Zhao Yilin,Wang Haojie,Zhan Jianghua.Recent advances of TGFβ1 induced EMT-related signaling pathways in biliary atresia[J].Journal of Clinical Pediatric Surgery,2021,20(12):1189-1193.[doi:10.12260/lcxewkzz.2021.12.017]
胆道闭锁TGFβ1诱导EMT相关通路研究进展
- Title:
- Recent advances of TGFβ1 induced EMT-related signaling pathways in biliary atresia
- Keywords:
- Biliary Atresia/ET; Epithelial-Mesenchymal Transition; Transforming Growth Factor Beta1; Liver Cirrhosis
- 分类号:
- R722.1;R657.4
- 摘要:
- 胆道闭锁(biliary atresia,BA)是以肝内外胆管进行性炎症及纤维化为特征的疾病,其发病原因不明,可能与病毒感染、免疫损伤有关。BA确诊后应先行Kasai手术,部分患者可恢复胆流,但纤维化过程并没有停止且影响BA预后。上皮-间质转化(epithelial-mesenchymal transition,EMT)参与肝纤维化过程,EMT在外界因素刺激下,极化的上皮细胞逐渐松解,转化成为具有间质细胞特征的细胞,导致肝纤维化进一步加重。转化生长因子-β1(transforming growth factor-β1,TGFβ1)可诱导上皮-间质转化,其诱导EMT通过TGFβ1/Smad通路及不依赖Smad的其他TGFβ1信号通路。微小RNA可影响相关信号通路参与肝纤维化进程。本文将阐述BA中TGFβ1诱导EMT信号通路的研究进展,为抑制甚至逆转EMT进程、延缓肝纤维化提供思路。
- Abstract:
- Biliary atresia (BA) is a disease characterized by progressive inflammation and fibrosis of intra/extrahepatic bile ducts.The cause of disease has remained elsusive.It may be related with virus infection and immune response.The major treatment for BA is Kasai surgery while liver fibrosis is an important factor affecting the prognosis of Kasai surgery.Involved in the process of liver fibrosis, epithelial-mesenchymal transition (EMT) refers to that polarized epithelial cells are released gradually and transformed into cells with mesenchymal characteristics under stimulation.Transforming growth factor-β1 (TGFβ1) induces EMT through TGFβ1/Smad signaling pathway and other TGFβ1/non-Smad signaling pathways.And microRNA affects signaling pathways and participates in the process of liver fibrosis.This review was intended to elaborate the possible pathways associated with TGFβ1 inducing EMT in BA and to provide rationales for delaying liver fibrosis and inhibiting or even reversing EMT process.
参考文献/References:
1 Bezerra JA, Wells RG, Mack CL, et al.Biliary atresia:clinical and research challenges for the twenty-first century[J].Hepatology, 2018, 68(3):1163-1173.DOI:10.1002/hep.29905.
2 Ortiz-Perez A, Donnelly B, Temple H, et al.Innate immunity and pathogenesis of biliary atresia[J].Front Immunol, 2020, 11:329.DOI:10.3389/fimmu.2020.00329.
3 余晨, 詹江华, 高伟, 等.胆道闭锁Kasai术后肝移植患儿不同自体肝生存的临床与病理分析[J].临床小儿外科杂志, 2017, 16(6):552-558.DOI:10.3969/j.issn.1671-6353.2017.06.007. Yu C, Zhan JH, Gao W, et al.Clinicopathological analysis with different native liver survivals for biliary atresia after Kasai[J].J Clin Ped Sur, 2017, 16(6):552-558.DOI:10.3969/j.issn.1671-6353.2017.06.007.
4 Harada K.Sclerosing and obstructive cholangiopathy in biliary atresia:mechanisms and association with biliary innate immunity[J].Pediatr Surg Int, 2017, 33(12):1243-1248.DOI:10.1007/s00383-017-4154-8.
5 Díaz R, Kim JW, Hui JJ, et al.Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis[J].Hum Pathol, 2009, 40(6):908.DOI:10.1016/j.humpath.2007.05.021.
6 Zeisberg M, Neilson EG.Biomarkers for epithelial-mesenchymal transitions[J].Clin Invest, 2009, 119(6):1429-1437.DOI:10.1172/JCI36183.
7 高婷.TGF-β1信号通路相关蛋白在胆道闭锁肝脏中的表达及作用[D].天津:天津医科大学, 2017. Gao T.Expression and significance of the TGF-β1 signaling pathways related protein in biliary atresia[D].Tianjin:Tianjin Medical University, 2017.
8 Chen J, Zhu HD, Liu QM, et al.DEPTOR induces a partial epithelial-to-mesenchymal transition and metastasis via autocrine TGFβ1 signaling and is associated with poor prognosis in hepatocellular carcinoma[J].J Exp Clin Cancer Res, 2019, 38(1):273.DOI:10.1186/s13046-019-1220-1.
9 Zhang S, Sun WY, Wu JJ, et al.Decreased expression of the type III TGF-β receptor enhances metastasis and invasion in hepatocellular carcinoma progression[J].Oncol Rep, 2016, 35(4):2373-2381.DOI:10.3892/or.2016.4615.
10 高婷, 詹江华, 丁美云, 等.整合素αvβ8、p38及ERK1/2在胆道闭锁患儿肝脏中的表达及意义[J].天津医药, 2016, 44(7):821-824.DOI:10.11958/20160362. Gao T, Zhan JH, Ding MY, et al.Expression and significance of integrin αvβ8, p38 and ERK1/2 in liver of children with biliary atresia[J].Tianjin Med J, 2016, 44(7):821-824.DOI:10.11958/20160362.
11 Lamouille S, Xu J, Derynck R.Molecular mechanisms of epithelial-mesenchymal transition[J].Nat Rev Mol Cell Biol, 2014, 15(3):178-196.DOI:10.1038/nrm3758.
12 Wang JY, Cheng H, Zhang HY, et al.Suppressing microRNA-29c promotes biliary atresia-related fibrosis by targeting DNMT3A and DNMT3B[J].Cell Mol Biol Lett, 2019, 24:10.DOI:10.1186/s11658-018-0134-9.
13 Schmierer B, Hill CS.TGF beta-SMAD signal transduction:molecular specificity and functional flexibility[J].Nat Rev Mol Cell Biol, 2007, 8(12):970-982.DOI:10.1038/nrm2297.
14 Triantafyllou EA, Mylonis I, Simos G, et al.Hypoxia induces pro-fibrotic and fibrosis marker genes in hepatocellular carcinoma cells independently of inflammatory stimulation and the NF-κΒ pathway[J].Hypoxia (Auckl), 2019, 7:87-91.DOI:10.2147/HP.S235967.
15 刘东红, 林峰, 杨再兴, 等.原发性胆汁性胆管炎肝内胆管上皮细胞TLR4及上皮-间质转化相关标志物的表达[J].温州医科大学学报, 2018, 48(8):567-571.DOI:10.3969/j.issn.2095-9400.2018.08.005. Liu DH, Lin F, Yang ZX, et al.Expression of TLR4 and epithelial-mesenchymal transition-related markers in intrahepatic biliary epithelial cells of patients with primary biliary cholangitis[J].Journal of Wenzhou Medical University, 2018, 48(8):567-571.DOI:10.3969/j.issn.2095-9400.2018.08.005.
16 Zeisberg M, Yang C, Martino M, et al.Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition[J].Biol Chem, 2007, 282(32):23337-23347.DOI:10.1074/jbc.M700194200.
17 Deng H, Wang HF, Gao YB, et al.Hepatic progenitor cell represents a transitioning cell populaition between liver epithelium and stroma[J].Med Hypotheses, 2017, 76(6):809-812.DOI:10.1016/j.mehy.2011.02.024.
18 Shen WJ, Chen G, Wang M, et al.Liver fibrosis in biliary atresia[J].World J Pediatr, 2019, 15(2):117-123.DOI:10.1007/s12519-018-0203-1.
19 Deng YH, Pu CL, Li YC, et al.Analysis of biliary epithelial-mesenchymal transition in portal tract fibrogenesis in biliary atresia[J].Dig Dis Sci, 2011, 56(3):731-740.DOI:10.1007/s10620-010-1347-6.
20 Xiao Y, Zhou Y, Chen Y, et al.The expression of epithelial-mesenchymal transition-related proteins in biliary epithelial cells is associated with liver fibrosis in biliary atresia[J].Pediatr Res, 2015, 77(2):310-315.DOI:10.1038/pr.2014.181.
21 胡传兵.BDL所致幼鼠胆道闭锁后肝脏纤维化相关生物分子的时序性变化[D].沈阳:中国医科大学, 2009. Hu CB.The sequencial changes of hepatic fibrosis relevant genes in rat biliary atresia induced by bile duct ligation[D].Shenyang:China Medical University, 2009.
22 Zhao D, Luo Y, Xia Y, et al.MicroRNA-19b expression in human biliary atresia specimens and its role in BA-related fibrosis[J].Dig Dis Sci, 2017, 62(3):689-698.DOI:10.1007/s10620-016-4411-z.
23 Lin YC, Luo HY, Wang X, et al.Flavanones from sedum sarmentosum bunge alleviate CCl4-induced liver fibrosis in rats by targeting TGF-β1/TβR/Smad pathway in turn inhibiting epithelial mesenchymal transition[J].Evid Based Complement Alternat Med, 2018, 2018:3080837.DOI:10.1155/2018/3080837.
24 丁美云, 詹江华, 赵丽, 等.TGF-β1、Smad2在胆道闭锁肝纤维化中的作用[J].天津医药, 2016, 44(7):810-813.DOI:10.11958/20150242. Ding MY, Zhan JH, Zhao L, et al.The effects of TGF-β1 and Smad2 on liver fibrosis of biliary atresia[J].Tianjin Med J, 2016, 44(7):810-813.DOI:10.11958/20150242.
25 Zou YT, Li SY, Li ZL, et al.MiR-146a attenuates liver fibrosis by inhibiting transforming growth factor-β1 mediated epithelial-mesenchymal transition in hepatocytes[J].Cell Signal, 2019, 58:1-8.DOI:10.1016/j.cellsig.2019.01.012.
26 Zhang T, Liu W, Meng W, et al.Downregulation of miR-542-3p promotes cancer metastasis through activating TGF-β/Smad signaling in hepatocellular carcinoma[J].Onco Targets Ther, 2018, 11:1929-1939.DOI:10.2147/OTT.S154416.
27 Liu L, Li NF, Zhang Q, et al.Inhibition of ERK 1/2 signaling impairs the promoting effects of TGFβ1 on hepatocellular carcinoma cell invasion and epithelial-mesenchymal transition[J].Oncol Res, 2017, 25(9):1607-1616.DOI:10.3727/09650401X14938093512742.
28 Jiang YF, Wu C, Boye A, et al.MAPK inhibitors modulate Smad2/3/4 complex cyto-nuclear translocation in myofibroblasts via Imp7/8mediation[J].Mol Cell Biochem, 2015, 406(1/2):255-262.DOI:10.1007/s11010-015-2443-x.
29 Zhang L, Zhou J, Qin XK, et al.Astragaloside IV inhibits the invasion and metastasis of SiHa cervical cancer cells via the TGF β1 mediated PI3K and MAPK pathways[J].Oncol Rep, 2019, 41(5):2975-2986.DOI:10.3892/or.2019.7062.
30 Jafri M, Donnelly B, McNeal M, et al.MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication[J].Surgery, 2007, 142(2):192-201.DOI:10.1016/j.surg.2007.03.008.
31 Lobeck I, Donnelly B, Dupree P, et al.Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes[J].Virology, 2016, 499:185-195.DOI:10.1016/j.virol.2016.09.014.
32 Wendt MK, Balanis N, Carlin CR, et al.STAT3 and epithelial?mesenchymal transitions in carcinomas[J].JAKSTAT, 2014, 3(1):e28975.DOI:10.4161/jkst.28975.
33 Lin XL, Liu MH, Liu YB, et al.Transforming growth factor β1 promotes migration and invasion in HepG2 cells:Epithelial-to-mesenchymal transition via JAK/STAT3 signaling[J].Int J Mol Med, 2018, 41(1):129-136.DOI:10.3892/ijmm.2017.3228.
34 Wang B, Liu T, Wu JC, et al.STAT3 aggravates TGF-β1-induced hepatic epithelial-to-mesenchymal transition and migration[J].Biomed Pharmacother, 2018, 98:214-221.DOI:10.1016/j.biopha.2017.12.035.
35 Luo Z, Jegga AG, Bezerra JA.Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies[J].Hepatology, 2018, 67(2):676-689.DOI:10.1002/hep.29504.
36 Xiao YT, Wang J, Yan WH, et al.Dysregulated miR-124 and miR-200 expression contribute to cholangiocyte proliferation in the cholestatic liver by targeting IL-6/STAT3 signalling[J].Hepatol, 2015, 62(4):889-896.DOI:10.1016/j.jhep.2014.10.033.
37 Mao YZ, Tang ST, Yang L, et al.Inhibition of the notch signaling pathway reduces the differentiation of hepatic progenitor cells into cholangiocytes in biliary atresia[J].Cell Physiol Biochem, 2018, 49(3):1074-1082.DOI:10.1159/000493290.
38 贾金富, 詹江华, 余晨, 等.Notch-1、Jagged-1、Hes-1在胆道闭锁患儿肝纤维化中的表达及意义[J].中华小儿外科杂志, 2019, 40(5):399-403.DOI:10.3760/cma.j.issn.0253-3006.2019.05.004. Jia JF, Zhan JH, Yu C, et al.Expressions and significance of Notch-1, Jagged-1 and Hes-1 in liver fibrosis of children with biliary atresia[J].Chin J Pediatr Surg, 2019, 40(5):399-403.DOI:10.3760/cma.j.issn.0253-3006.2019.05.004.
相似文献/References:
[1]孙雪,任红霞.胆道闭锁发生与肝纤维化的分子机制研究进展[J].临床小儿外科杂志,2019,18(05):432.[doi:10.3969/j.issn.1671-6353.2019.05.019]
Sun Xue,Ren Hongxia.Advances in molecular mechanisms of biliary atresia and hepatic fibrosis[J].Journal of Clinical Pediatric Surgery,2019,18(12):432.[doi:10.3969/j.issn.1671-6353.2019.05.019]
[2]葛亮,詹江华.胆道闭锁肝纤维化与自体肝生存关系的研究进展[J].临床小儿外科杂志,2020,19(02):171.[doi:10.3969/j.issn.1671-6353.2020.02.016]
Ge Liang,Zhan Jianghua.Relationship between liver fibrosis and native liver survival in infants with biliary atresia[J].Journal of Clinical Pediatric Surgery,2020,19(12):171.[doi:10.3969/j.issn.1671-6353.2020.02.016]
[3]卫园园,范晋楠,李亚蕊.ADD3基因rs17095355位点多态性与胆道闭锁相关性研究的Meta分析[J].临床小儿外科杂志,2020,19(06):496.[doi:10.3969/j.issn.1671-6353.2020.06.007]
Wei Yuanyuan,Fan Jinnan,Li Yarui.Meta-analysis of the relationship between single nucleotide polymorphism of rs17095355 and biliary atresia[J].Journal of Clinical Pediatric Surgery,2020,19(12):496.[doi:10.3969/j.issn.1671-6353.2020.06.007]
[4]阿里木江·阿不都热依木,林峰,王皓洁,等.Notch信号通路活化协同巨噬细胞对胆道闭锁肝纤维化的作用研究[J].临床小儿外科杂志,2021,20(04):376.[doi:10.12260/lcxewkzz.2021.04.014]
Alimujiang·Abudureyimu,Lin Feng,Wang Haojie,et al.Activation of Notch signaling pathway collaborated with macrophages for promoting liver fibrosis in biliary atresia[J].Journal of Clinical Pediatric Surgery,2021,20(12):376.[doi:10.12260/lcxewkzz.2021.04.014]
[5]周辉,李索林,时保军,等.PDGF-BB在胆道闭锁患儿肝脏中的表达及其与上皮间质转化的相关性研究[J].临床小儿外科杂志,2023,22(03):238.[doi:10.3760/cma.j.cn101785-202012064-007]
Zhou Hui,Li Suolin,Shi Baojun,et al.Hepatic expression of PDGF-BB in infants with biliary atresia and its correlation with epithelial mesenchymal transition[J].Journal of Clinical Pediatric Surgery,2023,22(12):238.[doi:10.3760/cma.j.cn101785-202012064-007]
备注/Memo
收稿日期:2020-04-30。
基金项目:国家自然科学基金(编号:81570471);天津市卫生行业重点攻关项目(编号:14KG129);新疆维吾尔自治区自然科学基金(2019D01A12)
通讯作者:詹江华,Email:zhanjianghuatj@163.com