Chang (2019) An integrated analysis of the circRNA-miRNA-mRNA network reveals novel insights into potential mechanisms of cell proliferation during liver regeneration,

BackgroundLiver -cell proliferation occurs in hepatocellular carcinoma (HCC) and liver regeneration (LR). The development and progression of HCC and LR have many similar molecular pathways with very different results. In simple terms, LR is a controllable process of organ recovery and function reconstruction, whereas liver cancer is uncontrollable. Do they share common key pathways and genes?MethodsIn this study, the dynamic transcriptome profile at ten time points (0, 2, 6, 12, 24, 30, 36, 72, 120, and 168 hours) during LR in rats after two-thirds hepatectomy and eight stages (normal, cirrhosis without HCC, cirrhosis, low-grade dysplastic, high-grade dysplastic, and very early, early advanced, and very advanced HCC) representing a stepwise carcinogenic process from preneoplastic lesions to end-stage HCC were analyzed in detail. A variety of bioinformatic methods, including MaSigPro, weighted gene-coexpression network analysis, and spatial analysis of functional enrichment, were used to analyze, elucidate, and compare similarities and differences between LR and HCC formation.ResultsKey biological processes and genes were identified. From the comparison, we found that cell proliferation and angiogenesis were the most significantly dysregulated processes shared by LR and HCC. The pattern of cell-proliferation-related gene expression in progression stage during LR is similar to the transition process from dysplasia to early-stage HCC. LR and HCC showed different expression patterns as a whole. Some key genes, including FYN, XPO1, FOXM1, EZH2, and NRF1, were identified as playing critical roles in both LR and HCC.ConclusionThese findings could contribute to revealing the molecular mechanism of development and regulation mechanism of normal and abnormal proliferation, which could provide new ideas and treatment methods for regenerative medicine, oncological drug development, and oncological treatment.

The priming stage is the first step of liver regeneration (LR). This stage is characterized by the transition from G0 to cell cycle for 4 hours in rat. In this study, individual gene level and gene set level (GSEA) was performed to identify the candidate genes and significantly changed biological processes at 2 h after partial hepatectomy (PH). The leading edge analysis is performed to identify the key genes and iRegulon was employed for transcription factor (TF) analysis. A total of 53 differentially expressed genes were identified using RMA package based on R language at 2 h after PH, including the transcription factor, enzyme and cytokine. As the most important genes in our analysis, Socs3 was selected with a special analysis so as to find the pathways correlate to the expression of it. The changed significantly pathways in LR involved response to stress, ATP metabolism, and regulation of cell cycle mainly. Several transcription factors were identified including Stat5a, Cnot3 and zfp384. Taken together, at the early priming stage of LR in rat, the liver is experiencing some changes including response to stress, activated ATP metabolism and inhibition of cell cycle. Our analysis provided a detailed and comprehensive map for further research of the early priming stage of LR in rat.

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This study aims to reveal the regulatory mechanism of lncRNAs–miRNAs–mRNAs network during the proliferative phase of liver regeneration (LR). High‐throughput sequencing technology was performed, and a total of 1,738 differentially expressed lncRNAs (DE lncRNAs), 167 known differentially expressed miRNAs (DE miRNAs), and 2,727 differentially expressed mRNAs were identified. Then, the target DE lncRNAs and DE mRNAs regulated by the same miRNAs were screened and a ceRNA regulatory network containing 32 miRNAs, 107 lncRNAs, and 270 mRNAs was constructed. Insulin signaling pathway, pyrimidine metabolism, axon guidance, carbohydrate digestion and absorption, and pyruvate metabolism were significantly enriched in the network. Through literature review and the regulatory relationship between lncRNAs and miRNAs, nine core lncRNAs were identified, which might play important roles during the proliferative phase of rat LR. This study analyzed lncRNA–miRNA–mRNA regulatory network for the first time during the proliferative phase of rat LR, providing clues for exploring the mechanism of LR and the treatment of liver diseases.

Guo (2019) Large-scale quantitative genomics analyzes the circRNA expression profile and identifies the key circRNA in regulating cell proliferation during the proliferation phase of rat LR,

Circular RNA (circRNA) is a subclass of noncoding RNA (ncRNA) detected within mammalian tissues and cells. However, its regulatory role during the proliferation phase of rat liver regeneration (LR) remains unreported. This study was designed to explore their regulatory mechanisms in cell proliferation of LR. The circRNA expression profile was detected by high‐throughput sequencing. It was indicated that 260 circRNAs were differentially expressed during the proliferation phase of rat LR. Among them, circ‐14723 displayed a significantly differential expression. We further explored its regulatory mechanism in rat hepatocytes (BRL‐3A cells). First, EdU, flow cytometry and western blot (WB) indicated that knocking down circ‐14723 inhibited BRL‐3A cells proliferation. Second, RNA‐Pulldown and dual‐luciferase report assay showed that circ‐14723 could sponge rno‐miR‐16‐5p. At last, WB showed that the reported target genes of rno‐miR‐16‐5p, CCND1, and CCNE1 were downregulated after knocking down circ‐14723. In conclusion, we found that circ‐14723 exerted a critical role in G1/S arrest to promote cell proliferation via rno‐miR‐16‐5p/CCND1 and CCNE1 axis in rat LR. This finding further revealed the regulatory mechanisms of circRNA on cell proliferation of LR, and might provide a potential target for clinical problems.

Abstract14-3-3 proteins play a vital part in the regulation of cell cycle and apoptosis as signaling integration points. During liver regeneration, the quiescent hepatocytes go through hypertrophy and proliferation to restore liver weight. Therefore, we speculated that 14-3-3 proteins regulate the progression of liver regeneration. In this study, we analyzed the expression patterns of 14-3-3 proteins during liver regeneration of rat to provide an insight into the regenerative mechanism using western blotting. Only four isoforms (γ, ε, σ and τ/θ) of the 14-3-3 proteins were expressed in regenerative liver after partial hepatectomy (PH). The dual effects, the significant down-regulation of 14-3-3ε and the significant up-regulation of 14-3-3τ/θ at 2 h after PH, might play particularly important roles in S-phase entry. The significant peaks of 14-3-3σ at 30 h and of ε and τ/θ at 24 h might be closely related not only to the G2/M transition but also to the size of hepatocytes. Possibly, the peak of 14-3-3ε expression seen at 168 h plays critical roles in the termination of liver regeneration by inhibiting cellular proliferation.