Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid

Yijun Xia; Youbin Wang; Mengjie Shan; Yan Hao; Hao Liu; Qiao Chen; Zhengyun Liang

doi:10.1093/burnst/tkac025

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Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid

更新时间：2023-09-05

- Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid
- Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid
- Burns & Trauma 2022年10卷第1期
- 作者机构：
  
  1. Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College
  2. Department of Plastic Surgery, Peking Union Medical College Hospital
- 作者简介：
- 基金信息：
  
  This study was supported by The National Natural Science Foundation of China (81871538) and Beijing Municipal Commission of Science and Technology (Z191100006619009).
- DOI：10.1093/burnst/tkac025
  中图分类号：
- 纸质出版日期：2022，
  
  网络出版日期：2022-6-25，
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Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid[J]. Burns & Trauma, 2022,10(1).

Yijun Xia, Youbin Wang, Mengjie Shan, Yan Hao, Hao Liu, Qiao Chen, Zhengyun Liang, Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid, Burns & Trauma, Volume 10, 2022, tkac025, https://doi.org/10.1093/burnst/tkac025
Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid[J]. Burns & Trauma, 2022,10(1). DOI： 10.1093/burnst/tkac025.

Yijun Xia, Youbin Wang, Mengjie Shan, Yan Hao, Hao Liu, Qiao Chen, Zhengyun Liang, Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid, Burns & Trauma, Volume 10, 2022, tkac025, https://doi.org/10.1093/burnst/tkac025 DOI：

摘要

Abstract

Keloid scarring is a kind of pathological healing manifestation after skin injury and possesses various tumor properties

such as the Warburg effect

epithelial–mesenchymal transition (EMT)

expression imbalances of apoptosis-related genes and the presence of stem cells. Abnormal expression of tumor signatures is critical to the initiation and operation of these effects. Although previous experimental studies have recognized the potential value of a single or several tumor biomolecules in keloids

a comprehensive evaluation system for multiple tumor signatures in keloid scarring is still lacking. This paper aims to summarize tumor biomolecules in keloids from the perspectives of liquid biopsy

genetics

proteomics and epigenetics and to investigate their mechanisms of action and feasibility from bench to bedside. Liquid biopsy is suitable for the early screening of people with keloids due to its noninvasive and accurate performance. Epigenetic biomarkers do not require changes in the gene sequence and their reversibility and tissue specificity make them ideal therapeutic targets. Nonetheless

given the ethnic specificity and genetic predisposition of keloids

more large-sample multicenter studies are indispensable for determining the prevalence of these signatures and for establishing diagnostic criteria and therapeutic efficacy estimations based on these molecules.

关键词

Keywords

Tumor signaturesKeloidProteomeEpigeneticsExosomesTumor biomoleculesBiomarkers

references

1.Tan S, Khumalo N, Bayat A. Understanding keloid pathobiology from a quasi-neoplastic perspective: less of a scar and more of a chronic inflammatory disease with cancer-like tendencies. Front Immunol. 2019;10:1810. https://doi.org/10.3389/fimmu.2019.01810.

2.Ogawa R. Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis. Int J Mol Sci. 2017;18:606. https://doi.org/10.3390/ijms18030606.

3.Macarak EJ, Wermuth PJ, Rosenbloom J, Uitto J. Keloid disorder: fibroblast differentiation and gene expression profile in fibrotic skin diseases. Exp Dermatol. 2021;30:132–45.

4.Al-Attar A, Mess S, Thomassen JM, Kauffman CL, Davison SP. Keloid pathogenesis and treatment. Plast Reconstr Surg. 2006;117:286–300.

5.Park TH, Park JH, Tirgan MH, Halim AS, Chang CH. Clinical implications of single- versus multiple-site keloid disorder: a retrospective study in an Asian population. Ann Plast Surg. 2015;74:248–51.

6.Ogawa R. Keloid and hypertrophic scarring may result from a mechanoreceptor or mechanosensitive nociceptor disorder. Med Hypotheses. 2008;71:493–500.

7.Butler PD, Longaker MT, Yang GP. Current progress in keloid research and treatment. J Am Coll Surg. 2008;206:731–41.

8.Arno AI, Amini-Nik S, Blit PH, Al-Shehab M, Belo C, Herer E, et al. Effect of human Wharton's jelly mesenchymal stem cell paracrine signaling on keloid fibroblasts. Stem Cells Transl Med. 2014;3:299–307.

9.Hahn JM, McFarland KL, Combs KA, Supp DM. Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1. Burns Trauma. 2016;4:30. https://doi.org/10.1186/s41038-016-0055-7.

10.Lim KH, Itinteang T, Davis PF, Tan ST. Stem cells in keloid lesions: a review. Plast Reconstr Surg Glob Open. 2019;7:e2228. https://doi.org/10.1097/GOX.0000000000002228.

11.Kawarazaki A, Horinaka M, Yasuda S, Numajiri T, Nishino K, Sakai T. Sulforaphane suppresses cell growth and collagen expression of keloid fibroblasts. Wound Repair Regen. 2017;25:224–33.

12.Jian X, Qu L, Wang Y, Zou Q, Zhao Q, Chen S, Gao X, Chen H, He C. Trichostatin A-induced miR-30a-5p regulates apoptosis and proliferation of keloid fibroblasts via targeting BCL2. Mol Med Rep. 2019;19:5251–62.

13.Shi K, Qiu X, Zheng W, Yan D, Peng W. MiR-203 regulates keloid fibroblast proliferation, invasion, and extracellular matrix expression by targeting EGR1 and FGF2. Biomed Pharmacother. 2018;108:1282–8.

14.Wentzensen N, Clarke MA. Liquid biopsy for cancer detection: clinical and epidemiologic considerations. Clin Cancer Res. 2021;27:5733–5.

15.Keup C, Suryaprakash V, Hauch S, Storbeck M, Hahn P, Sprenger-Haussels M, et al. Integrative statistical analyses of multiple liquid biopsy analytes in metastatic breast cancer. Genome Med. 2021;13:85. https://doi.org/10.1186/s13073-021-00902-1.

16.Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol. 2019;16:409–24.

17.Xu H, Zhu Z, Hu J, Sun J, Wo Y, Wang X, et al. Downregulated cytotoxic CD8(+) T-cell identifies with the NKG2A-soluble HLA-E axis as a predictive biomarker and potential therapeutic target in keloids. Cell Mol Immunol. 2022;19:527–39.

18.Chen H, Chengalvala V, Hu H, Sun D. Tumor-derived exosomes: Nanovesicles made by cancer cells to promote cancer metastasis. Acta Pharm Sin B. 2021;11:2136–49.

19.Liu J, Ren L, Li S, Li W, Zheng X, Yang Y, et al. The biology, function, and applications of exosomes in cancer. Acta Pharm Sin B. 2021;11:2783–97.

20.Li M, Jiang M, Meng J, Tao L. Exosomes: carriers of pro-fibrotic signals and therapeutic targets in fibrosis. Curr Pharm Des. 2019;25:4496–509.

21.Qin XJ, Zhang JX, Wang RL. Exosomes as mediators and biomarkers in fibrosis. Biomark Med. 2020;14:697–712.

22.Lin F, Zeng Z, Song Y, Li L, Wu Z, Zhang X, et al. YBX-1 mediated sorting of miR-133 into hypoxia/reoxygenation-induced EPC-derived exosomes to increase fibroblast angiogenesis and MEndoT. Stem Cell Res Ther. 2019;10:263. https://doi.org/10.1186/s13287-019-1377-8.

23.Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFβ Signaling. Molecular Cancer Research: MCR. 2018;16:1196–204.

24.Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70:9621–30.

25.Xie F, Wen G, Sun W, Jiang K, Chen T, Chen S, et al. Mechanical stress promotes angiogenesis through fibroblast exosomes. Biochem Biophys Res Commun. 2020;533:346–53.

26.He C, Zheng S, Luo Y, Wang B. Exosome Theranostics: biology and translational medicine. Theranostics. 2018;8:237–55.

27.Sheridan C. Exosome cancer diagnostic reaches market. Nat Biotechnol. 2016;34:359–60.

28.Li Q, Fang L, Chen J, Zhou S, Zhou K, Cheng F, et al. Exosomale microRNA-21 promotes keloid fibroblast proliferation and collagen production by inhibiting Smad7. J Burn Care Res. 2021;42:1266–74.

29.Li Y, Zhang J, Lei Y, Lyu L, Zuo R, Chen T. MicroRNA-21 in skin fibrosis: potential for diagnosis and treatment. Mol Diagn Ther. 2017;21:633–42.

30.Aheget H, Tristán-Manzano M, Mazini L, Cortijo-Gutierrez M, Galindo-Moreno P, Herrera C, Martin F, Marchal JA, Benabdellah K: Exosome: A new player in translational Nanomedicine. J Clin Med 2020;9:2380. https://doi.org/10.3390/jcm9082380.

31.Jiang L, Zhang Y, Liu T, Wang X, Wang H, Song H, et al. Exosomes derived from TSG-6 modified mesenchymal stromal cells attenuate scar formation during wound healing. Biochimie. 2020;177:40–9.

32.Hu S, Li Z, Cores J, Huang K, Su T, Dinh P-U, et al. Needle-free injection of exosomes derived from human dermal fibroblast spheroids ameliorates skin Photoaging. ACS Nano. 2019;13:11273–82.

33.Marneros AG, Norris JEC, Watanabe S, Reichenberger E, Olsen BR. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol. 2004;122:1126–32.

34.Roovers RC, Laeremans T, Huang L, De Taeye S, Verkleij AJ, Revets H, et al. Van Bergen en Henegouwen PMP: efficient inhibition of EGFR signaling and of tumour growth by antagonistic anti-EFGR Nanobodies. Cancer Immunology, Immunotherapy: CII. 2007;56:303–17.

35.Chin GS, Liu W, Steinbrech D, Hsu M, Levinson H, Longaker MT. Cellular signaling by tyrosine phosphorylation in keloid and normal human dermal fibroblasts. Plast Reconstr Surg. 2000;106:1532–40.

36.Tsai C-H, Ogawa R. Keloid research: current status and future directions. Scars, Burns & Healing. 2019;5:2059513119868659. https://doi.org/10.1177/2059513119868659.

37.Dmytrzak A, Boroń A, Łoniewska B, Lewandowska K, Gorący I, Kaczmarczyk M, et al. Two functional genetic variants and predisposition to keloid scarring in Caucasians. Dermatol Res Pract. 2019;2019:6179063. https://doi.org/10.1155/2019/6179063.

38.Jiao H, Dong P, Yan L, Yang Z, Lv X, Li Q, et al. TGF-β1 induces Polypyrimidine tract-binding protein to Alter fibroblasts proliferation and fibronectin deposition in keloid. Sci Rep. 2016;6:38033. https://doi.org/10.1038/srep38033.

39.Saed GM, Ladin D, Olson J, Han X, Hou Z, Fivenson D. Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing. Arch Dermatol. 1998;134:963–7.

40.Liu Y-b, Gao J-h, Duan H-j, Liu X-j. Investigation of p53 gene mutations in keloids using PCR-SSCP. Chin J Burns. 2003;19:258–60.

41.Nyika DT, Khumalo N, Bayat A. Genetics and epigenetics of keloids. Adv Wound Care. 2022;11:192–201.

42.Brown JJ, Ollier WER, Thomson W, Bayat A. Positive association of HLA-DRB1*15 with keloid disease in Caucasians. Int J Immunogenet. 2008;35:303–7.

43.Lu W-S, Wang J-F, Yang S, Xiao F-L, Quan C, Cheng H, et al. Association of HLA-DQA1 and DQB1 alleles with keloids in Chinese Hans. J Dermatol Sci. 2008;52:108–17.

44.Cao ZD, Liu W. Examining the pathogenesis and therapeutic strategy of keloids from the perspective of systemic inflammation. Chin J Burns. 2020;36:334–8.

45.Ogawa R, Akaishi S. Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis - keloids and hypertrophic scars may be vascular disorders. Med Hypotheses. 2016;96:51–60.

46.Suarez E, Syed F, Alonso-Rasgado T, Bayat A. Identification of biomarkers involved in differential profiling of hypertrophic and keloid scars versus normal skin. Arch Dermatol Res. 2015;307:115–33.

47.Sayah DN, Soo C, Shaw WW, Watson J, Messadi D, Longaker MT, et al. Downregulation of apoptosis-related genes in keloid tissues. J Surg Res. 1999;87:209–16.

48.Teofoli P, Barduagni S, Ribuffo M, Campanella A, De Pita O, Puddu P. Expression of Bcl-2, p53, c-Jun and c-fos protooncogenes in keloids and hypertrophic scars. J Dermatol Sci. 1999;22:31–7.

49.Hu Z, Lou L, Luo S. Experimental study of the expression of c-myc, c-fos and proto-oncogenes on hypertrophic and scars. Chin J Burns. 2002;18:165–7.

50.De Felice B, Ciarmiello LF, Mondola P, Damiano S, Seru R, Argenziano C, et al. Differential p63 and p53 expression in human keloid fibroblasts and hypertrophic scar fibroblasts. DNA Cell Biol. 2007;26:541–7.

51.Chen ZY, Yu XF, Huang JQ, Li DL. The mechanisms of β-catenin on keloid fibroblast cells proliferation and apoptosis. Eur Rev Med Pharmacol Sci. 2018;22:888–95.

52.Igota S, Tosa M, Murakami M, Egawa S, Shimizu H, Hyakusoku H, et al. Identification and characterization of Wnt signaling pathway in keloid pathogenesis. Int J Med Sci. 2013;10:344–54.

53.Yu D, Shang Y, Yuan J, Ding S, Luo S, Hao L. Wnt/β-catenin Signaling exacerbates keloid cell proliferation by regulating telomerase. Cell Physiol Biochem. 2016;39:2001–13.

54.Hamburg-Shields E, DiNuoscio GJ, Mullin NK, Lafyatis R, Atit RP. Sustained β-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes. J Pathol. 2015;235:686–97.

55.Canfield AE, Hadfield KD, Rock CF, Wylie EC, Wilkinson FL. HtrA1: a novel regulator of physiological and pathological matrix mineralization? Biochem Soc Trans. 2007;35:669–71.

56.Yamawaki S, Naitoh M, Kubota H, Aya R, Katayama Y, Ishiko T, et al. HtrA1 is specifically up-regulated in active keloid lesions and stimulates keloid development. Int J Mol Sci. 2018;19:1275. https://doi.org/10.3390/ijms19051275.

57.Jiao H, Zhang T, Fan J, Xiao R. The superficial dermis may initiate keloid formation: histological analysis of the keloid dermis at different depths. Front Physiol. 2017;8:885. https://doi.org/10.3389/fphys.2017.00885.

58.Shin JU, Kim SH, Kim H, Noh JY, Jin S, Park CO, et al. TSLP is a potential initiator of collagen synthesis and an activator of CXCR4/SDF-1 Axis in keloid pathogenesis. J Invest Dermatol. 2016;136:507–15.

59.Campbell CA, Burdick MD, Strieter RM. Systemic Fibrocyte levels and keloid expression of the chemoattractant CXCL12 are upregulated compared with patients with normal scar. Ann Plast Surg. 2021;87:150–5. https://doi.org/10.1097/SAP.0000000000002929.

60.Zhang M, Xu Y, Liu Y, Cheng Y, Zhao P, Liu H, et al. Chemokine-like factor 1 (CKLF-1) is overexpressed in keloid patients: a potential indicating factor for keloid-predisposed individuals. Medicine. 2016;95:e3082. https://doi.org/10.1097/MD.0000000000003082.

61.Dong X, Zhang M, Chen Y, Li C, Wang Y, Jin X. A comparison expression analysis of CXCR4, CXCL9 and Caspase-9 in dermal vascular endothelial cells between keloids and normal skin on chemotaxis and apoptosis. J Plast Surg Hand Surg. 2022;56:93–102.

62.Campbell CA, Burdick MD, Strieter RM. Systemic Fibrocyte levels and keloid expression of the chemoattractant CXCL12 are upregulated compared with patients with normal scar. Ann Plast Surg. 2021;87:150–5.

63.Le Huu D, Matsushita T, Jin G, Hamaguchi Y, Hasegawa M, Takehara K, et al. IL-6 blockade attenuates the development of murine sclerodermatous chronic graft-versus-host disease. J Invest Dermatol. 2012;132:2752–61.

64.Juhl P, Bondesen S, Hawkins CL, Karsdal MA, Bay-Jensen A-C, Davies MJ, et al. Dermal fibroblasts have different extracellular matrix profiles induced by TGF-β, PDGF and IL-6 in a model for skin fibrosis. Sci Rep. 2020;10:17300. https://doi.org/10.1038/s41598-020-74179-6.

65.Luckett LR, Gallucci RM. Interleukin-6 (IL-6) modulates migration and matrix metalloproteinase function in dermal fibroblasts from IL-6KO mice. Br J Dermatol. 2007;156:1163–71.

66.Uchida G, Yoshimura K, Kitano Y, Okazaki M, Harii K. Tretinoin reverses upregulation of matrix metalloproteinase-13 in human keloid-derived fibroblasts. Exp Dermatol. 2003;12:35–42.

67.Imaizumi R, Akasaka Y, Inomata N, Okada E, Ito K, Ishikawa Y, et al. Promoted activation of matrix metalloproteinase (MMP)-2 in keloid fibroblasts and increased expression of MMP-2 in collagen bundle regions: implications for mechanisms of keloid progression. Histopathology. 2009;54:722–30.

68.Fujiwara M, Muragaki Y, Ooshima A. Keloid-derived fibroblasts show increased secretion of factors involved in collagen turnover and depend on matrix metalloproteinase for migration. Br J Dermatol. 2005;153:295–300.

69.Gauglitz GG, Bureik D, Zwicker S, Ruzicka T, Wolf R. The antimicrobial peptides psoriasin (S100A7) and koebnerisin (S100A15) suppress extracellular matrix production and proliferation of human fibroblasts. Skin Pharmacol Physiol. 2015;28:115–23.

70.Kuwatsuka Y, Murota H. Involvement of Periostin in skin function and the pathogenesis of skin diseases. Adv Exp Med Biol. 2019;1132:89–98.

71.Supp DM, Hahn JM, Glaser K, McFarland KL, Boyce ST. Deep and superficial keloid fibroblasts contribute differentially to tissue phenotype in a novel in vivo model of keloid scar. Plast Reconstr Surg. 2012;129:1259–71.

72.Subraman V, Thiyagarajan M, Malathi N, Rajan ST. OPN-revisited. J Clin Diagn Res. 2015;9:ZE10–3. https://doi.org/10.7860/JCDR/2015/12872.6111.

73.Miragliotta V, Pirone A, Donadio E, Abramo F, Ricciardi MP, Theoret CL. Osteopontin expression in healing wounds of horses and in human keloids. Equine Vet J. 2016;48:72–7.

74.Shevtsov M, Multhoff G. Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Front Immunol. 2016;7:171. https://doi.org/10.3389/fimmu.2016.00171.

75.Calderwood SK, Gong J. Heat shock proteins promote cancer: It's a protection racket. Trends Biochem Sci. 2016;41:311–23.

76.Totan S, Echo A, Yuksel E. Heat shock proteins modulate keloid formation. Eplasty. 2011;11:e21.

77.Chen JJ, Zhao S, Cen Y, Liu XX, Yu R, Wu DM. Effect of heat shock protein 47 on collagen accumulation in keloid fibroblast cells. Br J Dermatol. 2007;156:1188–95.

78.Leite de Oliveira R, Hamm A, Mazzone M. Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies. Mol Asp Med. 2011;32:71–87.

79.Cho WC, Jour G, Aung PP. Role of angiogenesis in melanoma progression: update on key angiogenic mechanisms and other associated components. Semin Cancer Biol. 2019;59:175–86.

80.Tanaka R, Umeyama Y, Hagiwara H, Ito-Hirano R, Fujimura S, Mizuno H, et al. Keloid patients have higher peripheral blood endothelial progenitor cell counts and CD34(+) cells with normal vasculogenic and angiogenic function that overexpress vascular endothelial growth factor and interleukin-8. Int J Dermatol. 2019;58:1398–405.

81.Tanaka R, Umeyama Y, Hagiwara H, Ito-Hirano R, Fujimura S, Mizuno H, et al. Keloid patients have higher peripheral blood endothelial progenitor cell counts and CD34 cells with normal vasculogenic and angiogenic function that overexpress vascular endothelial growth factor and interleukin-8. Int J Dermatol. 2019;58:1398–405.

82.Syed F, Bayat A. Notch signaling pathway in keloid disease: enhanced fibroblast activity in a Jagged-1 peptide-dependent manner in lesional vs. extralesional fibroblasts. Wound Repair Regen. 2012;20:688–706.

83.Syed F, Bayat A. Notch signaling pathway in keloid disease: enhanced fibroblast activity in a Jagged-1 peptide-dependent manner in lesional vs. extralesional fibroblasts. Wound Repair Regen. 2012;20:688–706.

84.Jiang D-y, Fu X-b, Chen W, Sun T-z. Relationship of overexpression of angiogenesis factors and their receptors with invasive growth of keloid. Chinese Journal of Plastic Surgery. 2004;20:128–31.

85.Jiang DY, Fu XB, Chen W, Sun TZ. Relationship of overexpression of angiogenesis factors and their receptors with invasive growth of keloid. Zhonghua Zheng Xing Wai Ke Za Zhi. 2004;20:128–31.

86.Wu WS, Wang FS, Yang KD, Huang CC, Kuo YR. Dexamethasone induction of keloid regression through effective suppression of VEGF expression and keloid fibroblast proliferation. J Invest Dermatol. 2006;126:1264–71.

87.Ogawa R, Akaishi S. Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis - keloids and hypertrophic scars may be vascular disorders. Med Hypotheses. 2016;96:51–60.

88.Ong CT, Khoo YT, Tan EK, Mukhopadhyay A, Do DV, Han HC, et al. Epithelial-mesenchymal interactions in keloid pathogenesis modulate vascular endothelial growth factor expression and secretion. J Pathol. 2007;211:95–108.

89.Jumper N, Paus R, Bayat A. Functional histopathology of keloid disease. Histol Histopathol. 2015;30:1033–57.

90.Kurokawa N, Ueda K, Tsuji M. Study of microvascular structure in keloid and hypertrophic scars: density of microvessels and the efficacy of three-dimensional vascular imaging. J Plast Surg Hand Surg. 2010;44:272–7.

91.Li Q, Qin Z, Nie F, Bi H, Zhao R, Pan B, et al. Metabolic reprogramming in keloid fibroblasts: aerobic glycolysis and a novel therapeutic strategy. Biochem Biophys Res Commun. 2018;496:641–7.

92.Vincent AS, Phan TT, Mukhopadhyay A, Lim HY, Halliwell B, Wong KP. Human skin keloid fibroblasts display bioenergetics of cancer cells. J Invest Dermatol. 2008;128:702–9.

93.Lei R, Li J, Liu F, Li W, Zhang S, Wang Y, et al. HIF-1α promotes the keloid development through the activation of TGF-β/Smad and TLR4/MyD88/NF-κB pathways. Cell Cycle. 2019;18:3239–50.

94.Lin X, Wang Y, Jiang Y, Xu M, Pang Q, Sun J, et al. Sumoylation enhances the activity of the TGF-β/SMAD and HIF-1 signaling pathways in keloids. Life Sci. 2020;255:117859. https://doi.org/10.1016/j.lfs.2020.117859.

95.Hong KH, Yoo SA, Kang SS, Choi JJ, Kim WU, Cho CS. Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts. Clin Exp Immunol. 2006;146:362–70.

96.Persa OD, Niessen CM. Epithelial polarity limits EMT. Nat Cell Biol. 2019;21:299–300.

97.Venhuizen JH, Jacobs FJC, Span PN, Zegers MM. P120 and E-cadherin: double-edged swords in tumor metastasis. Semin Cancer Biol. 2020;60:107–20.

98.Do DV, Ong CT, Khoo YT, Carbone A, Lim CP, Wang S, et al. Interleukin-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions. Br J Dermatol. 2012;166:1275–88. https://doi.org/10.1111/j.1365-2133.2011.10721.x.

99.Yan L, Cao R, Liu Y, Wang L, Pan B, Lv X, et al. MiR-21-5p links epithelial-mesenchymal transition phenotype with stem-like cell signatures via AKT Signaling in keloid keratinocytes. Sci Rep. 2016;6:28281. https://doi.org/10.1038/srep28281.

100.Yan L, Wang LZ, Xiao R, Cao R, Pan B, Lv XY, et al. Inhibition of microRNA-21-5p reduces keloid fibroblast autophagy and migration by targeting PTEN after electron beam irradiation. Lab Investig. 2020;100:387–99. https://doi.org/10.1038/s41374-019-0323-9.

101.Lim CP, Phan TT, Lim IJ, Cao X. Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration. Oncogene. 2006;25:5416–25.

102.Lee WJ, Park JH, Shin JU, Noh H, Lew DH, Yang WI, et al. Endothelial-to-mesenchymal transition induced by Wnt 3a in keloid pathogenesis. Wound Repair Regen. 2015;23:435–42.

103.Ma X, Chen J, Xu B, Long X, Qin H, Zhao RC, et al. Keloid-derived keratinocytes acquire a fibroblast-like appearance and an enhanced invasive capacity in a hypoxic microenvironment in vitro. Int J Mol Med. 2015;35:1246–56.

104.Zhang M, Liu S, Guan E, Liu H, Dong X, Hao Y, et al. Hyperbaric oxygen therapy can ameliorate the EMT phenomenon in keloid tissue. Medicine (Baltimore). 2018;97:e11529. https://doi.org/10.1097/md.0000000000011529.

105.Macarak EJ, Wermuth PJ, Rosenbloom J, Uitto J. Keloid disorder: fibroblast differentiation and gene expression profile in fibrotic skin diseases. Exp Dermatol. 2021;30:132–45.

106.Qu M, Song N, Chai G, Wu X, Liu W. Pathological niche environment transforms dermal stem cells to keloid stem cells: a hypothesis of keloid formation and development. Med Hypotheses. 2013;81:807–12.

107.Zhang YX, Liu LP, Li M, Huang JL, Xu H, Chen XD, et al. Development of individualized induced pluripotent stem cells from fibroblasts of keloid lesions in patients. Transplant Proc. 2018;50:2868–71.

108.Simandi Z, Horvath A, Wright LC, Cuaranta-Monroy I, De Luca I, Karolyi K, et al. OCT4 acts as an integrator of pluripotency and signal-induced differentiation. Mol Cell. 2016;63:647–61.

109.Zhang Q, Yamaza T, Kelly AP, Shi S, Wang S, Brown J, et al. Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis. PLoS One. 2009;4:e7798. https://doi.org/10.1371/journal.pone.0007798.

110.Lee SY, Kim EK, Seo HB, Choi JW, Yoo JH, Jung KA, et al. IL-17 induced stromal cell-derived Factor-1 and Profibrotic factor in keloid-derived skin fibroblasts via the STAT3 pathway. Inflammation. 2020;43:664–72.

111.Bagabir RA, Syed F, Shenjere P, Paus R, Bayat A. Identification of a potential molecular diagnostic biomarker in keloid disease: Syndecan-1 (CD138) is overexpressed in keloid scar tissue. J Invest Dermatol. 2016;136:2319–23.

112.Couchman JR. Syndecan-1 (CD138), carcinomas and EMT. Int J Mol Sci. 2021;22:4227. https://doi.org/10.3390/ijms22084227.

113.Cui J, Jin S, Jin C, Jin Z. Syndecan-1 regulates extracellular matrix expression in keloid fibroblasts via TGF-β1/Smad and MAPK signaling pathways. Life Sci. 2020;254:117326. https://doi.org/10.1016/j.lfs.2020.117326.

114.Stevenson AW, Melton PE, Moses EK, Wallace HJ, Wood FM, Rea S, et al. A Methylome and transcriptome analysis of normal human scar cells reveals a role for FOXF2 in scar maintenance. J Invest Dermatol. 2021;142:1489–98.

115.Shin JU, Lee WJ, Tran T-N, Jung I, Lee JH. Hsp70 knockdown by siRNA decreased collagen production in keloid fibroblasts. Yonsei Med J. 2015;56:1619–26.

116.Yun IS, Lee MH, Rah DK, Lew DH, Park J-C, Lee WJ. Heat shock protein 90 inhibitor (17-AAG) induces apoptosis and decreases cell migration/motility of keloid fibroblasts. Plast Reconstr Surg. 2015;136:44e–53. https://doi.org/10.1097/PRS.0000000000001362.

117.Tan KT, McGrouther DA, Day AJ, Milner CM, Bayat A. Characterization of hyaluronan and TSG-6 in skin scarring: differential distribution in keloid scars, normal scars and unscarred skin. J Eur Acad Dermatol Venereol. 2011;25:317–27.

118.Li X-Y, Weng X-J, Li X-J, Tian X-Y. TSG-6 inhibits the growth of keloid fibroblasts via mediating the TGF-β1/Smad Signaling pathway. J Invest Surg. 2021;34:947–56.

119.Li X, Chen Z, Li X, Wang H. In vitro analysis of the role of tumor necrosis factor-stimulated gene-6 in keloid. Mol Med Rep. 2019;19:919–26.

120.Zhang Q, Oh CK, Messadi DV, Duong HS, Kelly AP, Soo C, et al. Hypoxia-induced HIF-1 alpha accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells: involvement of ERK1/2 and PI-3K/Akt. Exp Cell Res. 2006;312:145–55.

121.Song KX, Liu S, Zhang MZ, Liang WZ, Liu H, Dong XH, et al. Hyperbaric oxygen therapy improves the effect of keloid surgery and radiotherapy by reducing the recurrence rate. J Zhejiang Univ Sci B. 2018;19:853–62.

122.Long F, Si L, Long X, Yang B, Wang X, Zhang F. 2ME2 increase radiation-induced apoptosis of keloid fibroblasts by targeting HIF-1α in vitro. Australas J Dermatol. 2016;57:e32–8. https://doi.org/10.1111/ajd.12340.

123.Si L, Zhang M, Guan E, Han Q, Liu Y, Long X, et al. Resveratrol inhibits proliferation and promotes apoptosis of keloid fibroblasts by targeting HIF-1α. J Plast Surg Hand Surg. 2020;54:290–6.

124.Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK. miRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov. 2016;6:235–46.

125.Sandiford OA, Moore CA, Du J, Boulad M, Gergues M, Eltouky H, et al. Human aging and cancer: role of miRNA in tumor microenvironment. Adv Exp Med Biol. 2018;1056:137–52.

126.Xu M, Sun J, Yu Y, Pang Q, Lin X, Barakat M, et al. TM4SF1 involves in miR-1-3p/miR-214-5p-mediated inhibition of the migration and proliferation in keloid by regulating AKT/ERK signaling. Life Sci. 2020;254:117746. https://doi.org/10.1016/j.lfs.2020.117746.

127.Huang Y, Wang Y, Lin L, Wang P, Jiang L, Liu J, et al. Overexpression of miR-133a-3p inhibits fibrosis and proliferation of keloid fibroblasts by regulating IRF5 to inhibit the TGF-β/Smad2 pathway. Mol Cell Probes. 2020;52:101563. https://doi.org/10.1016/j.mcp.2020.101563.

128.Feng J, Xue S, Pang Q, Rang Z, Cui F. miR-141-3p inhibits fibroblast proliferation and migration by targeting GAB1 in keloids. Biochem Biophys Res Commun. 2017;490:302–8.

129.Wang R, Bai Z, Wen X, Du H, Zhou L, Tang Z, et al. MiR-152-3p regulates cell proliferation, invasion and extracellular matrix expression through by targeting FOXF1 in keloid fibroblasts. Life Sci. 2019;234:116779. https://doi.org/10.1016/j.lfs.2019.116779.

130.Zhu W, Wu X, Yang B, Yao X, Cui X, Xu P, et al. miR-188-5p regulates proliferation and invasion via PI3K/Akt/MMP-2/9 signaling in keloids. Acta Biochim Biophys Sin. 2019;51:185–96.

131.Xu Z, Guo B, Chang P, Hui Q, Li W, Tao K. The differential expression of miRNAs and a preliminary study on the mechanism of miR-194-3p in keloids. Biomed Res Int. 2019;2019:8214923. https://doi.org/10.1155/2019/8214923.

132.Xu Q, Jiang S. miR-194-5p serves a suppressive role in human keloid fibroblasts via targeting NR2F2. Mol Med Rep. 2021;2357. https://doi.org/10.3892/mmr.2020.11695.

133.Kashiyama K, Mitsutake N, Matsuse M, Ogi T, Saenko VA, Ujifuku K, et al. miR-196a downregulation increases the expression of type I and III collagens in keloid fibroblasts. J Invest Dermatol. 2012;132:1597–604.

134.Yang J, Deng P, Qi Y, Feng X, Wen H, Chen F. NEAT1 knockdown inhibits keloid fibroblast progression by miR-196b-5p/FGF2 Axis. J Surg Res. 2021;259:261–70.

135.Shi K, Qiu X, Zheng W, Yan D, Peng W. MiR-203 regulates keloid fibroblast proliferation, invasion, and extracellular matrix expression by targeting EGR1 and FGF2. Biomed Pharmacother. 2018;108:1282–8.

136.Yuan W, Sun H, Yu L. Long non-coding RNA LINC01116 accelerates the progression of keloid formation by regulating miR-203/SMAD5 axis. Burns. 2021;47:665–75.

137.Tang H, Chen Q, Yu W, Zhao T. MiR-4328 inhibits proliferation, metastasis and induces apoptosis in keloid fibroblasts by targeting BCL2 expression. Open Life Sci. 2020;15:638–46.

138.Liu P, Hu Y, Xia L, Du M, Hu Z. miR-4417 suppresses keloid fibrosis growth by inhibiting CyclinD1. J Biosci. 2020;45:47.

139.Wu ZY, Lu L, Liang J, Guo XR, Zhang PH, Luo SJ. Keloid microRNA expression analysis and the influence of miR-199a-5p on the proliferation of keloid fibroblasts. Genetics and Molecular Research: GMR. 2014;13:2727–38.

140.El-Kott AF, Shati AA, Ali Al-Kahtani M, Alharbi SA. The apoptotic effect of resveratrol in ovarian cancer cells is associated with downregulation of galectin-3 and stimulating miR-424-3p transcription. J Food Biochem. 2019;43:e13072. https://doi.org/10.1111/jfbc.13072.

141.Zhang J, Xu D, Li N, Li Y, He Y, Hu X, et al. Downregulation of microRNA-31 inhibits proliferation and induces apoptosis by targeting in human keloid. Oncotarget. 2017;8:74623–34.

142.Rang Z, Wang Z-Y, Pang Q-Y, Wang Y-W, Yang G, Cui F. MiR-181a targets PHLPP2 to augment AKT Signaling and regulate proliferation and apoptosis in human keloid fibroblasts. Cell Physiol Biochem. 2016;40:796–806.

143.Yang D, Li M, Du N. Effects of the circ_101238/miR-138-5p/CDK6 axis on proliferation and apoptosis keloid fibroblasts. Exp Ther Med. 2020;20:1995–2002.

144.Wu W, Xie F, Zhang Y, Wang X, Xia L, Wu X, et al. A novel regulatory function for miR-217 targetedly suppressing fibronectin expression in keloid fibrogenesis. Int J Clin Exp Pathol. 2018;11:1866–77.

145.Wang Z, Feng C, Song K, Qi Z, Huang W, Wang Y. lncRNA-H19/miR-29a axis affected the viability and apoptosis of keloid fibroblasts through acting upon COL1A1 signaling. J Cell Biochem. 2020;121:4364–76.

146.Wu D, Zhou J, Tan M, Zhou Y. LINC01116 regulates proliferation, migration, and apoptosis of keloid fibroblasts by the TGF-β1/SMAD3 signaling via targeting miR-3141. Anal Biochem. 2021;627:114249. https://doi.org/10.1016/j.ab.2021.114249.

147.Lv W, Ren Y, Wu M, Luo X, Yu J, Zhang Q, et al. Identifying miRNA modules associated with progression of keloids through weighted gene co-expression network analysis and experimental validation in vitro. Burns: J Int Soc Burn Injur. 2021;47:1359–72.

148.Chao L, Hua-Yu Z, Wen-Dong B, Mei S, Bin X, Da-Hai H, et al. miR-96 promotes collagen deposition in keloids by targeting Smad7. Exp Ther Med. 2019;17:773–81.

149.Su X, Ma Y, Wang Q, Gao Y. LncRNA HOXA11-AS aggravates keloid progression by the regulation of HOXA11-AS-miR-205-5p-FOXM1 pathway. J Surg Res. 2021;259:284–95.

150.Yao X, Cui X, Wu X, Xu P, Zhu W, Chen X, et al. Tumor suppressive role of miR-1224-5p in keloid proliferation, apoptosis and invasion via the TGF-β1/Smad3 signaling pathway. Biochem Biophys Res Commun. 2018;495:713–20.

151.Pang Q, Wang Y, Xu M, Xu J, Xu S, Shen Y, et al. MicroRNA-152-5p inhibits proliferation and migration and promotes apoptosis by regulating expression of Smad3 in human keloid fibroblasts. BMB Rep. 2019;52:202–7.

152.Zhang Y, Guo B, Hui Q, Li W, Chang P, Tao K. Downregulation of miR-637 promotes proliferation and metastasis by targeting Smad3 in keloids. Mol Med Rep. 2018;18:1628–36.

153.Zhu H-Y, Bai W-D, Li C, Zheng Z, Guan H, Liu J-Q, et al. Knockdown of lncRNA-ATB suppresses autocrine secretion of TGF-β2 by targeting ZNF217 via miR-200c in keloid fibroblasts. Sci Rep. 2016;6:24728. https://doi.org/10.1038/srep24728.

154.Liu Y, Ren L, Liu W, Xiao Z. MiR-21 regulates the apoptosis of keloid fibroblasts by caspase-8 and the mitochondria-mediated apoptotic signaling pathway via targeting FasL. Biochem Cell Biol. 2018;96:548–55.

155.Hou Z, Fan F, Liu P. BTXA regulates the epithelial-mesenchymal transition and autophagy of keloid fibroblasts via modulating miR-1587/miR-2392 targeted ZEB2. Biosci Rep. 2019;39:BSR20190679. https://doi.org/10.1042/BSR20190679.

156.Li J, Meng H, Bai Y, Wang K. Regulation of lncRNA and its role in cancer metastasis. Oncol Res. 2016;23:205–17.

157.Li J, Zhang X, Liu C. The computational approaches of lncRNA identification based on coding potential: status quo and challenges. Comput Struct Biotechnol J. 2020;18:3666–77.

158.Wang C, Wang L, Ding Y, Lu X, Zhang G, Yang J, et al. LncRNA structural characteristics in epigenetic regulation. Int J Mol Sci. 2017;18:2659. https://doi.org/10.3390/ijms18122659.

159.Dhamija S, Diederichs S. From junk to master regulators of invasion: lncRNA functions in migration, EMT and metastasis. Int J Cancer. 2016;139:269–80.

160.McCabe EM, Rasmussen TP. lncRNA involvement in cancer stem cell function and epithelial-mesenchymal transitions. Semin Cancer Biol. 2021;75:38–48.

161.Zhang J, Le TD, Liu L, Li J. Inferring and analyzing module-specific lncRNA-mRNA causal regulatory networks in human cancer. Brief Bioinform. 2019;20:1403–19.

162.Deng Y, Xu Y, Xu S, Zhang Y, Han B, Liu Z, et al. Secondary data mining of GEO database for long non-coding RNA and competing endogenous RNA network in keloid-prone individuals. Aging. 2020;12:25076–89.

163.Xu L, Sun N, Li G, Liu L. LncRNA H19 promotes keloid formation through targeting the miR-769-5p/EIF3A pathway. Mol Cell Biochem. 2021;476:1477–87.

164.Wan J, He X-L, Jian Q-C, Fan Z-F, Shi Y, Luo L-F. LINC00937 suppresses keloid fibroblast proliferation and extracellular matrix deposition by targeting the miR-28-5p/MC1R axis. Histol Histopathol. 2021;36:995–1005.

165.Jin J, Jia Z-H, Luo X-H, Zhai H-F. Long non-coding RNA HOXA11-AS accelerates the progression of keloid formation via miR-124-3p/TGFβR1 axis. Cell Cycle. 2020;19:218–32.

166.Jin J, Zhai H-F, Jia Z-H, Luo X-H. Long non-coding RNA HOXA11-AS induces type I collagen synthesis to stimulate keloid formation via sponging miR-124-3p and activation of Smad5 signaling. Am J Physiol Cell Physiol. 2019;317:C1001–10. https://doi.org/10.1152/ajpcell.00319.2018.

167.Duan X, Wu Y, Zhang Z, Lu Z. Identification and analysis of dysregulated lncRNA and associated ceRNA in the pathogenesis of keloid. Ann Transl Med. 2020;8:222. https://doi.org/10.21037/atm.2020.01.07.

168.Zhao X, Jie X, Gao Y-K, Nie B, Jiang H. Long non-coding RNA CACNA1G-AS1 promotes proliferation and invasion and inhibits apoptosis by regulating expression of miR-205 in human keloid fibroblasts. Biosci Rep. 2020;40:BSR20192839. https://doi.org/10.1042/BSR20192839.

169.Yin Y, Long J, He Q, Li Y, Liao Y, He P, et al. Emerging roles of circRNA in formation and progression of cancer. J Cancer. 2019;10:5015–21.

170.Zhang HD, Jiang LH, Sun DW, Hou JC, Ji ZL. CircRNA: a novel type of biomarker for cancer. Breast Cancer. 2018;25:1–7.

171.Lv W, Liu S, Zhang Q, Hu W, Wu Y, Ren Y. Circular RNA CircCOL5A1 sponges the MiR-7-5p/Epac1 Axis to promote the progression of keloids through regulating PI3K/Akt Signaling pathway. Front Cell Dev Biol. 2021;9:626027. https://doi.org/10.3389/fcell.2021.626027.

172.Wang B, Yin H, Zhang H, Wang T. circNRIP1 facilitates keloid progression via FXR1-mediated upregulation of miR-503-3p and miR-503-5p. Int J Mol Med. 2021;47:70. https://doi.org/10.3892/ijmm.2021.4903.

173.Shi J, Yao S, Chen P, Yang Y, Qian M, Han Y, et al. The integrative regulatory network of circRNA and microRNA in keloid scarring. Mol Biol Rep. 2020;47:201–9.

174.Zhang Z, Yu K, Liu O, Xiong Y, Yang X, Wang S, et al. Expression profile and bioinformatics analyses of circular RNAs in keloid and normal dermal fibroblasts. Exp Cell Res. 2020;388:111799. https://doi.org/10.1016/j.yexcr.2019.111799.

175.Chater-Diehl E, Goodman SJ, Cytrynbaum C, Turinsky AL, Choufani S, Weksberg R. Anatomy of DNA methylation signatures: emerging insights and applications. Am J Hum Genet. 2021;108:1359–66.

176.Wang R, Xu J. Genomic DNA methylation and histone methylation. Yi Chuan. 2014;36:191–9.

177.Jones LR, Young W, Divine G, Datta I, Chen KM, Ozog D, et al. Genome-wide scan for methylation profiles in keloids. Dis Markers. 2015;2015:943176. https://doi.org/10.1155/2015/943176.

178.Russell SB, Russell JD, Trupin KM, Gayden AE, Opalenik SR, Nanney LB, et al. Epigenetically altered wound healing in keloid fibroblasts. J Invest Dermatol. 2010;130:2489–96.

179.Zhang G, Guan Q, Chen G, Qian F, Liang J. DNA methylation of the CDC2L1 gene promoter region decreases the expression of the CDK11p58 protein and reduces apoptosis in keloid fibroblasts. Arch Dermatol Res. 2018;310:107–15.

180.Liu J, Zhu H, Wang H, Li J, Han F, Liu Y, et al. Methylation of secreted frizzled-related protein 1 (SFRP1) promoter downregulates Wnt/β-catenin activity in keloids. J Mol Histol. 2018;49:185–93.

181.Houseman EA, Kim S, Kelsey KT, Wiencke JK. DNA methylation in whole blood: uses and challenges. Curr Environ Health Rep. 2015;2:145–54.

182.Raut JR, Guan Z, Schrotz-King P, Brenner H: Whole-blood DNA methylation markers for risk stratification in colorectal cancer screening: : a systematic review. Cancers (Basel) 2019;11:912. https://doi.org/10.3390/cancers11070912.

183.Cowan LA, Talwar S, Yang AS. Will DNA methylation inhibitors work in solid tumors? A review of the clinical experience with azacitidine and decitabine in solid tumors. Epigenomics. 2010;2:71–86.

184.Guzzetta AA, Pisanic Ii TR, Sharma P, Yi JM, Stark A, Wang TH, et al. The promise of methylation on beads for cancer detection and treatment. Expert Rev Mol Diagn. 2014;14:845–52.

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