miRNA-101调控转化生长因子-β1信号通路参与肝纤维化的研究
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摘要
目的探讨miRNA-101及转化生长因子(TGF)-β1信号通路在肝纤维化中的作用。方法选取2013年1月～2018年1月新疆医科大学第二附属医院手术切除的20例肝纤维化组织作为研究组,选择20例正常肝脏组织作为对照。采用免疫组化法分别检测肝组织中TGF-β1、平滑肌α-肌动蛋白(α-SMA)的表达水平,采用实时定量PCR(q RT-PCR)检测肝组织中TGF-β1、α-SMA的mRNA及miRNA-101的表达情况,分析TGF-β1、α-SMA及miRNA-101的相关性。结果肝纤维化组织中TGF-β1的mRNA表达水平明显高于正常肝组织(P <0.05),肝纤维化组织中α-SMA的mRNA表达水平与正常肝组织比较,差异无统计学意义(P> 0.05)。TGF-β1和α-SMA在肝纤维化组织中的阳性表达随肝纤维化程度的加重而增强,呈正相关(r=0.53、0.57,均P <0.05)。TGF-β1和α-SMA的mRNA表达水平呈正相关(r=0.633,P <0.01)。肝纤维化组织miRNA-101水平低于正常肝组织,差异有统计学意义(P <0.05)。miRNA-101与TGF-β1、α-SMA的mRNA表达水平呈负相关(r=-0.442、-0.327,均P <0.01)。结论 miRNA-101下调可能通过调控TGF-β1而参与肝纤维化。
Objective To explore the roles of miRNA-101 and transforming growth factor(TGF)-β1 signalling pathway in human liver fibrosis. Methods Twenty cases of liver fibrosis tissues from January 2013 to January 2018 of the Second Affiliated Hospital of Xinjiang Medical University were selected as observation group. Twenty cases of normal liver firosis were selected as control. The expression of TGF-β1 and α-smooth muscle actin(α-SMA) were detected by immunohistochemistry. The expression levels of TGF-β1 mRNA, α-SMA mRNA and miRNA-101 in liver tissues were detected by quantitative real time polymerase chain reaction(qRT-PCR). The correlation of TGF-β1 and α-SMA expression with miRNA-101 in the liver tissues was analyzed. Results The expression level of TGF-β1 m RNA was much higher in fibrotic liver than that in normal liver tissues(P < 0.05), there was no statistically significant differencce on the expression level of α-SMA mRNA between fibrotic liver and normal liver tissues(P > 0.05). The positive expression of TGF-β1 and α-SMA in hepatic fibrosis tissues increased with the degree of hepatic fibrosis, showing a positive correlation(r = 0.53, 0.57, all P < 0.05). The mRNA expression level of TGF-β1 mRNA in fibrotic liver was positively correlated with α-SMA(r = 0.633, P < 0.01). The expression level of miRNA-101 in liver fibrotic tissues was lower than that in normal liver tissues(P < 0.05). The expression of miRNA-101 was negatively correlated with the mRNA expression levels of TGF-β1 and α-SMA(r =-0.442,-0.327, all P < 0.01). Conclusion Downregulation of miRNA-101 may contribute to liver fibrosis by targeting TGF-β1.
Objective To explore the roles of miRNA-101 and transforming growth factor(TGF)-β1 signalling pathway in human liver fibrosis. Methods Twenty cases of liver fibrosis tissues from January 2013 to January 2018 of the Second Affiliated Hospital of Xinjiang Medical University were selected as observation group. Twenty cases of normal liver firosis were selected as control. The expression of TGF-β1 and α-smooth muscle actin(α-SMA) were detected by immunohistochemistry. The expression levels of TGF-β1 mRNA, α-SMA mRNA and miRNA-101 in liver tissues were detected by quantitative real time polymerase chain reaction(qRT-PCR). The correlation of TGF-β1 and α-SMA expression with miRNA-101 in the liver tissues was analyzed. Results The expression level of TGF-β1 m RNA was much higher in fibrotic liver than that in normal liver tissues(P < 0.05), there was no statistically significant differencce on the expression level of α-SMA mRNA between fibrotic liver and normal liver tissues(P > 0.05). The positive expression of TGF-β1 and α-SMA in hepatic fibrosis tissues increased with the degree of hepatic fibrosis, showing a positive correlation(r = 0.53, 0.57, all P < 0.05). The mRNA expression level of TGF-β1 mRNA in fibrotic liver was positively correlated with α-SMA(r = 0.633, P < 0.01). The expression level of miRNA-101 in liver fibrotic tissues was lower than that in normal liver tissues(P < 0.05). The expression of miRNA-101 was negatively correlated with the mRNA expression levels of TGF-β1 and α-SMA(r =-0.442,-0.327, all P < 0.01). Conclusion Downregulation of miRNA-101 may contribute to liver fibrosis by targeting TGF-β1.
引文
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[2] Resser LD,Mcrae S,Waris G. Activation of TGF-beta l promoter by hepatitis C virus-induced AP-l and Spl:role of TGF-beta 1 in hepatic stellate cell activation and invasion[J]. PLoS One,2013,8(2):e56367.
[3] van der Ree MH,de Bruijne J,Kootstra NA,et al. MiemRNAs:role and therapeutic targets in viral hepatitis[J].Antivir Ther,2014,19(6):533-541.
[4] Kim KM,Kim SG. Autophagy and micmRNA dysregulation in liver diseases[J]. Arch Pham Res,2014,37(9):1097-1116.
[5] Roderburg C,Luedde M,Vargas Cardenas D,et al. miR-133a mediates TGF dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis[J].J Hepatol,2013,58(4):736-742.
[6]蒋智渊,钟国强,肖飞,等.微小RNA-101在心房颤动心房纤维化中的作用[J].实用医学杂志,2015,31(6):890-893.
[7] Kumar V,Mahato RI. Delivery and targeting of miRNAs for trearing liver fibrosis[J]. Pharm Res,2015,32(2):341-361.
[8] Chen SL,Zheng MH,Shi KQ,et al. A new strategy for treatment of liver fibrosis:letting microRNA do the job[J].BioDrugs,2013,27(1):25-34.
[9]程丹,汤绍迁.微小RNA在肝纤维化中作用的研究进展[J].国际消化病杂志,2016,36(6):336-339.
[10]谢云,闾军.微小RNA-101在炎症与纤维化及肿瘤中的研究进展[J].中华肝脏病杂志,2015,23(3):231-233.
[11] Zeng W,van den Berg A,Huitema S,et al. Correlation of microRNA-16,microRNA-21 and microRNA-101 expression with cyclooxygenase-2 expression and angiogenic factors in cirrhotic and noncirrhotic human hepatocellular carcinoma[J]. PLoS One,2014,9(4):e95826.
[12]王军,李光明.microRNAs在肝纤维化形成中的作用[J].胃肠病学和肝病学杂志,2014,23(6):618-620.
[13]马玉桃,何阳,孟佩佩,等.微小RNA-195调控转化生长因子-β/Smad信号通路影响肝纤维化机制研究[J].中国临床药理学杂志,2017,33(20):2035-2038.
[14]邓国孙,李镇伽.mi RNA-101a对小鼠肝纤维化细胞增殖及TGFβ1/Smads信号转导通路表达的影响[J].海军医学杂志,2017,38(3):222-225.
[15] Liu Z,Yi J,Ye R,et al. miR-144 regulates transforming growth factor-β1 iduced hepatic stellate cell activation in human fibrotic liver[J]. Int J Clin Exp Pathol,2015,8(4):3994-4000.
[16] Xie Y,Yao Q,Butt AM,et al. Expression profiling of serum microRNA-101 in HBV-associated chronic hepatitis,liver cirrhosis,and hepatocellular carcinoma[J]. Cancer Biol Ther,2014,15(9):1248-1255.
[17] Chen K,Fan W,Wang X,et al. MicroRNA-101 mediates the suppressive effect of laminar shear stress on m TOR expression in vascular endothelial cells[J]. Biochem Biophys Res Commun,2012,427(1):138-142.
[18] Wei X,Xiang T,Ren G,et al. miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A[J]. Cell Signal,2013,25(2):439-446.
[19] Noetel A,Elfimova N,Ahmuller J,et al. Next generation sequencing of the A902 interacting transeriptome identified chemokine family members as novel targets of neuronal microRNAs in hepatic stellate cells[J]. J Hepatol,2013,58(2):335-341.
[20] Huang C,Xiao X,Yang Y,et al. MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation[J]. J Biol Chem,2017,292(40):16420-16439.