Mechanism Underlying The Regulation Of Hepatocyte Proliferation By LncRNAs During Liver Regeneration

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 signalingWnt/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.