Proliferation Of Hepatic Cells Research Articles

Retracted: miR-10b-5p Suppresses the Proliferation and Invasion of Primary Hepatic Carcinoma Cells by Downregulating EphA2.

[This retracts the article DOI: 10.1155/2021/1382061.].

Testosterone, β-estradiol, and hepatocellular carcinoma: stimulation or inhibition? A comparative effect analysis on cell cycle, apoptosis, and Wnt signaling of HepG2 cells.

Unlike breast and prostate cancers, which are specifically affected by estrogens or androgens, hepatocellular carcinoma has been reported to be influenced by both sex hormones. Given the coincidental differences of hepatocellular carcinoma in men and women, we investigated the effects of β-estradiol and testosterone on the cell cycle, apoptosis, and Wnt signaling in a model of hepatocellular carcinoma to understand the sex hormone-related etiology. To determine the effective concentration of both hormones, an MTT assay was performed. The effects of β-estradiol and testosterone on cell proliferation and death were evaluated by specific staining and flow cytometry. In addition, gene expression levels of estimated factors involved in GPC3-Wnt survival signaling were analyzed using quantitative real-time polymerase chain reaction. Both hormones inhibited hepatic cell proliferation through arresting the cell cycle at S/G2 and increased the apoptosis rate in HepG2 cells. Both hormones dose-dependently decreased GPC3, Wnt, and DVL expression levels as activators of the Wnt-signaling pathway. In the case of Wnt-signaling inhibitors, the effects of both hormones on WIF were negligible, but they increased DKK1 levels in a dose-dependent manner. In each of the effects mentioned above, β-estradiol was notably more potent than testosterone. In contrast to the primary hypothesis of the project, in which testosterone was considered a stimulating carcinogenic factor in HCC pathogenesis, testosterone inhibited the occurrence of HCC similarly to β-estradiol. However, this inhibitory effect was weaker than that of β-estradiol and requires further study.

Implicating the cholecystokinin B receptor in liver stem cell oncogenesis.

Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related deaths worldwide. Chronic inflammation and fibrosis are the greatest risk factors for the development of HCC. Although the cell of origin for HCC is uncertain, many theories believe this cancer may arise from liver progenitor cells or stem cells. Here, we describe the activation of hepatic stem cells that overexpress the cholecystokinin-B receptor (CCK-BR) after liver injury with either a DDC diet (0.1% 3, 5-diethoxy-carbonyl 1,4-dihydrocollidine) or a NASH-inducing CDE diet (choline-deficient ethionine) in murine models. Pharmacologic blockade of the CCK-BR with a receptor antagonist proglumide or knockout of the CCK-BR in genetically engineered mice during the injury diet reduces the expression of hepatic stem cells and prevents the formation of three-dimensional tumorspheres in culture. RNA sequencing of livers from DDC-fed mice treated with proglumide or DDC-fed CCK-BR knockout mice showed downregulation of differentially expressed genes involved in cell proliferation and oncogenesis and upregulation of tumor suppressor genes compared with controls. Inhibition of the CCK-BR decreases hepatic transaminases, fibrosis, cytokine expression, and alters the hepatic immune cell signature rendering the liver microenvironment less oncogenic. Furthermore, proglumide hastened recovery after liver injury by reversing fibrosis and improving markers of synthetic function. Proglumide is an older drug that is orally bioavailable and being repurposed for liver conditions. These findings support a promising therapeutic intervention applicable to patients to prevent the development of HCC and decrease hepatic fibrosis.NEW & NOTEWORTHY This investigation identified a novel pathway involving the activation of hepatic stem cells and liver oncogenesis. Receptor blockade or genetic disruption of the cholecystokinin-B receptor (CCK-BR) signaling pathway decreased the activation and proliferation of hepatic stem cells after liver injury without eliminating the regenerative capacity of healthy hepatocytes.

Gliosis induction on locus coeruleus in a living liver donor experimental model: A brief review.

Living Donor Liver Transplantation (LDLT) is a promising approach to treating end-stage liver diseases, however, some post-operatory complications such as pneumonia, bacteremia, urinary tract infections, and hepatic dysfunction have been reported. In murine models using partial hepatectomy (PHx), a model that emulates LDLT, it has been determined that the synthesis of hepatic cell proliferation factors that are associated with noradrenaline synthesis are produced in locus coeruleus (LC). In addition, studies have shown that PHx decreases GABA and 5-HT2A receptors, promotes loss of dendritic spines, and favors microgliosis in rat hippocampus. The GABA and serotonin-altered circuits suggest that catecholaminergic neurons such as dopamine and noradrenaline neurons, which are highly susceptible to cellular stress, can also be damaged. To understand post-transplant affections and to perform well-controlled studies it is necessary to know the potential causes that explain as a liver surgical procedure can produce brain damage. In this paper, we review several cellular processes that could induce gliosis in LC after rat PHx.

Corydaline binds to a druggable pocket of hEAG1 channel and inhibits hepatic carcinoma cell viability

Ether-à-go-go (EAG) potassium channels play a crucial role in the regulation of neuronal excitability and cancer progression, rendering them potential drug targets for cancer therapy. However, the scarcity of information regarding the selection sites on hEAG1 has posed a challenge in the discovery of new hEAG1 inhibitors. In this study, we introduced a novel natural product, corydaline, which selectively inhibits the hEAG1 channel without sensitivity to other KCNH channels. The IC50 of corydaline for the hEAG1 channel was 11.3 ± 0.6 μM, whereas the IC50 for hEAG2 and hERG1 were 73.6 ± 9.9 μM and 111.4 ± 8.5 μM, respectively. Molecular dynamics simulations together with site-directed mutagenesis, have unveiled that the site corydaline forms interactions with Lys217, Phe273, Pro276, Trp295 and Arg366, situated within the intracellular transmembrane segments S1–S4 of the voltage-sensor domain, be considered a novel drug pocket for hEAG1. Additionally, the intergaration of sequence alignment and 3D structural modeling revealed differences between the voltage sensor domain of hEAG1 channel and other EAG channels, suggesting the feasibility of a VSD modulation approach that could potentially lead to the selective inhibition of hEAG1 channels. Furthermore, antitumor experiments demonstrated that corydaline can inhibit the proliferation and migration of hepatic carcinoma cells by targeting hEAG1. The identification of this novel druggable pocket offers the possibility for drug screening against diseases linked to abnormal hEAG1 channels.

A combined bioinformatics and experimental approach identifies RMI2 as a Wnt/β-catenin signaling target gene related to hepatocellular carcinoma

BackgroundThe Wnt/β-catenin signaling pathway plays an important role in embryogenesis and tumorigenesis. In human cancer, abnormal activity of Wnt/β-catenin signaling pathway induces overexpressed of downstream genes, and initiate oncogene. There are several target genes known to be key players in tumorigenesis, such as c-myc, cyclin D1, MMPs or survivin. Therefore, identifying the target genes of Wnt/β-catenin signaling pathway is important to understanding Wnt/β-catenin-mediated carcinogenesis. In this study, we developed a combined bioinformatics and experimental approach to find potential target genes.MethodsLuciferase reporter assay was used to analyze the promoter activity of RMI2. WST1 cell proliferation assays and transwell assays were performed to determine the proliferation and migration capacities of RMI2 overexpressing or knockdown stable hepatic cells. Finally, xenograft experiments were performed to measure the tumor formation capacity in vivo.ResultsThe results showed that RMI2 mRNA was upregulated after LiCl treatment and Wnt3a-conditioned medium in a culture of SK-hep-1 cell lines. A chromatin immunoprecipitation (ChIP) assay showed that the β-catenin/T cell-specific factor (TCF) complex binds to the putative TCF binding site of the RMI2 promoter. We then found a TCF binding site at − 333/− 326 of the RMI2 promoter, which is crucial for β-catenin responsiveness in liver cell lines. RMI2 was overexpressed in hepatoma tissue and cell lines, and it promoted the migration and invasion of HCC cells. Moreover, RMI2 upregulated the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt3a/β-catenin-related genes, but silencing RMI2 had the opposite effects. Notably, the expression of RMI2 was positively correlated with the clinical data of HCC patients who had significantly shorter overall survival (OS) and disease-free survival (DFS) (Both: P < 0.05). In addition, a total of 373 HCC patients’ data from the Caner Genome Atlas project (TCGA) were used to validate our findings.ConclusionsTaking all these findings together, we determined that RMI2 was a new target gene of the Wnt/β-catenin signaling pathway. We also found that RMI2 promotes EMT markers, HCC cell invasion, and metastasis, which indicated that RMI2 is a potential target for preventing or at least mitigating the progression of HCC.

Efficacy of Autologous Skeletal Myoblast Cell Sheet Transplantation for Liver Regeneration in Liver Failure.

No effective therapies have yet been established for liver regeneration in liver failure. Autologous skeletal myoblast cell sheet transplantation has been proven to improve cardiac function in patients with heart failure, and one of the mechanisms has been reported to be a paracrine effect by various growth factors associated with liver regeneration. Therefore, the present study focused on the effect of myoblast cells on liver regeneration in vitro and in vivo. We assessed the effect of myoblast cells on the cells comprising the liver in vitro in association with liver regeneration. In addition, we examined in vivo effect of skeletal myoblast cell sheet transplantation in C57/BL/6 mouse models of liver failure, such as liver fibrosis induced by thioacetamide and hepatectomy. In vitro, the myoblast cells exhibited a capacity to promote the proliferation of hepatic epithelial cells and the angiogenesis of liver sinusoidal endothelial cells, and suppress the activation of hepatic stellate cells. In vivo, sheet transplantation significantly suppressed liver fibrosis in the induced liver fibrosis model and accelerated liver regeneration in the hepatectomy model. Autologous skeletal myoblast cell sheet transplantation significantly improved the liver failure in the in vitro and in vivo models. Sheet transplantation is expected to have the potential to be a clinically therapeutic option for liver regeneration in liver failure.

Sublethal necroptosis signaling promotes inflammation and liver cancer

It is currently not well known how necroptosis and necroptosis responses manifest invivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

Antioxidant, Anti-Inflammatory, Antimicrobial, and Anticancer Activities of Pomegranate Juice Concentrate.

Pomegranate juice concentrate (PJC) is a rich source of polyphenols, which exhibit significant antioxidant activity and potential health benefits for disease prevention and therapy. In this study, the polyphenolic profile of PJC was investigated for the first time, and it was found that PJC can inhibit oxidative damage to bovine serum albumin (BSA) and deoxyribonucleic acid (DNA), as well as acetylcholinesterase, α-amylase, and tyrosinase activities. The primary polyphenols identified in PJC were 4-Hydroxy-3-Methoxybenzoate, epicatechin, catechin, rutin, ferulic acid, P-coumaric acid, and cinnamic acid. Additionally, PJC demonstrated potent antibacterial effects against human pathogens such as Streptococcus mutans and Aeromonas hydrophila and dose-dependently reduced the proliferation of colorectal, breast, and hepatic cancer cells via apoptosis. Furthermore, PJC blocked B-cell lymphoma 2 (BCl-2) and the expression of a potent cyclin-dependent kinase inhibitor (P21) and enhanced tumor protein (P53) expression, compared to both untreated cells and cells treated with fluoropyrimidine 5-fluorouracil (5-FU). As a result, PJC may be a beneficial ingredient in the formulation of emerging natural-compound-based chemotherapy and functional foods and could be utilized by the food, nutraceutical, and pharmaceutical industries.

Rutin Inhibits Hepatic and Pancreatic Cancer Cell Proliferation by Inhibiting CYP3A4 and GST

Abstract: Background: Digestive cancer is among the major causes of mortality and morbidity worldwide. Rutin, a bioactive secondary metabolite belonging to flavonoids and distributed in many fruits and vegetables has shown anti-proliferative, anti-cancer, and neuroprotective activities. In this study, the antiproliferative, antioxidant and apoptotic activities of rutin on hepatic and pancreatic cancer cell lines were investigated. Materials and Methods: The effect on cellular viability was monitored by SRB assay. Increasing activity of caspases (3/7) was used as an indicator of apoptosis. Additionally, the anti-inflammatory and antioxidant activities of rutin were evaluated after measuring amount of prostaglandin E2 (PGE2) produced and through DPPH free radical scavenging assays, respectively. Moreover, the inhibitory effect on both CYP3A4 and GST enzymes has also been evaluated. Results: According to the data presented here, rutin has anti-proliferative effect and raises the number of caspases 3/7 in investigated cell lines. Conclusion: HepG-2 cells showed the highest cellular growth inhibition, followed by BxPC-3, Huh-7, MiaPaCa-2, Suit-2, and the normal cell line HPDE. Rutin also inhibited the cyctochrome P450 enzyme (CYP450 3A4) and glutatihione-S-transferase activity, with dose-dependent inhibition. Furthermore, suppression of PGE2 synthesis in BxPC-3 cells supported rutin's anti-inflammatory action (high COX-2 expression). Keywords: Rutin, Pancreatic and Liver cancer, Apoptosis and Anti-inflammatory, Antioxidant.

Abstract 254: Apolipoprotein B Mediates Hepatic Proliferation And Cell Survival Signalling: A Crispr/cas-9 Gene Editing ApoB-knockout Study

Introduction: Apolipoprotein B (ApoB) is a key structure protein in very-low-density lipoprotein (VLDL). Ample research has been focusing on its crucial role in lipoprotein metabolism and the onset of cardiovascular disease (CVD). However, in vivo research on the broader pathophysiological function of ApoB has been hindered by the embryonic lethality of ApoB knockout (ApoB-KO) animal models. Thus, the objective of this study is to establish ApoB-KO cell models and demonstrate ApoB as a key determinant in governing hepatocyte proliferation and apoptosis. Approaches and Results: the Crispr/Cas-9 gene editing technology was applied to genetically disrupt ApoB expression in both human and mouse hepatocytes. Total RNAs of the parental and ApoB-KO cells were subjected to RNA sequencing profiling for whole transcriptome. Subsequent bioinformatics analysis revealed that ApoB-KO significantly altered expression of more than 2000 genes in hepatocytes. More importantly, expression of genes involved in DNA replication, cell cycle, cell proliferation and apoptotic signaling were the genes mostly affected, which were either up- or down-regulated by more than 5-folds. These included the histone associated genes H2ac10-12, cyclin Ccna2, Ccnb1 and Cdc20, cell proliferation gene Fosb and apoptosis gene P53. A BrDU cell proliferation assay detecting the actively proliferating cells further demonstrated that depletion of ApoB greatly inhabited cell proliferation, indicated by the markedly reduced cell numbers and the prolonged cell doubling time in ApoB-KO cells compared to their parental cells. Mechanistic study revealed that cAMP signaling, and the insulin associated PI3K kinase pathway that medicated gene transcription, cell growth and proliferation were profoundly impaired upon ApoB depletion. Reconstitution of ApoB in the KO cells by expressing a truncated ApoB protein, ApoB72, was able to promote cell growth rate and improve cell survival to a level comparable to the parental cells. Conclusion: This is the first study that characterizes a novel function of ApoB as a key determinant in hepatic cell proliferation and survival pathways. This novel finding greatly advances our knowledge of ApoB beyond the boundary of VLDL metabolism and CVD.

SH3BGRL Suppresses Liver Tumor Progression through Enhanced ATG5-Dependent Autophagy.

SH3BGRL, an adaptor protein, is upregulated in breast cancers and indicates its tumorigenic role. But the function of SH3BGRL in other types of cancers is largely unknown. Here, we modulate SH3BGRL expression level in two liver cancer cells and conduct both in vitro and in vivo analyses of SH3BGRL in cell proliferation and tumorigenesis. Results demonstrate that SH3BGRL notably inhibits cell proliferation and arrests the cell cycle in both LO2 and HepG2 cells. Molecularly, SH3BGRL upregulates the expression of ATG5 from proteasome degradation as well as the inhibitions of Src activation and its downstream ERK and AKT signaling pathways, which eventually enhance autophagic cell death. The xenograft mouse model reveals that SH3BGRL overexpression can efficiently suppress tumorigenesis in vivo, while the additional silencing ATG5 in SH3BGRL-overexpressing cells attenuates the inhibitory effect of SH3BGRL on both hepatic tumor cell proliferation and tumorigenicity in vivo. The relevance of SH3BGRL downregulation in liver cancers and their progression is validated based on the large-scale tumor data. Taken together, our results clarify the suppressive role of SH3BGRL in tumorigenesis of liver cancer, which would be of help to the diagnosis of liver cancer, while either promoting the autophagy of liver cancer cells or inhibiting the downstream signaling induced from SH3BGRL downregulation would be a promising therapy.

Differential Impact of Intermittent vs. Sustained Hypoxia on HIF-1, VEGF and Proliferation of HepG2 Cells.

Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main landmark of OSA, and local sustained hypoxia (SH), a classical feature at the core of tumors, may act separately or synergistically on tumor cells. Our aim was to compare the respective consequences of intermittent and sustained hypoxia on HIF-1, endothelin-1 and VEGF expression and on cell proliferation and migration in HepG2 liver tumor cells. Wound healing, spheroid expansion, proliferation and migration were evaluated in HepG2 cells following IH or SH exposure. The HIF-1α, endothelin-1 and VEGF protein levels and/or mRNA expression were assessed, as were the effects of HIF-1 (acriflavine), endothelin-1 (macitentan) and VEGF (pazopanib) inhibition. Both SH and IH stimulated wound healing, spheroid expansion and proliferation of HepG2 cells. HIF-1 and VEGF, but not endothelin-1, expression increased with IH exposure but not with SH exposure. Acriflavine prevented the effects of both IH and SH, and pazopanib blocked those of IH but not those of SH. Macitentan had no impact. Thus, IH and SH stimulate hepatic cancer cell proliferation via distinct signaling pathways that may act synergistically in OSA patients with cancer, leading to enhanced tumor progression.

A Comprehensive Genome-Wide Analysis of lncRNA Expression Profile during Hepatic Carcinoma Cell Proliferation Promoted by Phospholipase Cγ2

A Comprehensive Genome-Wide Analysis of lncRNA Expression Profile during Hepatic Carcinoma Cell Proliferation Promoted by Phospholipase Cγ2

In vitro expansion of human mesenchymal stem cells and hepatocytes using purified platelet derived growth factors, a potential therapeutic modality for liver fibrosis

Mesenchymal stem cells (MSCs) and hepatocytes are considered valuable candidates for cell-based therapy. The use of free zoonotic media, as purified platelets derived growth factors (L-GF) and human platelet lysate (hPL), instead of using fetal bovine serum (FBS) to support the growth and proliferation of these cells could be used as a promising therapeutic tool in hepatic regeneration. This study aimed to evaluate the usage of purified platelet derived growth factors and platelet lysate in both MSCs and hepatocyte cultures and to compare them with the usage of FBS. MSCs and hepatocytes were cultured in growth media supplemented with L-GF or hPL and compared them to their culture in growth media supplemented with FBS. Cells were subjected to population doubling (PD) and generation time (GT) calculations. The best result for MSCs was that obtained by using 10% hPL or 10% FBS with the highest cell count, highest viability and shortest incubation time needed to reach confluency compared to supplementation with 10%, 20% or 30% L-GF. As for hepatocyte culture, the use of 10% FBS for supplementation of media used for hepatic cell proliferation showed better performance regarding cell count, viability, and incubation time to reach confluency compared to the use of either hPL or L-GF. In conclusion, our study showed that 10% hPL had the best results in MSCs culture which suggests that hPL could be a better alternative for the development of xenofree stem cell culture that can be used for many clinical applications. On the other hand, 10% FBS showed the best results in hepatocyte culture.

LncRNA SNHG12 promotes proliferation and migration of hepatic progenitor cells via the Wnt/β-catenin pathway.

Hepatic progenitor cells (HPCs) play an important role in the treatment of chronic liver disease. To investigate the effect and mechanism of long noncoding RNAs/small nucleolar RNA host gene 12 (lncRNA SNHG12) on the proliferation and migration of the HPC cell line WB-F344. Hepatic progenitor cells were divided into a no-treatment group (sham), empty vector transfection of plasmid pcDNA3.1 (NC vector), pcDNA3.1-SNHG12 (SNHG12), negative short hairpin RNA (sh-NC), SNHG12 shRNA (sh-SNHG12), and pcDNA3.1-SNHG12+salinomycin intervention (SNHG12+salinomycin) groups. Cell proliferation, cell cycle and migration ability, as well as albumin (ALB), alpha-fetoprotein (AFP), â-catenin, cyclin D1, and c-Myc protein expression in each group were determined using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell migration assays, enzyme-linked immunosorbent assay (ELISA), and western blot. The overexpression of lncRNA SNHG12 significantly upregulated proliferation, migration and cell cycle progression of WB-F344 cells. Furthermore, the overexpression of lncRNA SNHG12 increased the level of ALB, and the protein expression of â-catenin, cyclin D1 and c-Myc in the cell line, while decreasing the level of AFP. Conversely, the knockdown of lncRNA SNHG12 displayed the opposite effects. The inhibition of the Wnt/â-catenin signaling pathway with salinomycin significantly downregulated the â-catenin, cyclin D1 and c-Myc protein expression in WB-F344 cells. The lncRNA SNHG12 promotes the proliferation and migration of WB-F344 cells via activating the Wnt/â-catenin pathway.

The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics

The proliferation and differentiation of hepatic progenitor cells (HPCs) drive the homeostatic renewal of the liver under diverse conditions. Liver regeneration is associated with an increase in Axin2+Cnr1+ HPCs, along with a marked increase in the levels of the endocannabinoid anandamide (AEA). But the molecular mechanism linking AEA signaling to HPC proliferation and/or differentiation has not been explored. Here, we show that in vitro exposure of HPCs to AEA triggers both cell cycling and differentiation along with increased expression of Cnr1, Krt19, and Axin2. Mechanistically, we found that AEA promotes the nuclear localization of the transcription factor β-catenin, with subsequent induction of its downstream targets. Systemic analyses of cells after CRISPR-mediated knockout of the β-catenin-regulated transcriptome revealed that AEA modulates β-catenin-dependent cell cycling and differentiation, as well as interleukin pathways. Further, we found that AEA promotes OXPHOS in HPCs when amino acids and glucose are readily available as substrates, but AEA inhibits it when the cells rely primarily on fatty acid oxidation. Thus, the endocannabinoid system promotes hepatocyte renewal and maturation by stimulating the proliferation of Axin2+Cnr1+ HPCs via the β-catenin pathways while modulating the metabolic activity of their precursor cells.

Ypel5 regulates liver development and function in zebrafish.

YPEL5 is a member of the Yippee-like (YPEL) gene family that is evolutionarily conserved in eukaryotic species. To date, the physiological function of YPEL5 has not been assessed due to a paucity of genetic animal models. Here, using CRISPR/Cas9-mediated genome editing, we generated a stable ypel5-/- mutant zebrafish line. Disruption of ypel5 expression leads to liver enlargement associated with hepatic cell proliferation. Meanwhile, hepatic metabolism and function are dysregulated in ypel5-/- mutant zebrafish, as revealed by metabolomic and transcriptomic analyses. Mechanistically, Hnf4a is identified as a crucial downstream mediator that is positively regulated by Ypel5. Zebrafish hnf4a overexpression could largely rescue ypel5 deficiency-induced hepatic defects. Furthermore, PPARα signaling mediates the regulation of Hnf4a by Ypel5 through directly binding to the transcriptional enhancer of the Hnf4a gene. Herein, this work demonstrates an essential role of Ypel5 in hepatocyte proliferation and function and provides the first in vivo evidence for a physiological role of the ypel5 gene in vertebrates.

SNAI1-activated long non-coding RNA LINC01711 promotes hepatic fibrosis cell proliferation and migration by regulating XYLT1

Liver fibrosis is the result of the accumulation of extracellular matrix (ECM) that cannot be cleared. Bioinformatic analysis showed that LINC01711 was significantly overexpressed in hepatic fibrosis. The regulatory mechanism of LINC01711 was clarified and confirmed the transcription factors associated with LINC01711. Functionally, LINC01711 promoted LX-2 cell proliferation and migration, indicating that it exerts effects promoting the progression of hepatic fibrosis. Mechanistically, LINC01711 increased the expression of xylosyltransferase 1 (XYLT1), which is an important protein for constructing the ECM. We also confirmed that SNAI1 activated LINC01711 transcription. Taking these findings together, LINC01711 was induced by SNAI1 and promoted the proliferation and migration of LX-2 cells via XYLT1. This study will help to understand the function of LINC01711 and its regulatory mechanism in hepatic fibrosis.

Role of Hepatocyte Growth Regulators in Liver Regeneration

We have studied whether growth factors, cytokines, hormones, neurotransmitters, and local hormones (autacoids) promote the proliferation of hepatic parenchymal cells (i.e., hepatocytes) using in vitro primary cultured hepatocytes. The indicators used for this purpose include changes in DNA synthesis activity, nuclear number, cell number, cell cycle, and gene expression. In addition, the intracellular signaling pathways from the plasma membrane receptors to the nucleus have been examined in detail for representative growth-promoting factors that have been found to promote DNA synthesis and cell proliferation of hepatocytes. In examining intracellular signaling pathways, the effects of specific inhibitors of presumed signaling factors involved have been pharmacologically confirmed, and the phosphorylation activities of the signaling factors (e.g., RTK, ERK, mTOR, and p70 S6K) have been evaluated. As a result, it has been found that there are many factors that promote the proliferation of hepatocytes (e.g., HGF, EGF, TGF-α, IL-1β, TNF-α, insulin, growth hormone (GH), prostaglandin (PG)), and serotonin (5-HT)), while there are very few factors (e.g., TGF-β1 and glucocorticoids) that inhibit the effects of growth-promoting factors. We have also found that 5-HT and GH promote the proliferation of hepatocytes via different autocrine factors (e.g., TGF-α and IGF-I, respectively). Using primary cultured hepatocytes, it will be possible to further study the molecular and cellular aspects of liver regeneration.