scholarly journals Integrative Network Analysis Revealed Genetic Impact of Pyruvate Kinase L/R on Hepatocyte Proliferation and Graft Survival after Liver Transplantation

2021 ◽  
Vol 2021 ◽  
pp. 1-31
Author(s):  
Zhengtao Liu ◽  
Junsheng Zhao ◽  
Wenchao Wang ◽  
Hai Zhu ◽  
Junjie Qian ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Pyruvate Kinase ◽  
De Novo ◽  
Hepatoma Cell ◽  
Hepatoma Cells ◽  
Arachidonic Acid Metabolism ◽  
De Novo Lipogenesis ◽  
Hepatocyte Proliferation ◽  
Human Hepatoma Cells ◽  
Genetic Impact

Background. Pyruvate kinase L/R (PKLR) has been suggested to affect the proliferation of hepatocytes via regulation of the cell cycle and lipid metabolism. However, its impact on the global metabolome and its clinical implications remain unclear. Aims. We aimed to clarify the genetic impact of PKLR on the metabolomic profiles of hepatoma cells and its potential effects on grafts for liver transplantation (LT). Methods. Nontargeted and targeted metabolomic assays were performed in human hepatoma cells transfected with lentiviral vectors causing PKLR overexpression and silencing, respectively. We then constructed a molecular network based on integrative analysis of transcriptomic and metabolomic data. We also assessed the biological functions of PKLR in the global metabolome in LT grafts in patients via a weighted correlation network model. Results. Multiomic analysis revealed that PKLR perturbations significantly affected the pyruvate, citrate, and glycerophospholipid metabolism pathways, as crucial steps in de novo lipogenesis (DNL). We also confirmed the importance of phosphatidylcholines (PC) and its derivative lyso-PC supply on improved survival of LT grafts in patients. Coexpression analysis revealed beneficial effects of PKLR overexpression on posttransplant prognosis by alleviating arachidonic acid metabolism of the grafts, independent of operational risk factors. Conclusion. This systems-level analysis indicated that PKLR affected hepatoma cell viability via impacts on the whole process of DNL, from glycolysis to final PC synthesis. PKLR also improved prognosis after LT, possibly via its impact on the increased genesis of beneficial glycerophospholipids.

Inhibitory Effects of Lycopene on the Adhesion, Invasion, and Migration of SK-Hep1 Human Hepatoma Cells

2006 ◽  
Vol 231 (3) ◽  
pp. 322-327 ◽  
Author(s):  
Eun-Sun Hwang ◽  
Hyong Joo Lee
Keyword(s):  
Cell Growth ◽  
Hepatoma Cell ◽  
Hepatoma Cells ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Human Hepatoma Cell ◽  
Invasion And Migration ◽  
And Migration

Lycopene, which is the predominant carotenoid in tomatoes and tomato-based foods, may protect humans against various cancers. Effects of lycopene on the adhesion, invasion, migration, and growth of the SK-Hep1 human hepatoma cell line were investigated. Lycopene inhibited cell growth in dose-dependent manners, with growth inhibition rates of 5% and 40% at 0.1 μM and 50 μM lycopene, respectively, after 24 hrs of incubation. Similarly, after 48 hrs of incubation, lycopene at 5 μM and 10 μM decreased the cell numbers by 30% and 40%, respectively. Lycopene decreased the gelatinolytic activities of both matrix metalloproteinase (MMP)-2 and MMP-9, which were secreted from the SK-Hep1 cells. Incubation of SK-Hep1 cells with 110 μM of lycopene for 60 mins significantly inhibited cell adhesion to the Matrigel-coated substrate in a concentration-dependent manner. To study invasion, SK-Hep1 cells were grown either on Matrigel-coated Transwell membranes or in 24-well plates. The cells were treated sequentially for 24 hrs with lycopene before the start of the invasion assays. Cell growth and death were assessed under the same conditions. The invasion of SK-Hep1 cells treated with lycopene was significantly reduced to 28.3% and 61.9% of the control levels at 5 μM and 10 μM lycopene, respectively (P < 0.05). In the migration assay, lycopene-treated cells showed lower levels of migration than untreated cells. These results demonstrate the antimetastatic properties of lycopene in inhibiting the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells.

scholarly journals Targeting Autophagy Augments Berberine-Mediated Cell Death in Human Hepatoma Cells Harboring Hepatitis C Virus RNA

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 908 ◽  
Author(s):  
Chen-Jei Tai ◽  
Alagie Jassey ◽  
Ching-Hsuan Liu ◽  
Cheng-Jeng Tai ◽  
Christopher D. Richardson ◽  
...  
Keyword(s):  
Cell Death ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatoma Cell ◽  
Treatment Strategies ◽  
Hepatoma Cells ◽  
Hcv Rna ◽  
Human Hepatoma Cells ◽  
Subgenomic Replicon ◽  
Pharmacological Inhibition

Hepatocellular carcinoma (HCC), including hepatitis C virus (HCV)-induced HCC, is a deadly disease highly refractory to chemotherapy, thus requiring the continuous identification of novel treatment strategies. Berberine (BBR) has been previously reported to inhibit hepatoma cell growth, but the main type of cell death elicited by BBR, and whether the alkaloid can inhibit hepatoma cells carrying HCV genomes, is unclear. Herein, we show that BBR treatment induced a biphasic cell death irrespective of the presence of HCV subgenomic replicon RNA, first triggering apoptosis that then progressed to necrosis between 24 and 48 h post-treatment. Furthermore, BBR treatment potentiated the HCV replicon-induced reactive oxygen species (ROS) production, inhibition of which with an antioxidant attenuated the cell death that was elicited by BBR in these cells. Moreover, BBR dampened the autophagic response in HCV RNA-positive or negative hepatoma cells, and pharmacological inhibition of autophagy conversely augmented the BBR-induced cell death. Finally, BBR inhibited the growth of Huh-7 cells that were persistently infected with the full-length genome HCV particles, and concomitant pharmacological inhibition of autophagy potentiated the killing of these cells by BBR. Our findings suggest that combining BBR with the inhibition of autophagy could be an attractive treatment strategy against HCC, irrespective of the presence of the HCV genome.

scholarly journals Elimination of Cancer Stem-Like “Side Population” Cells in Hepatoma Cell Lines by Chinese Herbal Mixture “Tien-Hsien Liquid”

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Chih-Jung Yao ◽  
Chi-Tai Yeh ◽  
Liang-Ming Lee ◽  
Shuang-En Chuang ◽  
Chuan-Feng Yeh ◽  
...  
Keyword(s):  
Side Population ◽  
Hepatoma Cell ◽  
Hepatoma Cells ◽  
Human Hepatoma Cells ◽  
Herbal Mixture ◽  
Hepatoma Cell Lines ◽  
Chinese Herbal ◽  
Huh7 Cells ◽  
Complementary And Integrative Medicine ◽  
Small Subpopulation

There are increasing pieces of evidence suggesting that the recurrence of cancer may result from a small subpopulation of cancer stem cells, which are resistant to the conventional chemotherapy and radiotherapy. We investigated the effects of Chinese herbal mixtureTien-Hsien Liquid(THL) on the cancer stem-like side population (SP) cells isolated from human hepatoma cells. After sorting and subsequent culture, the SP cells from Huh7 hepatoma cells appear to have higher clonogenicity and mRNA expressions of stemness genes such asSMO, ABCG2, CD133,β-catenin,andOct-4than those of non-SP cells. At dose of 2 mg/mL, THL reduced the proportion of SP cells in HepG2, Hep3B, and Huh7 cells from 1.33% to 0.49%, 1.55% to 0.43%, and 1.69% to 0.27%, respectively. The viability and colony formation of Huh7 SP cells were effectively suppressed by THL dose-dependently, accompanied with the inhibition of stemness genes, e.g.,ABCG2, CD133,andSMO. The tumorigenicity of THL-treated Huh7 SP cells in NOD/SCID mice was also diminished. Moreover, combination with THL could synergize the effect of doxorubicin against Huh7 SP cells. Our data indicate that THL may act as a cancer stem cell targeting therapeutics and be regarded as complementary and integrative medicine in the treatment of hepatoma.

scholarly journals Pharmacological or TRIB3-Mediated Suppression of ATF4 Transcriptional Activity Promotes Hepatoma Cell Resistance to Proteasome Inhibitor Bortezomib

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2341
Author(s):  
Tiit Örd ◽  
Daima Örd ◽  
Minna U. Kaikkonen ◽  
Tõnis Örd
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Proteasome Inhibitor ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hepatoma Cell ◽  
Hepatoma Cells ◽  
Cell Resistance ◽  
Human Hepatoma Cells

The proteasome is an appealing target for anticancer therapy and the proteasome inhibitor bortezomib has been approved for the treatment of several types of malignancies. However, the molecular mechanisms underlying cancer cell resistance to bortezomib remain poorly understood. In the current article, we investigate how modulation of the eIF2α–ATF4 stress pathway affects hepatoma cell response to bortezomib. Transcriptome profiling revealed that many ATF4 transcriptional target genes are among the most upregulated genes in bortezomib-treated HepG2 human hepatoma cells. While pharmacological enhancement of the eIF2α–ATF4 pathway activity results in the elevation of the activities of all branches of the unfolded protein response (UPR) and sensitizes cells to bortezomib toxicity, the suppression of ATF4 induction delays bortezomib-induced cell death. The pseudokinase TRIB3, an inhibitor of ATF4, is expressed at a high basal level in hepatoma cells and is strongly upregulated in response to bortezomib. To map genome-wide chromatin binding loci of TRIB3 protein, we fused a Flag tag to endogenous TRIB3 in HepG2 cells and performed ChIP-Seq. The results demonstrate that TRIB3 predominantly colocalizes with ATF4 on chromatin and binds to genomic regions containing the C/EBP–ATF motif. Bortezomib treatment leads to a robust enrichment of TRIB3 binding near genes induced by bortezomib and involved in the ER stress response and cell death. Disruption of TRIB3 increases C/EBP–ATF-driven transcription, augments ER stress and cell death upon exposure to bortezomib, while TRIB3 overexpression enhances cell survival. Thus, TRIB3, colocalizing with ATF4 and limiting its transcriptional activity, functions as a factor increasing resistance to bortezomib, while pharmacological over-activation of eIF2α–ATF4 can overcome the endogenous restraint mechanisms and sensitize cells to bortezomib.

Quantitative analysis of acetoacetate metabolism in AS-30D hepatoma cells with 13C and 14C isotopic techniques

1997 ◽  
Vol 272 (6) ◽  
pp. E945-E951 ◽  
Author(s):  
A. L. Holleran ◽  
G. Fiskum ◽  
J. K. Kelleher
Keyword(s):  
De Novo ◽  
Lipid Synthesis ◽  
Tca Cycle ◽  
Hepatoma Cells ◽  
Dichloroacetic Acid ◽  
De Novo Lipogenesis ◽  
Ratio Method ◽  
Acetyl Coa ◽  
Isotopic Methods ◽  
Host Metabolism

Experimental hepatoma cells utilize acetoacetate as an oxidative energy source and as a precursor for lipid synthesis. The significance of ketone body metabolism in tumors lies in the study of tumor-host metabolism and the ketoneMic condition that is often present in cancer patients. The quantitative importance of acetoacetate and glucose was investigated in AS-30D cells with use of 13C and 14C isotopic methods. In addition, the effects of acetoacetate were compared with those of dichloroacetic acid (DCA), an activator of pyruvate dehydrogenase (PDH). The 14CO2 ratio method evaluated the entry of pyruvate into the tricarboxylic acid (TCA) cycle and revealed that acetoacetate diverted pyruvate from PDH to pyruvate carboxylation. In contrast, DCA increased the oxidation of glucose largely through PDH, indicating that PDH is not maximally active in the absence of DCA. Isotopomer spectral analysis of lipid synthesis demonstrated that, in the absence of acetoacetate, glucose supplied 65% of the acetyl-CoA used for de novo lipogenesis. When 5 mM acetoacetate was included in the incubation, glucose was displaced as a lipogenic precursor and acetoacetate supplied 85% of the acetyl-CoA for lipogenesis vs. only 2% for glucose. Thus AS-30D cells have a large capacity for acetoacetate utilization for de novo lipogenesis.

Hepatic de novo Lipogenesis after Liver Transplantation

2001 ◽  
Vol 25 (5) ◽  
pp. 229-236 ◽  
Author(s):  
Kaori Minehira ◽  
Valérie Novel-Chaté ◽  
Jean-Marc Schwarz ◽  
Michel Gillet ◽  
Roger Darioli ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
De Novo ◽  
De Novo Lipogenesis

scholarly journals Induction of p21 and p27 expression by amino acid deprivation of HepG2 human hepatoma cells involves mRNA stabilization

2004 ◽  
Vol 379 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Van LEUNG-PINEDA ◽  
YuanXiang PAN ◽  
Hong CHEN ◽  
Michael S. KILBERG
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
De Novo ◽  
Hepatoma Cells ◽  
Specific Cell ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Mrna Stabilization ◽  
Amino Acid Availability ◽  
Mrna Content

mRNA abundance for a number of genes is increased by amino acid limitation. From an array screening study in HepG2 human hepatoma cells, it was established that one set of genes affected by amino acid availability is the set associated with cell-cycle control. The present study describes the increased expression of both mRNA and protein for the cyclin-dependent kinase inhibitors p21 and p27 in response to deprivation of HepG2 cells for a single essential amino acid, histidine. The increase in p21 and p27 mRNA content depended on de novo protein synthesis and involved a post-transcriptional mRNA stabilization component. For p21, increase in mRNA by histidine depletion appeared to be independent of p53 transactivation, and the absolute level of p53 protein was unaffected by this treatment. Histidine limitation caused an increase in the phosphorylation of ERK1/ERK2 (extracellular-signal-regulated kinase), and inhibition of the ERK signal transduction pathway resulted in a reduction in the starvation-dependent increase in p21 mRNA. Blockade of the phosphoinositide 3-kinase and mTOR (mammalian target of rapamycin) pathways also blunted the increase in p21 mRNA content. These results document the amino acid-dependent control of the synthesis of specific cell-cycle regulators and help to explain the block at G1 phase after amino acid limitation.

Abstract 434: Insig-2a Links CREBH Signaling to Hepatic Lipogenesis and Systemic Hyperlipidemia

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Hai Wang ◽  
Qiaozhu Su
Keyword(s):  
De Novo ◽  
Regulatory Element ◽  
Hepatoma Cell ◽  
Gene Promoter ◽  
De Novo Lipogenesis ◽  
Signal Pathways ◽  
Hepatoma Cell Line ◽  
Protein Levels ◽  
Element Binding Protein

The sterol regulatory element binding proteins (SREBPs) are master transcription factors that regulate hepatic de novo lipogenesis. Perturbation of SREBPs functionality is closely related to the onset of hyperlipidemia. The current investigation sought to advance our understanding on the activation of SREBP-1c via the interplay between the cAMP responsive element binding protein H (CREBH) and the liver specific insulin-induced gene 2a isoform (Insig-2a). Genetic depletion of CREBH specifically down regulated expression of both Insign-2a mRNA and protein levels which resulted in the hyperactivation of SREBP-1c and the subsequent hypertriglyceridemia. Challenging wild type (WT) mice with a high fat diet (HFD) specifically stimulated expression of Insig-2a mRNA and protein in the WT mice. In contrast, HFD failed to enhance expressions of Insig-2a mRNA and protein in CREBH-null mice. No alterations were detected on the mRNA transcription of another Insig-2 isoform, Insig-2b, in the livers of WT mice and CREBH-null mice under both chow and HFD conditions. Decrease of Insig-2a caused activation of hepatic de novo lipogenesis, mainly via SREBP-1c activation, which contributed to the development of sever systemic hypertriglyceridemia and hepatic steatosis in CREBH-null mice. Consistent with the in vivo observation, forced expression of CREBH cDNA in a rat hepatoma cell line, McA cells, specifically increased expressions of both Insig-2a mRNA and protein which in turn inhibited activation of SCREBP-1c. Analyzing the gene promoter of Insig-2a, we identified a CREB binding site at the promoter of the Insig-2a and a ChIP assay further confirmed the physical association between CREBH and the Insig-2a promoter. These data identify Insig-2a as a target gene of CREBH. Modulation of Insig-2a expression by CREBH is essentially involved in regulating hepatic triglyceride metabolism. Given the role of CREBH in hepatic acute phage response signaling, this finding further reveals the cross-talk between inflammatory and insulin signal pathways in maintaining systemic lipid homeostasis and may provide rationale for pharmaceutical design to specifically target CREBH and insig-2a in the prevention and treatment of hypertriglyceridemia.

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