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image of KIAA1429 Promotes Keloid Formation Through the TGF-Β1/Smad Pathway

Abstract

Background

Keloid formation is characterized by excessive production of extracellular matrix, leading to dysregulated fibroproliferative collagen response. N6-methyl-adenosine (m6A) modification plays an essential role in this process.

Objective

Our objective in this study was to explore the mechanism of m6A methyltransferase KIAA1429 in keloid formation.

Methods

We examined the impact of m6A methyltransferase KIAA1429 on keloid formation using qRT-PCR, Western blot, immunofluorescence, Transwell migration assay, and MeRIP-qPCR.

Results

KIAA1429 was downregulated in keloid tissue. Overexpression of KIAA1429 suppressed fibroblast migration and reduced COL1A1 and α-SMA levels. Conversely, the knockdown of KIAA1429 promoted fibroblast migration and COL1A1 and α-SMA levels. Additionally, overexpression of KIAA1429 inhibited the TGF-β1/Smad pathway. Mechanistic experiments suggested that KIAA1429 regulated TGF-β1 m6A modification, maintained TGF-β1 mRNA stability, and participated in the regulation of keloid formation. Furthermore, TGF-β1 could reverse the effects of KIAA1429 overexpression on fibroblast migration and collagen deposition.

Conclusion

Taken together, our study suggested that KIAA1429 promoted keloid formation through the TGF-β1/Smad pathway, providing new insights for the treatment of keloid.

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2024-11-07
2025-06-25
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References

  1. Lee C.C. Tsai C.H. Chen C.H. Yeh Y.C. Chung W.H. Chen C.B. An updated review of the immunological mechanisms of keloid scars. Front. Immunol. 2023 14 1117630 10.3389/fimmu.2023.1117630 37033989
    [Google Scholar]
  2. Walsh L.A. Wu E. Pontes D. Kwan K.R. Poondru S. Miller C.H. Kundu R.V. Keloid treatments: An evidence-based systematic review of recent advances. Syst. Rev. 2023 12 1 42 10.1186/s13643‑023‑02192‑7 36918908
    [Google Scholar]
  3. Hawash A.A. Ingrasci G. Nouri K. Yosipovitch G. Pruritus in keloid scars: Mechanisms and treatments. Acta Derm. Venereol. 2021 101 10 adv00582 10.2340/00015555‑3923 34518894
    [Google Scholar]
  4. Qiu Z. Zhang M. Zhang W. Li Z. Si L. Long X. Yu N. Wang X. Role of HIF‐1α in pathogenic mechanisms of keloids. J. Cosmet. Dermatol. 2023 22 5 1436 1448 10.1111/jocd.15601 36718786
    [Google Scholar]
  5. Limandjaja G.C. Niessen F.B. Scheper R.J. Gibbs S. The keloid disorder: Heterogeneity, histopathology, mechanisms and models. Front. Cell Dev. Biol. 2020 8 360 10.3389/fcell.2020.00360 32528951
    [Google Scholar]
  6. Knowles A. Glass D.A. Keloids and hypertrophic scars. Dermatol. Clin. 2023 41 3 509 517 10.1016/j.det.2023.02.010 37236718
    [Google Scholar]
  7. Swenson A. Paulus J.K. Jung Y. Weiss S. Berman B. Peeva E. Yamaguchi Y. George P. Jagun O. Natural history of keloids: A sociodemographic analysis using structured and unstructured data. Dermatol. Ther. (Heidelb.) 2024 14 1 131 149 10.1007/s13555‑023‑01070‑3 38066233
    [Google Scholar]
  8. Naik P.P. Novel targets and therapies for keloid. Clin. Exp. Dermatol. 2022 47 3 507 515 10.1111/ced.14920 34480483
    [Google Scholar]
  9. Ekstein S.F. Wyles S.P. Moran S.L. Meves A. Keloids: A review of therapeutic management. Int. J. Dermatol. 2021 60 6 661 671 10.1111/ijd.15159 32905614
    [Google Scholar]
  10. Zhao S.Y. Wu D. Cheng C. Xie J.H. Advances and future directions in keloid research: Pathogenesis, diagnosis and personalized treatment strategies. World J. Clin. Cases 2023 11 34 8094 8098 10.12998/wjcc.v11.i34.8094 38130783
    [Google Scholar]
  11. Zhang M. Hu T. Ma T. Huang W. Wang Y. Epigenetics and environmental health. Front. Med. 2024 18 4 571 596 10.1007/s11684‑023‑1038‑2 38806988
    [Google Scholar]
  12. Stevenson A.W. Deng Z. Allahham A. Prêle C.M. Wood F.M. Fear M.W. The epigenetics of keloids. Exp. Dermatol. 2021 30 8 1099 1114 10.1111/exd.14414 34152651
    [Google Scholar]
  13. Zhang M. Chen H. Qian H. Wang C. Characterization of the skin keloid microenvironment. Cell Commun. Signal. 2023 21 1 207 10.1186/s12964‑023‑01214‑0 37587491
    [Google Scholar]
  14. Zhao X. Li X. Li L. Zhang Y. Wu F. Yin R. Yuan M. Li X. Alterations of the m6A methylation induced by TGF-β2 in ARPE-19 cells. Frontiers in Bioscience-Landmark 2023 28 7 148 10.31083/j.fbl2807148 37525909
    [Google Scholar]
  15. Zhang C. Liu N. N6‐methyladenosine (m6A) modification in gynecological malignancies. J. Cell. Physiol. 2022 237 9 3465 3479 10.1002/jcp.30828 35802474
    [Google Scholar]
  16. Huang Y. Xue Q. Chang J. Wang Y. Cheng C. Xu S. Wang X. Miao C. M6A methylation modification in autoimmune diseases, a promising treatment strategy based on epigenetics. Arthritis Res. Ther. 2023 25 1 189 10.1186/s13075‑023‑03149‑w 37784134
    [Google Scholar]
  17. Wei Y. Li Y. Lu C. Exploring the role of m6A modification in cancer. Proteomics 2023 23 13-14 2200208 10.1002/pmic.202200208 36349736
    [Google Scholar]
  18. Ren S. Ji Y. Wang M. Ye M. Huang L. Cai X. The m6A demethylase FTO promotes keloid formation by up-regulating COL1A1. Ann. Transl. Med. 2023 11 1 15 10.21037/atm‑22‑6021 36760238
    [Google Scholar]
  19. Fu M. Chen Y. Shi X. ZC3H13 accelerates keloid formation by mediating N(6)-methyladenosine modification of HIPK2. Biochem. Genet. 2023 62 3 1857 1871 10.1007/s10528‑023‑10514‑6 37752292
    [Google Scholar]
  20. Song Y. Wei J. Li R. Fu R. Han P. Wang H. Zhang G. Li S. Chen S. Liu Z. Zhao Y. Zhu C. Zhu J. Zhang S. Pei H. Cheng J. Wu J. Dong L. Song G. Shen X. Yao Q. Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-β/SMAD signaling. Hepatology 2023 78 5 1433 1447 10.1097/HEP.0000000000000319 36800849
    [Google Scholar]
  21. Bao M. Feng Q. Zou L. Huang J. Zhu C. Xia W. Endoplasmic reticulum stress promotes endometrial fibrosis through the TGF-β/SMAD pathway. Reproduction 2023 165 2 171 182 10.1530/REP‑22‑0294 36342661
    [Google Scholar]
  22. Meng X. Nikolic-Paterson D.J. Lan H.Y. TGF-β: The master regulator of fibrosis. Nat. Rev. Nephrol. 2016 12 6 325 338 10.1038/nrneph.2016.48 27108839
    [Google Scholar]
  23. Hu H.H. Chen D.Q. Wang Y.N. Feng Y.L. Cao G. Vaziri N.D. Zhao Y.Y. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem. Biol. Interact. 2018 292 76 83 10.1016/j.cbi.2018.07.008 30017632
    [Google Scholar]
  24. Cohen A.J. Nikbakht N. Uitto J. Keloid disorder: Genetic Basis, gene expression profiles, and immunological modulation of the fibrotic processes in the skin. Cold Spring Harb. Perspect. Biol. 2023 15 7 a041245 10.1101/cshperspect.a041245 36411063
    [Google Scholar]
  25. Song J. Zhang Y. Pan H. Xu X. Deng C.C. Yang B. Isolation, culture, and characterization of primary dermal fibroblasts from human keloid tissue. J. Vis. Exp. 2023 197 10.3791/65153 37578255
    [Google Scholar]
  26. He Y. Zhang S. Bao W. Xue Y. Yin B. Cheng X. Zhang Z. Jia C. An improved explants culture method: Sustainable isolation of keloid fibroblasts with primary characteristics. J. Cosmet. Dermatol. 2022 21 12 7131 7139 10.1111/jocd.15416 36170348
    [Google Scholar]
  27. Wang J. Li B. Yang S. Ma C. Liu K. Chen X. Cui W. Upregulation of INHBA mediated by the transcription factor BHLHE40 promotes colon cancer cell proliferation and migration. J. Clin. Lab. Anal. 2022 36 7 e24539 10.1002/jcla.24539 35689549
    [Google Scholar]
  28. 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 259 261 270 10.1016/j.jss.2020.09.038 33162101
    [Google Scholar]
  29. Wang Y. Wang X. Yuan Z. Liu F. Luo X. Yang J. Identifying potential drug targets for keloid: A mendelian randomization study. J. Invest. Dermatol. 2024 ••• S0022-202X(24)00388-9 10.1016/j.jid.2024.04.023 38797322
    [Google Scholar]
  30. Chao H. Zheng L. Hsu P. He J. Wu R. Xu S. Zeng R. Zhou Y. Ma H. Liu H. Tang Q. IL-13RA2 downregulation in fibroblasts promotes keloid fibrosis via JAK/STAT6 activation. JCI Insight 2023 8 6 e157091 10.1172/jci.insight.157091 36757802
    [Google Scholar]
  31. Lombardi F. Augello F.R. Artone S. Bahiti B. Sheldon J.M. Giuliani M. Cifone M.G. Palumbo P. Cinque B. Efficacy of probiotic Streptococcus thermophilus in counteracting TGF-β1-induced fibrotic response in normal human dermal fibroblasts. J. Inflamm. (Lond.) 2022 19 1 27 10.1186/s12950‑022‑00324‑9 36536411
    [Google Scholar]
  32. Li L. He Z. Zhu Y. Shen Q. Yang S. Cao S. Hydrogen sulfide suppresses skin fibroblast proliferation via oxidative stress alleviation and necroptosis inhibition. Oxid. Med. Cell. Longev. 2022 2022 1 16 10.1155/2022/7434733 35774378
    [Google Scholar]
  33. Wang L. Zou Y. Huang Z. Wang W. Li J. Bi J. Huo R. KIAA1429 promotes infantile hemangioma regression by facilitating the stemness of hemangioma endothelial cells. Cancer Sci. 2023 114 4 1569 1581 10.1111/cas.15708 36572002
    [Google Scholar]
  34. Łasut-Szyszka B. Gdowicz-Kłosok A. Krześniak M. Głowala-Kosińska M. Będzińska A. Rusin M. Strong activation of p53 by actinomycin D and nutlin-3a overcomes the resistance of cancer cells to the pro-apoptotic activity of the FAS ligand. Apoptosis 2024 29 9-10 1515 1528 10.1007/s10495‑024‑02000‑0 39068622
    [Google Scholar]
  35. Wu S.B. Hou T.Y. Kau H.C. Tsai C.C. Effect of pirfenidone on TGF-β1-induced myofibroblast differentiation and extracellular matrix homeostasis of human orbital fibroblasts in graves’ ophthalmopathy. Biomolecules 2021 11 10 1424 10.3390/biom11101424 34680057
    [Google Scholar]
  36. Xie F. Teng L. Xu J. Lu J. Zhang C. Yang L. Ma X. Zhao M. Adipose‑derived mesenchymal stem cells inhibit cell proliferation and migration and suppress extracellular matrix synthesis in hypertrophic‑scar and keloid fibroblasts. Exp. Ther. Med. 2020 21 2 139 10.3892/etm.2020.9571 33456506
    [Google Scholar]
  37. Li Q. Cheng F. Zhou K. Fang L. Wu J. Xia Q. Cen Y. Chen J. Qing Y. Increased sensitivity to TNF‑α promotes keloid fibroblast hyperproliferation by activating the NF‑κB, JNK and p38 MAPK pathways. Exp. Ther. Med. 2021 21 5 502 10.3892/etm.2021.9933 33791011
    [Google Scholar]
  38. Delaleu J. Charvet E. Petit A. Keloid disease: Review with clinical atlas. Part I: Definitions, history, epidemiology, clinics and diagnosis. Ann. Dermatol. Venereol. 2023 150 1 3 15 10.1016/j.annder.2022.08.010 36494213
    [Google Scholar]
  39. Lv W. Ren Y. Hou K. Hu W. Yi Y. Xiong M. Wu M. Wu Y. Zhang Q. Epigenetic modification mechanisms involved in keloid: Current status and prospect. Clin. Epigenetics 2020 12 1 183 10.1186/s13148‑020‑00981‑8 33243301
    [Google Scholar]
  40. Liu S. Yang H. Song J. Zhang Y. Abualhssain A.T.H. Yang B. Keloid: Genetic susceptibility and contributions of genetics and epigenetics to its pathogenesis. Exp. Dermatol. 2022 31 11 1665 1675 10.1111/exd.14671 36052657
    [Google Scholar]
  41. Feng F. Liu M. Pan L. Wu J. Wang C. Yang L. Liu W. Xu W. Lei M. Biomechanical regulatory factors and therapeutic targets in keloid fibrosis. Front. Pharmacol. 2022 13 906212 10.3389/fphar.2022.906212 35614943
    [Google Scholar]
  42. Wei F. Zhang J.N. Zhao Y.Q. Lyu H. Chen F. Expression of m6A RNA methylation regulators and their clinical predictive value in intrahepatic cholangiocarcinoma. Frontiers in Bioscience-Landmark 2023 28 6 120 10.31083/j.fbl2806120 37395024
    [Google Scholar]
  43. Petri B.J. Klinge C.M. m6A readers, writers, erasers, and the m6A epitranscriptome in breast cancer. J. Mol. Endocrinol. 2023 70 2 e220110 10.1530/JME‑22‑0110 36367225
    [Google Scholar]
  44. Fan Y. Lv X. Chen Z. Peng Y. Zhang M. m6A methylation: Critical roles in aging and neurological diseases. Front. Mol. Neurosci. 2023 16 1102147 10.3389/fnmol.2023.1102147 36896007
    [Google Scholar]
  45. Jiang X. Liu B. Nie Z. Duan L. Xiong Q. Jin Z. Yang C. Chen Y. The role of m6A modification in the biological functions and diseases. Signal Transduct. Target. Ther. 2021 6 1 74 10.1038/s41392‑020‑00450‑x 33611339
    [Google Scholar]
  46. Zhang X. Li M. Xia L. Zhang H. The biological function of m6A methyltransferase KIAA1429 and its role in human disease. PeerJ 2022 10 e14334 10.7717/peerj.14334 36389416
    [Google Scholar]
  47. Shan M. Liu D. Sun L. Yang M. He M. Zhang Y. Xiang L. Lu L. He H. Niu D. Chen L. Li S. Chen A. He F. Wang Y. Lian J. KIAA1429 facilitates metastasis via m6A-YTHDC1-dependent RND3 down-regulation in hepatocellular carcinoma cells. Cancer Lett. 2024 584 216598 10.1016/j.canlet.2023.216598 38224863
    [Google Scholar]
  48. Lin X. Ye R. Li Z. Zhang B. Huang Y. Du J. Wang B. Meng H. Xian H. Yang X. Zhang X. Zhong Y. Huang Z. KIAA1429 promotes tumorigenesis and gefitinib resistance in lung adenocarcinoma by activating the JNK/ MAPK pathway in an m6A-dependent manner. Drug Resist. Updat. 2023 66 100908 10.1016/j.drup.2022.100908 36493511
    [Google Scholar]
  49. Lan T. Li H. Zhang D. Xu L. Liu H. Hao X. Yan X. Liao H. Chen X. Xie K. Li J. Liao M. Huang J. Yuan K. Zeng Y. Wu H. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol. Cancer 2019 18 1 186 10.1186/s12943‑019‑1106‑z 31856849
    [Google Scholar]
  50. Devos H. Zoidakis J. Roubelakis M.G. Latosinska A. Vlahou A. Reviewing the regulators of COL1A1. Int. J. Mol. Sci. 2023 24 12 10004 10.3390/ijms241210004 37373151
    [Google Scholar]
  51. 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 11 4364 4376 10.1002/jcb.29649 31930556
    [Google Scholar]
  52. Euler T. Valesky E.M. Meissner M. Hrgovic I. Kaufmann R. Kippenberger S. Zöller N.N. Normal and keloid fibroblasts are differentially influenced by IFN‐γ and triamcinolone as well as by their combination. Wound Repair Regen. 2019 27 5 450 461 10.1111/wrr.12722 30994217
    [Google Scholar]
  53. Marty P. Chatelain B. Lihoreau T. Tissot M. Dirand Z. Humbert P. Halofuginone regulates keloid fibroblast fibrotic response to TGF-β induction. Biomed. Pharmacother. 135 111182 2021 10.1016/j.biopha.2020.111182 33433355
    [Google Scholar]
  54. Su E. Han X. Jiang G. The transforming growth factor beta 1/SMAD signaling pathway involved in human chronic myeloid leukemia. Tumori 2010 96 5 659 666 10.1177/030089161009600503 21302608
    [Google Scholar]
  55. Chi C. Liang X. Cui T. Gao X. Liu R. Yin C. SKIL/SnoN attenuates TGF-β1/SMAD signaling-dependent collagen synthesis in hepatic fibrosis. Biomol. Biomed. 2023 23 6 1014 1025 10.17305/bb.2023.9000 37389959
    [Google Scholar]
  56. Chalkia A. Gakiopoulou H. Theochari I. Foukas P.G. Vassilopoulos D. Petras D. TGF-β1/Smad signalling in proliferative glomerulonephritis associated with autoimmune diseases. Mediterr. J. Rheumatol. 2022 33 2 176 184 10.31138/mjr.33.2.176 36128207
    [Google Scholar]
  57. Ren L.L. Li X.J. Duan T.T. Li Z.H. Yang J.Z. Zhang Y.M. Zou L. Miao H. Zhao Y.Y. Transforming growth factor-β signaling: From tissue fibrosis to therapeutic opportunities. Chem. Biol. Interact. 2023 369 110289 10.1016/j.cbi.2022.110289 36455676
    [Google Scholar]
  58. Wu C-S. Wu P-H. Fang A-H. Lan C-C.E. FK506 inhibits the enhancing effects of transforming growth factor (TGF)-β1 on collagen expression and TGF-β/Smad signalling in keloid fibroblasts: Implication for new therapeutic approach. Br. J. Dermatol. 2012 167 3 532 541 10.1111/j.1365‑2133.2012.11023.x 22540338
    [Google Scholar]
  59. 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 9 947 956 10.1080/08941939.2020.1716894 31986937
    [Google Scholar]
  60. Macias M.J. Martin-Malpartida P. Massagué J. Structural determinants of Smad function in TGF-β signaling. Trends Biochem. Sci. 2015 40 6 296 308 10.1016/j.tibs.2015.03.012 25935112
    [Google Scholar]
  61. Yu Z.L. Liu J. Ning Z.K. Tian H.K. Wu X. Huang Y.F. Wu Z.C. Zong Z. Zhou T.C. The TGF‐β/Smad 2/3 signaling pathway is involved in Musashi2‐induced invasion and metastasis of colorectal cancer. Mol. Carcinog. 2023 62 2 261 276 10.1002/mc.23484 36345938
    [Google Scholar]
  62. Ye Z. Hu Y. TGF‑β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (Review). Int. J. Mol. Med. 2021 48 1 132 10.3892/ijmm.2021.4965 34013369
    [Google Scholar]
  63. Guo H. Jian Z. Liu H. Cui H. Deng H. Fang J. Zuo Z. Wang X. Zhao L. Geng Y. Ouyang P. Tang H. TGF-β1-induced EMT activation via both Smad-dependent and MAPK signaling pathways in Cu-induced pulmonary fibrosis. Toxicol. Appl. Pharmacol. 2021 418 115500 10.1016/j.taap.2021.115500 33744278
    [Google Scholar]
  64. He L. Zhu C. Dou H. Yu X. Jia J. Shu M. Keloid core factor CTRP3 overexpression significantly controlled TGF-β1-induced propagation and migration in keloid fibroblasts. Dis. Markers 2023 2023 1 12 10.1155/2023/9638322 37091895
    [Google Scholar]
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  • Article Type:
    Research Article
Keywords: TGF-β1 ; m6A ; keloid ; Smad ; KIAA1429
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