Wang Tianqi, Zhang Chong, Meng Xiaoming, Zhu Benshuai, Wang Siyu, Yuan Wenkang, Zhang Sumei, Xu Jiegou, Zhang Chao
Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
Front Physiol. 2022 Feb 14;13:792182. doi: 10.3389/fphys.2022.792182. eCollection 2022.
Evidence shows that the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (Lnc-MALAT1) is associated with activation of hepatic stellate cells (HSCs) and liver fibrosis in animal and studies. However, its roles in human liver fibrosis and the underlying mechanism in HSC activation are not yet defined. In our current study, the expression of Lnc-MALAT1 in the fibrotic liver tissues and in the plasma extracelllar vesicles (EVs) of liver fibrosis patients was detected by FISH and qRT-PCR. The results revealed that enhanced expression of Lnc-MALAT1 was co-localized with increased expression of the fibrotic markers (collagen I and α-SMA) and the Wnt/β-catenin signaling proteins (β-catenin, cyclinD1 and c-myc) in the fibrotic liver tissues. The level of Lnc-MALAT1 in the plasma EVs isolated from 60 liver fibrosis patients was significantly increased compared with that of the 46 control patients, and area under receiver operating curve (AUROC) analysis showed that plasma EVs-Lnc-MALAT1 was a potential diagnostic marker for liver fibrosis, especially for high liver fibrosis. Plasma EVs with highly expressed Lnc-MALAT1 derived from high liver fibrosis patients up-regulated the expression of the fibrotic markers and enhanced the Wnt/β-catenin signaling in human hepatic stellate cells LX-2, and the fibrogenic effects in LX-2 were inhibited by Lnc-MALAT1 knock-down. Interestingly, TGF-β1, a potent pro-fibrotic cytokine, promoted the expression of Lnc-MALAT1 in LX-2 and its pro-fibrotic effects were also abolished by siRNA for Lnc-MALAT1, suggesting that Lnc-MALAT1 probably functions as a common mediator in the activation and fibrogenesis of HSCs. Our results indicate that enhanced expression of Lnc-MALAT1 in the fibrotic liver stimulate the activation of HSCs and thus promote their fibrogenic activity. These results also provide evidences that Lnc-MALAT1 is a potential therapeutic target and plasma EVs-Lnc-MALAT1 is a potential diagnostic biomarker for liver fibrosis.
证据表明，在动物和研究中，长链非编码RNA转移相关肺腺癌转录本1（Lnc-MALAT1）与肝星状细胞（HSC）的激活及肝纤维化有关。然而，其在人类肝纤维化中的作用以及HSC激活的潜在机制尚未明确。在我们目前的研究中，通过荧光原位杂交（FISH）和定量逆转录聚合酶链反应（qRT-PCR）检测了Lnc-MALAT1在肝纤维化患者纤维化肝组织和血浆细胞外囊泡（EV）中的表达。结果显示，在纤维化肝组织中，Lnc-MALAT1表达增强与纤维化标志物（I型胶原蛋白和α-平滑肌肌动蛋白）以及Wnt/β-连环蛋白信号蛋白（β-连环蛋白、细胞周期蛋白D1和c-myc）表达增加共定位。与46名对照患者相比，从60名肝纤维化患者分离的血浆EV中Lnc-MALAT1水平显著升高，受试者工作特征曲线下面积（AUROC）分析表明，血浆EV-Lnc-MALAT1是肝纤维化尤其是重度肝纤维化的潜在诊断标志物。来自重度肝纤维化患者的高表达Lnc-MALAT1的血浆EV上调了人肝星状细胞LX-2中纤维化标志物的表达并增强了Wnt/β-连环蛋白信号，而Lnc-MALAT1敲低可抑制LX-2中的纤维化作用。有趣的是，一种强效促纤维化细胞因子转化生长因子-β1（TGF-β1）促进了LX-2中Lnc-MALAT1的表达，其促纤维化作用也被Lnc-MALAT1的小干扰RNA（siRNA）消除，这表明Lnc-MALAT1可能在HSC激活和纤维化过程中起共同介质的作用。我们的结果表明，纤维化肝中Lnc-MALAT1表达增强会刺激HSC激活，从而促进其纤维化活性。这些结果还提供了证据，表明Lnc-MALAT1是潜在的治疗靶点，而血浆EV-Lnc-MALAT1是肝纤维化的潜在诊断生物标志物。
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