change of metastin/GPR54 in endometrium. Med Mol Morphol 2015; 48 (2): 76–84. doi: 10.1007/s00795-014-0081-0.

20. León S, Fernandois D, Sull A et al. Beyond the brain-peripheral kisspeptin signaling is essential for promoting endometrial gland development and function. Sci Rep 2016; 6 : 29073. doi: 10.1038/srep29073.

21. Mead EJ, Maguire JJ, Kuc RE et al. Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. Br J Pharmacol 2007; 151 (8): 1143–1153. doi: 10.1038/sj.bjp.0707295.

22. Lee JH, Miele ME, Hicks DJ et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996; 88 (23): 1731–1737. doi: 10.1093/jnci/88.23.1731.

23. Guzman S, Brackstone M, Radovick S et al. KISS1/KISS1R in cancer: friend or foe? Front Endocrinol (Lausanne) 2018; 9 : 437. doi: 10.3389/fedo.2018.00437.

24. Kolioulis I, Zafrakas M, Grimbizis G et al. Immunohistochemical expression pattern of metastasis suppressor KISS-1 protein in adenomyosis lesions and normal endometrium. Eur J Obstet Gynecol Reprod Biol 2017; 210 : 64–68. doi: 10.1016/j.ejogrb.2016.12.004.

25. Yildirim E, Derici MK, Simsek OY et al. Is there a relationship between serum kisspeptin levels and endometrial polyps in women with premenopausal status. Ann Med Res 2019; 26 (7): 1253–1257. doi: 10.5455/annalsmedres. 2019.04.216.

26. Makri A, Msaouel P, Petraki C et al. KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis. In Vivo 2012; 26 (1): 119–127.

27. Owens LA, Abbara A, Lerner A et al. The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function. Hum Reprod 2018; 33 (2): 292–302. doi: 10.1093/humrep/dex357.

28. Gorkem U, Togrul C, Arslan E et al. Is there a role for kisspeptin in pathogenesis of polycystic ovary syndrome? Gynecol Endocrinol 2018; 34 (2): 157–160. doi: 10.1080/09513590. 2017.1379499.

29. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008; 39 (10): 1411–1419. doi: 10.1016/j.humpath.2008.06.025.

30. Qiao C, Wang CH, Shang T et al. Clinical significance of KiSS-1 and matrix metalloproteinase-9 expression in trophoblasts of women with preeclampsia and their relation to perinatal outcome of neonates. Zhonghua Fu Chan Ke Za Zhi 2005; 40 (9): 585–590.

31. Ciaramella V, Della Corte CM, Ciardiello F et al. Kisspeptin and cancer: molecular interaction, biological functions, and future perspectives. Front Endocrinol (Lausanne) 2018; 9 : 115. doi: 10.3389/fedo.2018.00115.

32. Çolak E, Erinanç HÖ, Eroglu S et al. KISS1, P53, and PTEN immunoexpressions and prediction of malignancy in endometrial intraepithelial neoplasia lesion within endometrial polyp: KISS1, P53 and PTEN in endometrial polyp. Med Sci Disc 2020; 7 (10): 663–669. doi: 10.36472/msd.v7i10.425.

33. Kang HS, Baba T, Mandai M et al. GPR54 is a target for suppression of metastasis in endometrial cancer. Mol Cancer Ther 2011; 10 (4): 580–590. doi: 10.1158/1535-7163.MCT-10-0763.

34. Zhang J, Jin L, Kong L et al. Physiological and pathological roles of locally expressed kisspeptin and KISS1R in the endometrium. Hum Reprod 2023; 38 (7): 1253–1260. doi: 10.1093/humrep/ dead080.

35. Ziegler E, Olbrich T, Emons G et al. Antiproliferative effects of kisspeptin-10 depend on artificial GPR54 (KISS1R) expression levels. Oncol Rep 2013; 29 (2): 549–554. doi: 10.3892/or.2012.2135.

36. Tan K, Cho SG, Luo W et al. KiSS1-induced GPR54 signaling inhibits breast cancer cell migration and epithelial-mesenchymal transition via protein kinase D1. Curr Mol Med 2014; 14 (5): 652–662. doi: 10.2174/1566524014666140603115314.

37. Abdelkareem AO, Alotaibi FT, AlKusayer GM et al. Immunoreactivity of kisspeptin and kisspeptin receptor in eutopic and ectopic endometrial tissue of women with and without endometriosis. Reprod Sci 2020; 27 (9): 1731–1741. doi: 10.1007/s43032-020-00167-w.

38. Yan C, Wang H, Boyd DD. KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha –⁠ induced block of p65/p50 nuclear translocation. J Biol Chem 2001; 276 (2): 1164–1172. doi: 10.1074/jbc.M008681200.

39. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell 2019; 176 (6): 1248–1264. doi: 10.1016/j.cell.2019.02.021.

40. Cho SG, Yi Z, Pang X et al. Kisspeptin-10, a KISS1-derived decapeptide, inhibits tumor angiogenesis by suppressing Sp1-mediated VEGF expression and FAK/Rho GTPase activation. Cancer Res 2009; 69 (17): 7062–7070. doi: 10.1158/0008-5472.CAN-09-0476.

41. Li C, Zhao HL, Li YJ et al. The expression and significance of leukemia inhibitory factor, interleukin-6 and vascular endothelial growth factor in Chinese patients with endometriosis. Arch Gynecol Obstet 2021; 304 (1): 163–170. doi: 10.1007/s00404-021-05980-5.

42. Xuebing P, TinChiu L, Enlan X et al. Is endometrial polyp formation associated with increased expression of vascular endothelial growth factor and transforming growth factor-beta1? Eur J Obstet Gynecol Reprod Biol 2011; 159 (1): 198–203. doi: 10.1016/j.ejogrb.2011.06.036.

43. Gao GL, Liu LD, Zou XS et al. Expression of KiSS-1, matrix metalloproteinase-9, nuclear factor-kappaBp65 in ovarian tumour. Zhonghua Fu Chan Ke Za Zhi 2007; 42 (1): 34–38.

44. Cvetkovic D, Dragan M, Leith SJ et al. KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells. Endocrinology 2013; 154 (6): 1999–2014. doi: 10.1210/en2012-2164.

45. Alcin E, Ozcan M, Ayar A et al. Effects of peripheral administration of kisspeptin on pubertal maturation and serum leptin levels in female rats. Turkiye Klinikleri Tip Bilimleri Dergisi 2011; 31 (6): 1477–1483. doi: 10.5336/medsci. 2010-21945.

46. Wahab F, Atika B, Shahab M et al. Kisspeptin signalling in the physiology and pathophysiology of the urogenital system. Nat Rev Urol 2016; 13 (1): 21–32. doi: 10.1038/nrurol.2015.277.

Authorship

ÖKG, SİP: concept and design

ÖKG, MÖE, FF, GŞY, NA: ccquisition, analysis, or interpretation of data

ÖKG, SİP: drafting of the manuscript

ÖKG, MÖE, FF, GŞY, NA: critical review of the manuscript for important intellectual content

ÖKG, MÖE, FF, GŞY, NA: supervision

ORCID authors

Ş. İ. Paltacı 0009-0006-1038-2075

Ö. K. Günday 0000-0002-9249-679X

M. Ö. Erdoğan 0000-0002-3434-8545

F. Fırat 0000-0003-0027-5138

G. Ş. Yalçın 0000-0002-1944-2955