Di̇yabeti̇k Gebeli̇kte Homeobox A1 Ekspresyonu: İmmünohi̇stoki̇myasal ve Kompütasyonel Perspekti̇fler

Yıl 2025, Cilt: 22 Sayı: 2, 265 - 271, 27.06.2025

Ayşenur Sevinç Akdeniz , Gül Ebru Aydeniz Acar Zeynep Türe , Ayşegül Aşır , Ozan Akdeniz Ayfer Aktaş , Fırat Aşır , Tuğcan Korak , Elif Ağaçayak

https://doi.org/10.35440/hutfd.1639075

Öz

Amaç: Bu çalışmada, gestasyonel diyabet mellitus (GDM) hastalarına ait plasentalarda Homeobox A Cluster 1 (HOXA1) proteininin ekspresyonu immünohistokimyasal yöntemlerle değerlendirilmiş ve HOXA1'in GDM ile ilişkili biyolojik mekanizmalardaki rolü hesaplamalı analizlerle araştırılmıştır.
Materyal ve Metod: Çalışmaya 40 sağlıklı gebe ve 40 GDM tanılı gebe olmak üzere toplam 80 kadın dahil edilmiştir. Plasentalar, hematoksilen-eozin ve HOXA1 immün boyama yöntemleriyle histolojik olarak incelenmiştir. Ayrıca, HOXA1 ve GDM ile ilişkili proteinler STRING veri tabanından elde edilerek Cytoscape programı kullanılarak ortak etkileşim ağları analiz edilmiş, düğüm merkeziliği (degree, close-ness, betweenness) belirlenmiş ve gen ontolojisi (GO) moleküler fonksiyon analizleri yapılmıştır.
Bulgular: Histopatolojik analizde GDM grubunda villöz dejenerasyon, fibrin birikimi, hemoraji, sinsityal düğüm oluşumu ve lökosit infiltrasyonunda anlamlı artış saptanmıştır. İmmünohistokimyasal analizde, HOXA1 ekspresyonu GDM grubunda kontrol grubuna kıyasla belirgin şekilde artmıştır. Hesaplamalı analizlerde, HOXA1 ve GDM ağlarının kesişiminde 15 ortak protein belirlenmiş, H3C12, H3-3B, H3C13 ve ESR1 proteinleri ağın en merkezi düzenleyici proteinleri olarak tanımlanmıştır. GO analizi, bu pro-teinlerin kromatin organizasyonu, DNA bağlanması, epigenetik düzenleme ve protein-protein etkileşim-leri gibi temel moleküler süreçlerle ilişkili olduğunu göstermiştir.
Sonuç: GDM, plasental dokularda önemli histopatolojik ve moleküler değişikliklere yol açmakta, HOXA1 proteininin ekspresyonunda artış ile ilişkilendirilmektedir. HOXA1, GDM'ye bağlı plasental disfonksiyo-nun moleküler mekanizmalarında rol oynayabilecek potansiyel bir biyobelirteç ve hedef molekül olarak öne çıkmaktadır.

Anahtar Kelimeler

HOXA1 , GESTASYONEL DİYABETES MELLİTUS , PLASENTA , TOPOLOJİK ANALİZ , BİYOİNFORMATİK

Homeobox A1 Expression in Diabetic Pregnancy: Immunohistochemical and Computational Perspectives

Öz

Background: This study aimed to evaluate the expression of Homeobox A Cluster 1 (HOXA1) protein in placentas from patients with gestational diabetes mellitus (GDM) using immunohistochemical tech-niques and to investigate the role of HOXA1 in GDM-associated biological mechanisms through compu-tational analyses.
Materials and Methods: A total of 80 participants, including 40 healthy pregnant women and 40 wom-en diagnosed with GDM, were enrolled. Placental tissues were examined histologically using hematoxy-lin-eosin and HOXA1 immunostaining. Additionally, HOXA1 and GDM-related proteins were retrieved from the STRING database and analyzed using Cytoscape software to identify shared interaction net-works, determine node centrality (degree, closeness, betweenness), and perform Gene Ontology (GO) molecular function analyses.
Results: Histopathological analysis revealed significant increases in villous degeneration, fibrin deposi-tion, hemorrhage, syncytial knot formation, and leukocyte infiltration in the GDM group. Immunohisto-chemical analysis demonstrated a marked upregulation of HOXA1 protein expression in the GDM group compared to controls. Computational analyses identified 15 shared proteins within the HOXA1 and GDM networks, with H3C12, H3-3B, H3C13, and ESR1 emerging as central regulatory proteins. GO analysis indicated that these proteins are primarily involved in chromatin organization, DNA binding, epigenetic regulation, and protein–protein interactions.
Conclusions: GDM induces significant histopathological and molecular changes in placental tissues, associated with increased HOXA1 protein expression. HOXA1 may play a critical role in the molecular mechanisms underlying GDM-related placental dysfunction and could serve as a potential biomarker and therapeutic target.

Anahtar Kelimeler

HOXA1 , GESTATİONAL DIABETES MELLITUS , PLACENTA , TOPOLOGİCAL ANALYSİS , BIOINFIRMATICAL ANALYSIS

Kaynakça

• 1. Alfadhli EM. Gestational diabetes mellitus. Saudi medical journal. 2015;36(4):399.
• 2. Sweeting A, Wong J, Murphy HR, Ross GP. A clinical update on gestational diabetes mellitus. Endocrine reviews. 2022;43(5):763-93.
• 3. Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH. The pathophysiology of gestational diabetes mellitus. Internation-al journal of molecular sciences. 2018;19(11):3342.
• 4. Sert UY, Ozgu-Erdinc AS. Gestational diabetes mellitus screen-ing and diagnosis. Diabetes: from Research to Clinical Prac-tice: Volume 4: Springer; 2020. p. 231-55.
• 5. 5. Çelik Ö. Gestasyonel diyabet tanı ve tedavisi. Klinik Tıp Bilimleri. 2019;7(3):24-7.
• 6. Aydeniz Acar GE, Akdeniz AS, Türe Z, Aşır A, Acar M, Aşır F, et al. HOXA1 expression in placentas of woman with fetal growth restriction. Perinatal Journal. 2024;32(2).
• 7. Rezsohazy R, Saurin AJ, Maurel-Zaffran C, Graba Y. Cellular and molecular insights into Hox protein action. Development. 2015;142(7):1212-27.
• 8. Shenoy US, Adiga D, Kabekkodu SP, Hunter KD, Radhakrishnan R. Molecular implications of HOX genes targeting multiple signaling pathways in cancer. Cell biology and toxicology. 2022:1-30.
• 9. Aşır F, Oğlak SC, Ağaçayak E, Alabalık U. Homeobox A Cluster 7 (HOXA7) protein expression increased in the placentas of pa-tients with preterm delivery. Perinatal Journal. 2023;31(3):213-8.
• 10. 1TIP S. Gestasyonel diabetes mellitus tanısı. Selçuk Tıp Derg. 2014;30(1):39-41.
• 11. Crowe AR, Yue W. Semi-quantitative determination of protein expression using immunohistochemistry staining and analysis: an integrated protocol. Bio-protocol. 2019;9(24):e3465-e.
• 12. Scardoni G, Petterlini M, Laudanna C. Analyzing biological network parameters with CentiScaPe. Bioinformatics. 2009;25(21):2857-9.
• 13. Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic ac-ids research. 2022;50(W1):W216-W21.
• 14. Tang D, Chen M, Huang X, Zhang G, Zeng L, Zhang G, et al. SRplot: A free online platform for data visualization and gra-phing. PloS one. 2023;18(11):e0294236.
• 15. Zhang Z, Peng J, Li B, Wang Z, Wang H, Wang Y, Hong L. HOXA1 promotes aerobic glycolysis and cancer progression in cervical cancer. Cellular signalling. 2023;109:110747.
• 16. He L, Liang M, Guo W, Liu J, Yu Y. HOXA1 is a radioresistance marker in multiple cancer types. Frontiers in Oncology. 2022;12:965427.
• 17. Pustovrh M, Jawerbaum A, Capobianco E, White V, Lopez-Costa J, Gonzalez E. Increased matrix metalloproteinases 2 and 9 in placenta of diabetic rats at midgestation. Placenta. 2005;26(4):339-48.
• 18. Bernischke K, Kaufmann P, Baergen R. Pathology of the hu-man placenta. 4th edition: New-York Springer; 2000.
• 19. Desoye G, Shafrir E. The human placenta in diabetic pregnan-cy. Diabetes reviews. 1996;4(1):70-89.
• 20. Handwerger S, Freemark M. The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and development. Journal of Pediatric Endocri-nology and Metabolism. 2000;13(4):343-56.
• 21. Benirschke K, Kaufmann P, Benirschke K, Kaufmann P. Anato-my and pathology of the umbilical cord and major fetal ves-sels. Pathology of the human placenta. 2000:335-98.
• 22. Farrar D, Simmonds M, Bryant M, Sheldon T, Tuffnell D, Gold-er S, et al. Hyperglycaemia and risk of adverse perinatal out-comes: systematic review and meta-analysis. Obstetric Anes-thesia Digest. 2017;37(2):64-5.
• 23. Meyrueix LP, Gharaibeh R, Xue J, Brouwer C, Jones C, Adair L, et al. Gestational diabetes mellitus placentas exhibit epimu-tations at placental development genes. Epigenetics. 2022;17(13):2157-77.
• 24. Gheorghe CP, Goyal R, Mittal A, Longo LD. Gene expression in the placenta: maternal stress and epigenetic responses. The International journal of developmental biology. 2010;54(2-3):507.
• 25. Kohan-Ghadr H-R, Kadam L, Jain C, Armant DR, Drewlo S. Potential role of epigenetic mechanisms in regulation of trophoblast differentiation, migration, and invasion in the human placenta. Cell adhesion & migration. 2016;10(1-2):126-35.
• 26. Lizárraga D, García-Gasca A. The placenta as a target of epige-netic alterations in women with gestational diabetes mellitus and potential implications for the offspring. Epigenomes. 2021;5(2):13.