肝再生过程中的LncRNAs调控肝细胞增殖的机制研究
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摘要
肝脏是人体各种物质代谢、能量转换的枢纽消化器官，是机体内多种重要信息调控分子的重要场所。肝脏具有很强大的再生能力，物理性及化学性创伤和各种肝脏病后，残存的肝脏组织很快会进入复杂的肝再生过程。肝再生过程基本可分为三个阶段：早期阶段（启动期），中期阶段（增殖期）和晚期阶段（终止期）。肝再生一直是肝脏研究中的一个重要焦点，原发性肝癌、肝内胆结石等肝脏病进行肝部分切除术后常因肝功能储备不足，术后并发肝功能衰竭而死亡率较高。因此研究肝再生分子机理对于解释肝脏病人肝叶切除术后残余肝脏的再生机制，实施有效的促肝细胞增殖能力的手段，减轻肝叶切除术后的肝损害及评估预后具有重要的临床意义。
因为影响肝细胞再生的机制的因素非常复杂，对肝脏再生的启动和增殖信号（包括激素、生长因子和细胞因子等）的分子机制认识有了初步了解。主要研究发现有细胞因子(IL-6、TNF-a)和转录因子(c-jun、STAT3)等组成启动肝再生的信号转导通路，进而提高促有丝分裂因子对肝细胞的增殖能力的影响从而完成肝再生启动。在多种促有丝分裂因子如肝细胞生长因子（HGF）、表皮生长因子（EGF）、转化生长因子（TGF-a）等，以及辅有丝分裂因子去甲肾上腺素和胰岛素等的共同作用下促使肝细胞进入增殖阶段，进行细胞DNA合成和细胞有丝分裂。相关基因如c-myc、β-Catenin等，一些microRNA如miR-378、miR-221、miR-21等参与了这个复杂过程，但是对肝再生的分子作用机理，特别是肝再生不同再生阶段的机制仍不清楚。全面阐释肝再生过程中的调控机制，揭示肝再生过程中调控的关键分子，是研究肝细胞再生机制的关键科学问题。
随着短链非编码RNA（如microRNA）研究的深入，和一些新的克隆、测序和芯片（tiling array）技术的应用，大量长片段的非编码RNA被发现，他们在生命活动中的重要意义逐渐被揭示。目前，将这一类转录本长度超过200nt的ncRNA称为长链非编码RNA（Long noncoding RNA, LncRNA），哺乳动物基因组序列中4%-9%的序列产生的转录本是lncRNA（相应的蛋白编码RNA的比例是1%）。已有的研究显示，lncRNA参与了X染色体沉默、基因组印记、染色质修饰、转录激活、转录干扰及核内运输等多种重要的调控过程，在生理及病理过程中发挥着重要作用。如lincRNA-p21可被p53转录活化，并且可影响众多p53靶基因的表达，在p53信号通路中起着重要的作用。Zhu等鉴定的膀胱癌中的一个长链非编码RNA-ncRAN在膀胱癌中高表达，并且和膀胱癌的侵袭、分期相关。在前期研究中本课题组利用肝癌与癌旁组织lncRNA芯片，鉴定出lncRNA-HEIH在肝癌组织中高表达，并且和病人预后成负相关，过表达lncRNA-HEIH可促进肝癌的生长。但哪些lncRNA参与了肝再生过程还未见报道。
第一部分H19通过形成myc相关的自反馈环路促进肝细胞增殖
上皮-间质转化（Epithelial-mesenchymal transition, EMT）是上皮细胞来源的恶性肿瘤细胞获得转移和侵袭能力的重要生物学过程，也是参与肝脏损伤修复的重要环节，肝再生过程中内皮细胞分泌的肝生长因子HGF可以诱导肝细胞发生上皮-间质转化（EMT），新近的研究发现肝再生过程中存在上皮-间质转化（EMT）和间质-上皮转化（MET）的平衡，某些特定类型的上皮细胞发生上皮间质转化从而能够获得间质表型，其中一些间质细胞能够产生大量的细胞外基质最终导致肝的纤维化；但是另一些间质细胞能够经过其反过程间质上皮转化，这些间质细胞重新转变成上皮细胞，最终形成正常的肝细胞，使得损伤肝脏的修复正常，因此研究肝再生过程中调控肝细胞上皮-间质转化的新分子及其作用机制，对理解肝再生损伤修复的过程的分子机制有理论意义。但目前哪些lncRNA通过调控上皮-间质转化而参与了肝再生过程还未见报道。
H19是一个已知的长2.3kb的非编码RNA分子，其母系等位基因表达，父系印迹，在哺乳动物中呈现进化上的保守性，是最早被鉴定的印迹基因之一。近年发现H19可以通过调控上皮-间质转化在胚胎发育、肿瘤发生等过程中发挥重要作用，但目前H19调控肝再生的机制还尚不明确。
因此本课题建立小鼠肝大部分切除的肝再生模型，发现了在肝再生过程中发挥重要作用的已知长链非编码RNA H19。揭示了H19在肝再生过程中的调控机制：H19的5’端可与hnRNP U蛋白相互作用，并且增强了下游c-myc mRNA的稳定性使之上调表达，从而促进了肝细胞的增殖能力。同时，c-myc可以与H19的启动子区结合从而促进了H19的上调表达，形成H19的自反馈环路。H19/hnRNP U/c-myc调控网络通过调控EMT过程增强了H19在肝再生过程中促进肝细胞增殖能力的作用。
第二部分lncRNA-LALR1通过激活Wnt/β-Catenin信号通路促进肝细胞增殖
Wnt/β-Catenin信号通路在众多组织中是调控细胞增殖、分化和迁移的重要通路，在许多组织的损伤修复中都发现存在Wnt/β-Catenin信号通路的活化，并且这种活化与组织损伤修复能力和成瘤倾向有关。在肝脏中，越来越多的证据表明Wnt/β-Catenin信号通路在肝脏的各种生物学功能中发挥着重要作用。近年来的研究表明，Wnt/β-Catenin信号通路对于肝切除术后的肝脏再生至关重要。但是哪些lncRNAs通过调控Wnt/β-Catenin信号通路促进了肝细胞的增殖及肝脏的再生依然尚未明确。
因此本课题建立小鼠肝大部分切除的肝再生模型，通过lncRNA芯片筛选得到在肝再生过程中发挥重要作用的lncRNA-LALR1。揭示了lncRNA-LALR1在肝再生过程中的调控机制：在肝再生过程中，肝生长因子HGF上调，增加了lncRNA-LALR1表达。lncRNA-LALR1通过招募转录因子CTCF到AXIN1的启动子区抑制了Axin1的表达，激活了Wnt/β-Catenin信号通路，上调了cyclin D1的表达，加速了肝细胞G1期进程，缩短了细胞周期，促进了肝细胞增殖和肝脏再生。并在肝脏移植、各种肝病及肝肿瘤病人的组织中检测lncRNA-LALR1表达量，期望lncRNA-LALR1可能成为各种肝病及肝肿瘤肝叶切除术预后评估的检测指标。
The liver is the body metabolism, energy transformation of hub organ, is the body ofimportant information in a variety of molecular "distribution center". Liver has strongregeneration ability, trauma and various liver diseases, residual liver tissue will soon intothe complex hepatic regeneration process. Liver regeneration process can be divided intothree stages: basic phase (start) at an early stage, middle stage (proliferation) and the latestage (termination). Liver regeneration is a series of physio-pathological phenomenaresulting in quantitative recovery from the loss of liver mass to compensate for decreasedhepatic volume and impaired function. Clinically, liver regeneration has importantimplications because many therapeutic strategies for the surgical treatment of liverdiseases, such as removal of liver tumors and liver transplantation, depend on the abilityof the liver to regenerate physically and functionally. Insufficient liver regeneration maybe potentially fatal for these patients. Therefore, a better understanding of themechanisms of liver regeneration could lead to clinical benefits.
Because of the many factors that affect liver cell regeneration mechanism is verycomplicated, start of liver regeneration and proliferation signal (including hormone andgrowth factors and cytokines, etc.) have a preliminary understanding the molecularmechanisms of know. Research found that cytokines IL-6, TNF-a) and the transcriptionfactor (c-jun, STAT3) and so on start the liver regeneration of the signal transductionpathways, thus improve the promoting factors of liver cell mitosis and thus the influenceof the proliferation of liver regeneration. Promote mitosis in a variety of factors such ashepatocyte growth factor (HGF), epidermal growth factor (EGF) and transforminggrowth factor (TGF-a), as well as the auxiliary mitotic factor such as norepinephrineand insulin led under the function of liver cells entered the stage of proliferation, cellDNA synthesis and cell mitosis. Related genes, such as c-myc, beta-Catenin somemicroRNA such as miR-378, miR-221and miR-21is involved in the complicatedprocess. Although various cytokines, growth factors and miRNAs have been shown toregulate genes that orchestrate proliferation during liver regeneration, new moleculartherapeutic targets for liver failure and liver transplantation are still urgently needed. It isimportant to understand the overall molecular changes that occur during liverregeneration to enhance the effectiveness of current regenerative technology. The mammalian genome encodes thousands of non-coding transcripts that have structural,regulatory or unknown functions. Although studies of small non-coding RNAs havedominated the field of RNA biology in recent years, long ncRNAs (lncRNAs)—definedas non-coding RNA molecules greater than200nucleotides in length—have been shownto play significant regulatory roles in X chromosomal inactivation, chromatin remodelingand transcriptional repression. LncRNAs also regulate multiple major biologicalprocesses, including development, differentiation and carcinogenesis. In our previouswork, we showed that lncRNA-HEIH facilitates tumor cell growth through enhancer ofzeste homolog2. A recent study has implicated lncRNAs involved in liver regeneration.However, only preliminary studies have been conducted on the role of lncRNAs in liverregeneration, and the overall mechanisms remain largely unknown.
Section I: Long noncoding RNA H19complex with RNA binding protein hnRNP Uto promote proliferation and Epithelial-to-Mesenchymal transition by c-myc-relatedpositive feedback loop during early liver regeneration in mice.
Epithelium-mesenchymal transformed (Epithelial mesenchymal transition, EMT) is asource of Epithelial cells of malignant tumor cell metastasis and invasion ability ofimportant biological processes, and is also an important link of the involved in liverinjury repair, in the process of liver regeneration in endothelial cells of hepatic growthfactor HGF may induce Epithelial and mesenchymal changes of the liver cells (EMT).Recent studies found that exist in the process of liver regeneration inepithelium-mesenchymal (EMT) and mesenchymal-epithelial transformation (MET) inthe balance, when MET process is blocked, EMT can make liver fibrosis, liver cellmalignant transformation, even also has a study of oval cells in rats after inoculated nudemice EMT performance. So the regulation of liver cells in liver regeneration and liverepithelial-mesenchymal stem cells into new molecule and its mechanism of action, tounderstand the process of liver regeneration damage repair and molecular mechanisms ofliver cancer occurrence and development has theoretical significance. But now whatlncRNAby regulating the transformation of epithelial and mesenchymal involved in liverregeneration process has not been reported. H19gene is known as a2.3kb of long noncoding RNA molecules, the gene expressionof matrilineal and patrilineal imprinting, present in mammals evolved on the conservative,is one of the earliest identified imprinted genes. In recent years found that H19canthrough regulating epithelium-mesenchymal transformed in embryonic development andplay an important role in the tumorigenesis process, however, the H19regulation of liverregeneration mechanism still remains unclear.
In the present study, we found that the expression of lncRNA-H19, and to a lesser extentlncRNA-hcn, significantly increased after PHx in mice. The overexpression oflncRNA-H19promoted hepatocyte proliferation in vitro. Additionally, we found thatlncRNA-H19interacted with the hnRNP U protein and enhanced its stability through a5′domain region of lncRNA-H19. The increased hnRNP U levels upregulated theexpression of c-myc mRNA, which contributed to the function of lncRNA-H19in liverregeneration. Furthermore, c-myc directly bound to the promoter region of lncRNA-H19and promoted the expression of lncRNA-H19. The existence of a c-myc-related positivefeedback loop augmented the effect of lncRNA-H19during early liver regeneration.
Section II: LncRNA-LALR1accelerates hepatocyte proliferation during liverregeneration by activating Wnt/β-Catenin signaling
Wnt/beta-Catenin signaling pathway in many organizations is of great importance inregulating cell proliferation, differentiation and migration pathway, in manyorganizations there is found in the damage of Wnt/beta-Catenin signaling pathwayactivation, and the activation is associated with tissue damage repair ability. Recentstudies suggest that Wnt/beta-Catenin signaling pathway in the liver plays an importantrole in various biological functions. Recent studies have shown that Wnt/beta-Cateninsignaling pathway is vital for liver regeneration after liver resection. But which lncRNAsthrough regulating the Wnt/beta-Catenin signaling pathway to promote the proliferationof liver cells and liver regeneration is still not clear.
In this study, we performed a comprehensive expression profiling analysis of lncRNAs inmouse livers at various time points after2/3PH. The overall changes in lncRNA expression were described during mouse liver regeneration, leading to the identificationof lncRNA-LALR1as a regulator of liver regeneration. LncRNA-LALR1promotedhepatocyte proliferation by facilitating cyclin D1expression through the activation ofWnt/β-Catenin signaling. This study may provide a novel mechanism and potentialtherapeutic target for liver failure and liver transplantation.
因为影响肝细胞再生的机制的因素非常复杂，对肝脏再生的启动和增殖信号（包括激素、生长因子和细胞因子等）的分子机制认识有了初步了解。主要研究发现有细胞因子(IL-6、TNF-a)和转录因子(c-jun、STAT3)等组成启动肝再生的信号转导通路，进而提高促有丝分裂因子对肝细胞的增殖能力的影响从而完成肝再生启动。在多种促有丝分裂因子如肝细胞生长因子（HGF）、表皮生长因子（EGF）、转化生长因子（TGF-a）等，以及辅有丝分裂因子去甲肾上腺素和胰岛素等的共同作用下促使肝细胞进入增殖阶段，进行细胞DNA合成和细胞有丝分裂。相关基因如c-myc、β-Catenin等，一些microRNA如miR-378、miR-221、miR-21等参与了这个复杂过程，但是对肝再生的分子作用机理，特别是肝再生不同再生阶段的机制仍不清楚。全面阐释肝再生过程中的调控机制，揭示肝再生过程中调控的关键分子，是研究肝细胞再生机制的关键科学问题。
随着短链非编码RNA（如microRNA）研究的深入，和一些新的克隆、测序和芯片（tiling array）技术的应用，大量长片段的非编码RNA被发现，他们在生命活动中的重要意义逐渐被揭示。目前，将这一类转录本长度超过200nt的ncRNA称为长链非编码RNA（Long noncoding RNA, LncRNA），哺乳动物基因组序列中4%-9%的序列产生的转录本是lncRNA（相应的蛋白编码RNA的比例是1%）。已有的研究显示，lncRNA参与了X染色体沉默、基因组印记、染色质修饰、转录激活、转录干扰及核内运输等多种重要的调控过程，在生理及病理过程中发挥着重要作用。如lincRNA-p21可被p53转录活化，并且可影响众多p53靶基因的表达，在p53信号通路中起着重要的作用。Zhu等鉴定的膀胱癌中的一个长链非编码RNA-ncRAN在膀胱癌中高表达，并且和膀胱癌的侵袭、分期相关。在前期研究中本课题组利用肝癌与癌旁组织lncRNA芯片，鉴定出lncRNA-HEIH在肝癌组织中高表达，并且和病人预后成负相关，过表达lncRNA-HEIH可促进肝癌的生长。但哪些lncRNA参与了肝再生过程还未见报道。
第一部分H19通过形成myc相关的自反馈环路促进肝细胞增殖
上皮-间质转化（Epithelial-mesenchymal transition, EMT）是上皮细胞来源的恶性肿瘤细胞获得转移和侵袭能力的重要生物学过程，也是参与肝脏损伤修复的重要环节，肝再生过程中内皮细胞分泌的肝生长因子HGF可以诱导肝细胞发生上皮-间质转化（EMT），新近的研究发现肝再生过程中存在上皮-间质转化（EMT）和间质-上皮转化（MET）的平衡，某些特定类型的上皮细胞发生上皮间质转化从而能够获得间质表型，其中一些间质细胞能够产生大量的细胞外基质最终导致肝的纤维化；但是另一些间质细胞能够经过其反过程间质上皮转化，这些间质细胞重新转变成上皮细胞，最终形成正常的肝细胞，使得损伤肝脏的修复正常，因此研究肝再生过程中调控肝细胞上皮-间质转化的新分子及其作用机制，对理解肝再生损伤修复的过程的分子机制有理论意义。但目前哪些lncRNA通过调控上皮-间质转化而参与了肝再生过程还未见报道。
H19是一个已知的长2.3kb的非编码RNA分子，其母系等位基因表达，父系印迹，在哺乳动物中呈现进化上的保守性，是最早被鉴定的印迹基因之一。近年发现H19可以通过调控上皮-间质转化在胚胎发育、肿瘤发生等过程中发挥重要作用，但目前H19调控肝再生的机制还尚不明确。
因此本课题建立小鼠肝大部分切除的肝再生模型，发现了在肝再生过程中发挥重要作用的已知长链非编码RNA H19。揭示了H19在肝再生过程中的调控机制：H19的5’端可与hnRNP U蛋白相互作用，并且增强了下游c-myc mRNA的稳定性使之上调表达，从而促进了肝细胞的增殖能力。同时，c-myc可以与H19的启动子区结合从而促进了H19的上调表达，形成H19的自反馈环路。H19/hnRNP U/c-myc调控网络通过调控EMT过程增强了H19在肝再生过程中促进肝细胞增殖能力的作用。
第二部分lncRNA-LALR1通过激活Wnt/β-Catenin信号通路促进肝细胞增殖
Wnt/β-Catenin信号通路在众多组织中是调控细胞增殖、分化和迁移的重要通路，在许多组织的损伤修复中都发现存在Wnt/β-Catenin信号通路的活化，并且这种活化与组织损伤修复能力和成瘤倾向有关。在肝脏中，越来越多的证据表明Wnt/β-Catenin信号通路在肝脏的各种生物学功能中发挥着重要作用。近年来的研究表明，Wnt/β-Catenin信号通路对于肝切除术后的肝脏再生至关重要。但是哪些lncRNAs通过调控Wnt/β-Catenin信号通路促进了肝细胞的增殖及肝脏的再生依然尚未明确。
因此本课题建立小鼠肝大部分切除的肝再生模型，通过lncRNA芯片筛选得到在肝再生过程中发挥重要作用的lncRNA-LALR1。揭示了lncRNA-LALR1在肝再生过程中的调控机制：在肝再生过程中，肝生长因子HGF上调，增加了lncRNA-LALR1表达。lncRNA-LALR1通过招募转录因子CTCF到AXIN1的启动子区抑制了Axin1的表达，激活了Wnt/β-Catenin信号通路，上调了cyclin D1的表达，加速了肝细胞G1期进程，缩短了细胞周期，促进了肝细胞增殖和肝脏再生。并在肝脏移植、各种肝病及肝肿瘤病人的组织中检测lncRNA-LALR1表达量，期望lncRNA-LALR1可能成为各种肝病及肝肿瘤肝叶切除术预后评估的检测指标。
The liver is the body metabolism, energy transformation of hub organ, is the body ofimportant information in a variety of molecular "distribution center". Liver has strongregeneration ability, trauma and various liver diseases, residual liver tissue will soon intothe complex hepatic regeneration process. Liver regeneration process can be divided intothree stages: basic phase (start) at an early stage, middle stage (proliferation) and the latestage (termination). Liver regeneration is a series of physio-pathological phenomenaresulting in quantitative recovery from the loss of liver mass to compensate for decreasedhepatic volume and impaired function. Clinically, liver regeneration has importantimplications because many therapeutic strategies for the surgical treatment of liverdiseases, such as removal of liver tumors and liver transplantation, depend on the abilityof the liver to regenerate physically and functionally. Insufficient liver regeneration maybe potentially fatal for these patients. Therefore, a better understanding of themechanisms of liver regeneration could lead to clinical benefits.
Because of the many factors that affect liver cell regeneration mechanism is verycomplicated, start of liver regeneration and proliferation signal (including hormone andgrowth factors and cytokines, etc.) have a preliminary understanding the molecularmechanisms of know. Research found that cytokines IL-6, TNF-a) and the transcriptionfactor (c-jun, STAT3) and so on start the liver regeneration of the signal transductionpathways, thus improve the promoting factors of liver cell mitosis and thus the influenceof the proliferation of liver regeneration. Promote mitosis in a variety of factors such ashepatocyte growth factor (HGF), epidermal growth factor (EGF) and transforminggrowth factor (TGF-a), as well as the auxiliary mitotic factor such as norepinephrineand insulin led under the function of liver cells entered the stage of proliferation, cellDNA synthesis and cell mitosis. Related genes, such as c-myc, beta-Catenin somemicroRNA such as miR-378, miR-221and miR-21is involved in the complicatedprocess. Although various cytokines, growth factors and miRNAs have been shown toregulate genes that orchestrate proliferation during liver regeneration, new moleculartherapeutic targets for liver failure and liver transplantation are still urgently needed. It isimportant to understand the overall molecular changes that occur during liverregeneration to enhance the effectiveness of current regenerative technology. The mammalian genome encodes thousands of non-coding transcripts that have structural,regulatory or unknown functions. Although studies of small non-coding RNAs havedominated the field of RNA biology in recent years, long ncRNAs (lncRNAs)—definedas non-coding RNA molecules greater than200nucleotides in length—have been shownto play significant regulatory roles in X chromosomal inactivation, chromatin remodelingand transcriptional repression. LncRNAs also regulate multiple major biologicalprocesses, including development, differentiation and carcinogenesis. In our previouswork, we showed that lncRNA-HEIH facilitates tumor cell growth through enhancer ofzeste homolog2. A recent study has implicated lncRNAs involved in liver regeneration.However, only preliminary studies have been conducted on the role of lncRNAs in liverregeneration, and the overall mechanisms remain largely unknown.
Section I: Long noncoding RNA H19complex with RNA binding protein hnRNP Uto promote proliferation and Epithelial-to-Mesenchymal transition by c-myc-relatedpositive feedback loop during early liver regeneration in mice.
Epithelium-mesenchymal transformed (Epithelial mesenchymal transition, EMT) is asource of Epithelial cells of malignant tumor cell metastasis and invasion ability ofimportant biological processes, and is also an important link of the involved in liverinjury repair, in the process of liver regeneration in endothelial cells of hepatic growthfactor HGF may induce Epithelial and mesenchymal changes of the liver cells (EMT).Recent studies found that exist in the process of liver regeneration inepithelium-mesenchymal (EMT) and mesenchymal-epithelial transformation (MET) inthe balance, when MET process is blocked, EMT can make liver fibrosis, liver cellmalignant transformation, even also has a study of oval cells in rats after inoculated nudemice EMT performance. So the regulation of liver cells in liver regeneration and liverepithelial-mesenchymal stem cells into new molecule and its mechanism of action, tounderstand the process of liver regeneration damage repair and molecular mechanisms ofliver cancer occurrence and development has theoretical significance. But now whatlncRNAby regulating the transformation of epithelial and mesenchymal involved in liverregeneration process has not been reported. H19gene is known as a2.3kb of long noncoding RNA molecules, the gene expressionof matrilineal and patrilineal imprinting, present in mammals evolved on the conservative,is one of the earliest identified imprinted genes. In recent years found that H19canthrough regulating epithelium-mesenchymal transformed in embryonic development andplay an important role in the tumorigenesis process, however, the H19regulation of liverregeneration mechanism still remains unclear.
In the present study, we found that the expression of lncRNA-H19, and to a lesser extentlncRNA-hcn, significantly increased after PHx in mice. The overexpression oflncRNA-H19promoted hepatocyte proliferation in vitro. Additionally, we found thatlncRNA-H19interacted with the hnRNP U protein and enhanced its stability through a5′domain region of lncRNA-H19. The increased hnRNP U levels upregulated theexpression of c-myc mRNA, which contributed to the function of lncRNA-H19in liverregeneration. Furthermore, c-myc directly bound to the promoter region of lncRNA-H19and promoted the expression of lncRNA-H19. The existence of a c-myc-related positivefeedback loop augmented the effect of lncRNA-H19during early liver regeneration.
Section II: LncRNA-LALR1accelerates hepatocyte proliferation during liverregeneration by activating Wnt/β-Catenin signaling
Wnt/beta-Catenin signaling pathway in many organizations is of great importance inregulating cell proliferation, differentiation and migration pathway, in manyorganizations there is found in the damage of Wnt/beta-Catenin signaling pathwayactivation, and the activation is associated with tissue damage repair ability. Recentstudies suggest that Wnt/beta-Catenin signaling pathway in the liver plays an importantrole in various biological functions. Recent studies have shown that Wnt/beta-Cateninsignaling pathway is vital for liver regeneration after liver resection. But which lncRNAsthrough regulating the Wnt/beta-Catenin signaling pathway to promote the proliferationof liver cells and liver regeneration is still not clear.
In this study, we performed a comprehensive expression profiling analysis of lncRNAs inmouse livers at various time points after2/3PH. The overall changes in lncRNA expression were described during mouse liver regeneration, leading to the identificationof lncRNA-LALR1as a regulator of liver regeneration. LncRNA-LALR1promotedhepatocyte proliferation by facilitating cyclin D1expression through the activation ofWnt/β-Catenin signaling. This study may provide a novel mechanism and potentialtherapeutic target for liver failure and liver transplantation.
引文
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