转化生长因子β/Smad信号通路及相关影响因子在瘢痕疙瘩中的研究进展

doi:10.35541/cjd.20220556

Abstract

Abstract: 【Abstract】 The transforming growth factor-beta （TGF-β）/Smad pathway is crucial in the differentiation of keloid fibroblasts and the development of keloids. Hypoxia-inducible factor 1α, microRNAs, long non-coding RNAs, activating transcription factor 3, inflammatory factors and lysyl oxidase-like 2 are common factors in the TGF-β/Smad pathway during the occurrence of keloids. This review summarizes latest research progress on the TGF-β/Smad pathway and common factors in the pathogenesis of keloids.

Key words: Keloid, Fibroblasts, Fibrosis, Transforming growth factor beta, Smad proteins, receptor-regulated

Huang Wenhua, Zheng Zhenlong, Jin Zhehu. Role of transforming growth factor-β/Smad pathway and related factors in the pathogenesis of keloids[J]. Chinese Journal of Dermatology,2023,e20220556. doi:10.35541/cjd.20220556

References ［47］

［1］	刘晨阳, 元星花, 支嘉慧, 等. 跨膜蛋白45A对瘢痕疙瘩成纤维细胞合成细胞外基质的影响［J］. 中华皮肤科杂志, 2023,56（7）:666⁃669. doi: 10.35541/cjd.20220056.
［2］	Maeda T, Funayama E, Yamamoto Y, et al. Long⁃term outcomes and recurrence⁃free interval after the treatment of keloids with a standardized protocol［J］. J Tissue Viability, 2021,30（1）:128⁃132. doi: 10.1016/j.jtv.2020.11.003.
［3］	Deng Z, Subilia M, Chin IL, et al. Keloid fibroblasts have elevated and dysfunctional mechanotransduction signaling that is independent of TGF⁃β［J］. J Dermatol Sci, 2021,104（1）:11⁃20. doi: 10.1016/j.jdermsci.2021.09.002.
［4］	Niu T, Tian Y, Shi Y, et al. Antiﬁbrotic effects of hypocrellin a combined with LED red light irradiation on keloid fibroblasts by counteracting the TGF⁃β/Smad/autophagy/apoptosis signalling pathway［J］. Photodiagnosis Photodyn Ther, 2021,34:102202. doi: 10.1016/j.pdpdt.2021.102202.
［5］	Cui J, Jin S, Jin C, et al. Syndecan⁃1 regulates extracellular matrix expression in keloid fibroblasts via TGF⁃β1/Smad and MAPK signaling pathways［J］. Life Sci, 2020,254:117326. doi: 10.1016/j.lfs.2020.117326.
［6］	Moses H L, Roberts A B, Derynck R. The discovery and early days of TGF⁃β: a historical perspective ［J］. Cold Spring Harb Perspect Biol, 2016,8（7）:a021865. doi: 10.1101/cshperspect.a021865.
［7］	Finnson KW, Almadani Y, Philip A. Non⁃canonical（non⁃SMAD2/3） TGF⁃β signaling in fibrosis: mechanisms and targets［J］. Semin Cell Dev Biol, 2020,101:115⁃122. doi: 10.1016/j.semcdb.2019.11.013.
［8］	Hu HH, Chen DQ, Wang YN, et al. New insights into TGF⁃β/Smad signaling in tissue fibrosis［J］. Chem Biol Interact, 2018,292:76⁃83. doi: 10.1016/j.cbi.2018.07.008.
［9］	Wang Q, Wang P, Qin Z, et al. Altered glucose metabolism and cell function in keloid fibroblasts under hypoxia［J］. Redox Biol, 2021,38:101815. doi: 10.1016/j.redox.2020.101815.
［10］	崔晶, 金承龙, 金珊, 等. EMT在瘢痕疙瘩中的作用研究进展［J］. 中国皮肤性病学杂志, 2021,35（2）:217⁃221. doi: 10.13735/ j.cjdv.1001⁃7089.201.
［11］	Masoud GN, Li W. HIF⁃1α pathway: role, regulation and intervention for cancer therapy［J］. Acta Pharm Sin B, 2015,5（5）:378⁃389. doi: 10.1016/j.apsb.2015.05.007.
［12］	Touchi R, Ueda K, Kurokawa N, et al. Central regions of keloids are severely ischaemic ［J］. J Plast Reconstr Aesthet Surg, 2016, 69（2）: e35⁃e41. doi:10.1016/j.bjps.2015.11.006.
［13］	Zhao S, Gao Y, Xia X, et al. TGF⁃β1 promotes Staphylococcus aureus adhesion to and invasion into bovine mammary fibroblasts via the ERK pathway［J］. Microb Pathog, 2017,106:25⁃29. doi: 10.1016/j.micpath.2017.01.044.
［14］	Lei R, Li J, Liu F, et al. HIF⁃1α promotes the keloid development through the activation of TGF⁃β/Smad and TLR4/MyD88/NF⁃κB pathways［J］. Cell Cycle, 2019,18（23）:3239⁃3250. doi: 10.1080/15384101.2019.1670508.
［15］	Kang Y, Roh MR, Rajadurai S, et al. Hypoxia and HIF⁃1α regulate collagen production in keloids［J］. J Invest Dermatol, 2020,140（11）:2157⁃2165. doi: 10.1016/j.jid.2020.01.036.
［16］	Si L, Zhang M, Guan E, et al. Resveratrol inhibits proliferation and promotes apoptosis of keloid fibroblasts by targeting HIF⁃1α［J］. J Plast Surg Hand Surg, 2020,54（5）:290⁃296. doi: 10.1080/2000656X.2020.1771719.
［17］	Zhai XX, Ding JC, Tang ZM. Resveratrol inhibits proliferation and induces apoptosis of pathological scar fibroblasts through the mechanism involving TGF⁃β1/Smads signaling pathway［J］. Cell Biochem Biophys, 2015,71（3）:1267⁃1272. doi: 10.1007/s12013⁃014⁃0317⁃6.
［18］	Liu H, Lei C, He Q, et al. Nuclear functions of mammalian microRNAs in gene regulation, immunity and cancer［J］. Mol Cancer, 2018,17（1）:64. doi: 10.1186/s12943⁃018⁃0765⁃5.
［19］	Henry TW, Mendoza FA, Jimenez SA. Role of microRNA in the pathogenesis of systemic sclerosis tissue fibrosis and vasculopathy［J］. Autoimmun Rev, 2019,18（11）:102396. doi: 10.1016/j.autrev.2019.102396.
［20］	Li C, Bai Y, Liu H, et al. Comparative study of microRNA profiling in keloid fibroblast and annotation of differential expressed microRNAs［J］. Acta Biochim Biophys Sin（Shanghai）, 2013,45（8）:692⁃699. doi: 10.1093/abbs/gmt057.
［21］	Yang C, Zheng SD, Wu HJ, et al. Regulatory mechanisms of the molecular pathways in fibrosis induced by microRNAs［J］. Chin Med J（Engl）, 2016,129（19）:2365⁃2372. doi: 10.4103/0366⁃6999.190677.
［22］	Zhang GY, Wu LC, Liao T, et al. A novel regulatory function for miR⁃29a in keloid fibrogenesis［J］. Clin Exp Dermatol, 2016,41（4）:341⁃345. doi: 10.1111/ced.12734.
［23］	Liang C, Bu S, Fan X. Suppressive effect of microRNA⁃29b on hepatic stellate cell activation and its crosstalk with TGF⁃β1/Smad3［J］. Cell Biochem Funct, 2016,34（5）:326⁃333. doi: 10. 1002/cbf.3193.
［24］	Gallant⁃Behm CL, Piper J, Lynch JM, et al. A microRNA⁃29 mimic（remlarsen） represses extracellular matrix expression and fibroplasia in the skin［J］. J Invest Dermatol, 2019,139（5）:1073⁃1081. doi: 10.1016/j.jid.2018.11.007.
［25］	Lyu L, Zhao Y, Lu H, et al. Integrated interaction network of microRNA target genes in keloid scarring［J］. Mol Diagn Ther, 2019,23（1）:53⁃63. doi: 10.1007/s40291⁃018⁃0378⁃0.
［26］	Li Q, Fang L, Chen J, et al. Exosomal microRNA⁃21 promotes keloid fibroblast proliferation and collagen production by inhibiting Smad7［J］. J Burn Care Res, 2021,42（6）:1266⁃1274. doi: 10.1093/jbcr/irab116.
［27］	谢包根, 陈健, 翁明生, 等. VIM⁃AS1调控miR⁃143⁃3p/Smad3轴对瘢痕疙瘩成纤维细胞凋亡和细胞周期的影响［J］. 中国皮肤性病学杂志, 2022,36（4）:401⁃407. doi:10.13735/j.cjdv. 1001⁃7089.202110072.
［28］	朱学娥, 段曼曼, 丁媛. 长链非编码RNA介导的竞争性内源RNA调控网络在瘢痕疙瘩中的研究进展［J］. 中华皮肤科杂志, 2023,e20210471. doi: 10.35541/cjd.20210471.
［29］	Li Y, Liang X, Wang P, et al. Long non⁃coding RNA CACNA1G⁃AS1 promotes calcium channel protein expression and positively affects human keloid fibroblast migration［J］. Oncol Lett, 2018,16（1）:891⁃897. doi: 10.3892/ol.2018.8717.
［30］	Jin J, Zhai HF, Jia ZH, et al. 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［J］. Am J Physiol Cell Physiol, 2019,317（5）:C1001⁃C1010. doi:10.1152/ajpcell.00319.2018.
［31］	Xu L, Sun N, Li G, et al. LncRNA H19 promotes keloid formation through targeting the miR⁃769⁃5p/EIF3A pathway［J］. Mol Cell Biochem, 2021,476（3）:1477⁃1487. doi: 10.1007/s11010⁃ 020⁃04024⁃x.
［32］	Geng Y, Deng L, Su D, et al. Identification of crucial microRNAs and genes in hypoxia⁃induced human lung adenocarcinoma cells［J］. Onco Targets Ther, 2016,9:4605⁃4616. doi: 10.2147/OTT.S103430.
［33］	Li J, Cao LT, Liu HH, et al. Long non coding RNA H19: an emerging therapeutic target in fibrosing diseases［J］. Autoimmunity, 2020,53（1）:1⁃7. doi: 10.1080/08916934.2019.1681983.
［34］	Li Z, Gong C, Wei H. Long non⁃coding RNA H19 aggravates keloid progression by upregulating SMAD family member 5 expression via miR⁃196b⁃5p［J］. Bioengineered, 2022,13（1）:1447⁃1458. doi: 10.1080/21655979.2021.2019868.
［35］	Zhou H, Li N, Yuan Y, et al. Activating transcription factor 3 in cardiovascular diseases: a potential therapeutic target［J］. Basic Res Cardiol, 2018,113（5）:37. doi: 10.1007/s00395⁃018⁃0698⁃6.
［36］	Wang XM, Liu XM, Wang Y, et al. Activating transcription factor 3（ATF3） regulates cell growth, apoptosis, invasion and collagen synthesis in keloid fibroblast through transforming growth factor beta（TGF⁃beta）/SMAD signaling pathway［J］. Bioengineered, 2021,12（1）:117⁃126. doi: 10.1080/21655979. 2020.1860491.
［37］	Dohi T, Padmanabhan J, Akaishi S, et al. The interplay of mechanical stress, strain, and stiffness at the keloid periphery correlates with increased Caveolin⁃1/ROCK signaling and scar progression ［J］. Plast Reconstr Surg, 2019,144（1）:58e⁃67e. doi:10.1097/PRS.0000000000005717.
［38］	Lee TH, Wisniewski HG, Vilcek J. A novel secretory tumor necrosis factor⁃inducible protein（TSG⁃6） is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44［J］. J Cell Biol, 1992,116（2）:545⁃557. doi: 10.1083/jcb.116.2.545.
［39］	Liu Z, Pei Y, Zeng H, et al. Recombinant TSG⁃6 protein inhibits the growth of capsule fibroblasts in frozen shoulder via suppressing the TGF⁃β/Smad2 signal pathway［J］. J Orthop Surg Res, 2021,16（1）:564. doi: 10.1186/s13018⁃021⁃02705⁃x.
［40］	Li XY, Weng XJ, Li XJ, et al. TSG⁃6 inhibits the growth of keloid fibroblasts via mediating the TGF⁃β1/Smad signaling pathway ［J］. J Invest Surg, 2021,34（9）:947⁃956. doi: 10.1080/08941939.2020.1716894.
［41］	Pan SC, Lee CH, Chen CL, et al. Angiogenin attenuates scar formation in burn patients by reducing fibroblast proliferation and transforming growth factor β1 secretion ［J］. Ann Plast Surg, 2018,80（2S Suppl 1）:S79⁃S83. doi: 10.1097/SAP.000000000000 1306.
［42］	Fang QQ, Wang XF, Zhao WY, et al. The source of ACE during scar formation is from both bone marrow and skin tissue［J］. FASEB J, 2018,32（9）:5199⁃5208. doi: 10.1096/fj.201701575 RRR.
［43］	Tan WQ, Fang QQ, Shen XZ, et al. Angiotensin⁃converting enzyme inhibitor works as a scar formation inhibitor by down⁃regulating Smad and TGF⁃β⁃activated kinase 1（TAK1） pathways in mice［J］. Br J Pharmacol, 2018,175（22）:4239⁃4252. doi: 10. 1111/bph.14489.
［44］	Satish L, Evdokiou A, Geletu E, et al. Pirfenidone inhibits epithelial⁃mesenchymal transition in keloid keratinocytes［J］. Burns Trauma, 2020,8:tkz007. doi: 10.1093/burnst/tkz007.
［45］	Huang M, Liu Z, Baugh L, et al. Lysyl oxidase enzymes mediate TGF⁃β1⁃induced fibrotic phenotypes in human skin⁃like tissues［J］. Lab Invest, 2019,99（4）:514⁃527. doi: 10.1038/s41374⁃018⁃0159⁃8.
［46］	Semkova ME, Hsuan JJ. TGFβ⁃1 induced cross⁃linking of the extracellular matrix of primary human dermal fibroblasts［J］. Int J Mol Sci, 2021,22（3）:984. doi: 10.3390/ijms22030984.
［47］	Tong X, Zhang S, Wang D, et al. Azithromycin attenuates bleomycin⁃induced pulmonary fibrosis partly by inhibiting the expression of LOX and LOXL⁃2［J］. Front Pharmacol, 2021,12:709819. doi: 10.3389/fphar.2021.709819.

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Role of transforming growth factor-β/Smad pathway and related factors in the pathogenesis of keloids

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