Turkiye Klinikleri Journal of Dermatology

.: ORIGINAL RESEARCH
YAP/TAZ Sinyal Yolağının Mekanik Stres Kaynaklı Hipertrofik Skar Oluşumuna Etkisinin GEO2R ile Belirlenmesi: In Slico Analiz
Determination the Effect of YAP/TAZ Signaling Pathway on Mechanical Stress Induced Hypertrophic Scar Formation by GEO2R
Evin İŞCANa
aİzmir Biyotıp ve Genom Merkezi, İzmir, TÜRKİYE
bDokuz Eylül Üniversitesi İzmir Uluslararası Biyotıp ve Genom Enstitüsü, Biyotıp ve Sağlık Teknolojileri ABD, İzmir, TÜRKİYE
Turkiye Klinikleri J Dermatol. 2021;31(2):109-17
doi: 10.5336/dermato.2020-80691
Article Language: TR
Full Text
ÖZET
 Amaç: Hipertrofik skar travma, geçirilen ameliyatlar, yanık ve bazı cilt enfeksiyonları sonrası yaygın olarak görülebilen bir cilt sorunudur. Mevcut tedaviye verilen zayıf yanıt ve yüksek nüks oranları göz önüne alındığında hipertrofik skarların oluşumunun engellenmesinde hedeflenmiş, etkili topikal moleküler tedavi stratejilerinin belirlenmesine ve geliştirilmesine ihtiyaç vardır. YAP/TAZ, Hippo sinyal yolağı hedef molekülleridir. Bu çalışmada, mekanik stres kaynaklı hipertrofik skar oluşumunda rol alan YAP/TAZ hedef genlerinin belirlenmesi amaçlanmaktadır. Gereç ve Yöntemler: Mekanik stres kaynaklı hipertrofik skar oluşumunda rol oynayan genlerin ifade verisine 'Gene Expression Omnibus' veri tabanından erişildi. p<0,05 anlamlılık düzeyinde, 2 kat ve üzerinde değişim gösteren genlerin listesi oluşturuldu. Oluşturulan gen listesinde, YAP/TAZ sinyal yolağı hedef genleri belirlendi. Literatür taraması sonucunda, YAP/TAZ hedef genlerinin fonksiyonları belirlendi. Belirlenen genlerin etkileşim ağlarını ve rol oynadıkları sinyal yolaklarını bulmak için STRING protein etkileşim veritabanı kullanıldı. Bulgular: Anlamlı düzeyde değişim olan genlerin içinde YAP/TAZ sinyal yolağı hedef genlerinden; tenascin C, trombospondin 1, serin proteaz inhibitör 1'in ifadesinde artış gözlendi. Literatür taraması sonucunda bu genlerin yara iyileşmesi, hücre proliferasyonu, hücre farklılaşması ve hücre dışı matriksin yeniden yapılanmasında rol oynadıklarını gösterdik. Sonuç: Bu çalışmada, mekanik stres ile uyarılan hipertrofik skarlarda, YAP/TAZ sinyal iletim yolağının hedef genlerinin ifadesinin değiştiğini göstermiş bulunmaktayız. Hipertrofik skar oluşumunda YAP/TAZ sinyal yolağının rolünün belirlenmesine yönelik daha ileri çalışmaların yapılmasına ihtiyaç vardır.

Anahtar Kelimeler: Hipertrofik skar; YAP/TAZ sinyal iletim yolağı; GEO2R
ABSTRACT
 Objective: Hypertrophic scar is a common skin problem after trauma, previous surgeries, burns and some skin infections. Considering the weak response and high recurrence rates linked to current treatments, it is necessary to determine and develop effective topical molecular treatment strategies which could prevent the formation of hypertrophic scar. YAP and TAZ are effector molecules of the Hippo signaling. In this study, it is aimed to determine the YAP/TAZ target genes involved in the formation of the mechanical stress-induced hypertrophic scar. Material and Methods: The gene expression data implicated in the formation of mechanical stress-induced Hypertrophic scar accessed from the Gene Expression Omnibus database. Genes with a 2-fold or more change at p<0.05 significance level were included in the list. YAP/TAZ signaling target genes were determined among the upregulated genes. The functions of YAP/TAZ target genes were determined by literature searching. STRING protein interaction database was used to find the interaction networks of the identified genes and the signal pathways in which they play a role. Results: Among the genes with significant changes, YAP/TAZ signaling target genes tenascin C, thrombospondin 1, serine protease inhibitor 1 expressions were increased. As a result of the literature review, we showed that these genes play a role in wound healing, cell proliferation, cell differentiation, and remodeling of the extracellular matrix. Conclusion: In this study, we have shown that the YAP/TAZ signaling plays a role in mechanical stress-induced hypertrophic scar and further studies are needed to determine its role in the formation of hypertrophic scar.

Keywords: Hypertrophic scar; YAP/TAZ signaling; GE02R
REFERENCES:
  1. van den Broek LJ, Limandjaja GC, Niessen FB, Gibbs S. Human hypertrophic and keloid scar models: principles, limitations and future challenges from a tissue engineering perspective. Exp Dermatol. 2014;23(6):382-6. [Crossref]  [PubMed]  [PMC] 
  2. Rabello FB, Souza CD, Farina Júnior JA. Update on hypertrophic scar treatment. Clinics (Sao Paulo). 2014;69(8):565-73. [Crossref]  [PubMed]  [PMC] 
  3. Leventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic scars: a meta-analysis and review of the literature. Arch Facial Plast Surg. 2006;8(6):362-8. [Crossref]  [PubMed] 
  4. Mehta M, Branford OA, Rolfe KJ. The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring. Burns Trauma. 2016;4(1):15. [Crossref]  [PubMed]  [PMC] 
  5. Renò F, Sabbatini M, Lombardi F, Stella M, Pezzuto C, Magliacani G, et al. In vitro mechanical compression induces apoptosis and regulates cytokines release in hypertrophic scars. Wound Repair Regen. 2003;11(5):331-6. [Crossref]  [PubMed] 
  6. Costa AM, Peyrol S, Pôrto LC, Comparin JP, Foyatier JL, Desmoulière A. Mechanical forces induce scar remodeling. Study in non-pressure-treated versus pressure-treated hypertrophic scars. Am J Pathol. 1999;155(5): 1671-9. [Crossref]  [PubMed]  [PMC] 
  7. Nishimoto M, Uranishi K, Asaka MN, Suzuki A, Mizuno Y, Hirasaki M, et al. Transformation of normal cells by aberrant activation of YAP via cMyc with TEAD. Sci Rep. 2019;9(1): 10933. [Crossref]  [PubMed]  [PMC] 
  8. Dasgupta I, McCollum D. Control of cellular responses to mechanical cues through YAP/ TAZ regulation. J Biol Chem. 2019; 294 (46):17693-706. [Crossref]  [PubMed]  [PMC] 
  9. Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev. 2014;94(4):1287-312. [Crossref]  [PubMed] 
  10. Balazs L, Okolicany J, Ferrebee M, Tolley B, Tigyi G. Topical application of the phospholipid growth factor lysophosphatidic acid promotes wound healing in vivo. Am J Physiol Regul Integr Comp Physiol. 2001;280(2):R466-72. [Crossref]  [PubMed] 
  11. Rognoni E, Walko G. The Roles of YAP/TAZ and the hippo pathway in healthy and diseased skin. Cells. 2019;8(5):411. [Crossref]  [PubMed]  [PMC] 
  12. Wong VW, Rustad KC, Akaishi S, Sorkin M, Glotzbach JP, Januszyk M, et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med. 2011;18(1):148-52. [Crossref]  [PubMed]  [PMC] 
  13. Mo JS, Yu FX, Gong R, Brown JH, Guan KL. Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev. 2012;26(19):2138-43. [Crossref]  [PubMed]  [PMC] 
  14. Moroishi T, Park HW, Qin B, Chen Q, Meng Z, Plouffe SW, et al. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 2015;29(12):1271-84. [Crossref]  [PubMed]  [PMC] 
  15. Delve E, Co V, Regmi SC, Parreno J, Schmidt TA, Kandel RA. YAP/TAZ regulates the expression of proteoglycan 4 and tenascin C in superficial-zone chondrocytes. Eur Cell Mater. 2020;39:48-64. [Crossref]  [PubMed] 
  16. Kovar H, Bierbaumer L, Radic-Sarikas B. The YAP/TAZ pathway in osteogenesis and bone sarcoma pathogenesis. Cells. 2020;9(4):972. [Crossref]  [PubMed]  [PMC] 
  17. Yamashiro Y, Thang BQ, Ramirez K, Shin SJ, Kohata T, Ohata S, Nguyen TAV, Ohtsuki S, Nagayama K, Yanagisawa H. Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling. Proc Natl Acad Sci U S A. 2020;117(18):9896-905. [Crossref]  [PubMed]  [PMC] 
  18. Malakou LS, Gargalionis AN, Piperi C, Papadavid E, Papavassiliou AG, Basdra EK. Molecular mechanisms of mechanotransduction in psoriasis. Ann Transl Med. 2018;6(12):245. [Crossref]  [PubMed]  [PMC] 
  19. Lian N, Li T. Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications. Biomed Pharmacother. 2016;84:42-50. [Crossref]  [PubMed] 
  20. Bombaro KM, Engrav LH, Carrougher GJ, Wiechman SA, Faucher L, Costa BA, et al. What is the prevalence of hypertrophic scarring following burns? Burns. 2003;29(4):299-302. [Crossref]  [PubMed] 
  21. Walko G, Woodhouse S, Pisco AO, Rognoni E, Liakath-Ali K, Lichtenberger BM, et al. A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells. Nat Commun. 2017;8:14744. [Crossref]  [PubMed]  [PMC] 
  22. Zhang H, Pasolli HA, Fuchs E. Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci U S A. 2011; 108(6):2270-5. [Crossref]  [PubMed]  [PMC] 
  23. Zhao MJ, Chen SY, Qu XY, Abdul-Fattah B, Lai T, Xie M, et al. Increased Cthrc1 activates normal fibroblasts and suppresses keloid fibroblasts by ınhibiting TGF-β/smad signal pathway and modulating YAP subcellular location. Curr Med Sci. 2018;38(5):894-902. d [Crossref]  [PubMed] 
  24. Pocaterra A, Romani P, Dupont S. YAP/TAZ functions and their regulation at a glance. J Cell Sci. 2020;133(2):jcs230425. [Crossref]  [PubMed] 
  25. Aramaki-Hattori N, Okabe K, Hamada M, Takato T, Kishi K. Relationship between Keloid Formation and YAP/TAZ Signaling. Plast Reconstr Surg Glob Open. 2017;5(6):e1357. [Crossref]  [PubMed]  [PMC] 
  26. Jiang D, Guo B, Lin F, Hui Q, Tao K. Effect of THBS1 on the Biological Function of Hypertrophic Scar Fibroblasts. Biomed Res Int. 2020;2020:8605407. [Crossref]  [PubMed]  [PMC] 

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