scholarly journals Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma

Oncogene ◽  
2019 ◽  
Vol 39 (8) ◽  
pp. 1724-1738 ◽  
Author(s):  
Jing Zhao ◽  
Yiran Hou ◽  
Chun Yin ◽  
Jing Hu ◽  
Tian Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Histamine Receptor ◽  
Matrix Metalloproteinase 2 ◽  
Mice Model ◽  
Hcc Cells

AbstractH1 histamine receptor (H1HR) belongs to the family of rhodopsin-like G-protein-coupled receptors. Recent studies have shown that H1HR expression is increased in several types of cancer. However, its functional roles in tumor progression remain largely unknown, especially in hepatocellular carcinoma (HCC). We found that H1HR is frequently unregulated in HCC, which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression, formation of lamellipodia, production of matrix metalloproteinase 2, and suppression of cell apoptosis. Activation of cyclic adenosine monophosphate-dependent protein kinase A was found to be involved in H1HR-mediated HCC cell growth and metastasis. In addition, we found that overexpression of H1HR was mainly due to the downregulation of miR-940 in HCC cells. Moreover, the H1HR inhibitor terfenadine significantly suppressed tumor growth and metastasis in an HCC xenograft nude mice model. Our findings demonstrate that H1HR plays a critical role in the growth and metastasis of HCC cells, which provides experimental evidence supporting H1HR as a potential drug target for the treatment of HCC.

scholarly journals Circ_0091579 enhances the malignancy of hepatocellular carcinoma via miR-1287/PDK2 axis

2021 ◽  
Vol 16 (1) ◽  
pp. 69-83
Author(s):  
Junwei Shu ◽  
Jiayuan Du ◽  
Futao Wang ◽  
Yong Cheng ◽  
Gangxin Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
Pyruvate Dehydrogenase Kinase ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Western Blot Assay ◽  
Human Liver Cell ◽  
Normal Human Liver ◽  
Hcc Cells

Abstract Several articles have indicated that circular RNAs are involved in pathogenesis of human cancers. Nevertheless, the role of circ_0091579 in hepatocellular carcinoma (HCC) progression remains to be revealed. Quantitative reverse transcriptase polymerase chain reaction was carried out to examine the expression of circ_0091579 and miR-1287. The proliferation of HCC cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry was performed to analyze cell cycle progression and apoptosis. Western blot assay was conducted to detect the protein expression of CyclinD1, Cleaved caspase3, and pyruvate dehydrogenase kinase 2 (PDK2). Cell glycolysis was evaluated by measuring the uptake of glucose, the production of lactate, and extracellular acidification rate. The target relationship between miR-1287 and circ_0091579 or PDK2 was verified by dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA-pull down assay. The enrichment of circ_0091579 was enhanced in HCC tissues (n = 77) and four HCC cell lines (HB611, Huh-7, MHCC97, and SNU423) compared with adjacent non-tumor tissues (n = 77) and normal human liver cell line THLE-2. Circ_0091579 mediated the promotion of proliferation and glycolysis and the suppression of apoptosis of HCC cells. MiR-1287 was a direct target of circ_0091579 in HCC cells. MiR-1287 knockdown reversed the effects caused by circ_0091579 interference on the functions of HCC cells. PDK2 could bind to miR-1287 in HCC cells. Circ_0091579 upregulated the enrichment of PDK2 by acting as a sponge of miR-1287 in HCC cells. The influence caused by circ_0091579 intervention on HCC cells was attenuated by overexpression of PDK2. Circ_0091579 interference impeded the progression of HCC in vivo. Circ_0091579 deteriorated HCC by promoting the proliferation and glycolytic metabolism and suppressing the apoptosis of HCC cells via miR-1287/PDK2 axis.

scholarly journals Long non-coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Qun Dai ◽  
Jingyi Deng ◽  
Jinrong Zhou ◽  
Zhuhong Wang ◽  
Xiao-feng Yuan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Marked Rise ◽  
Hcc Cells

Abstract Background Accumulating evidence indicates that the long noncoding RNA taurine upregulated gene 1(TUG1) plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of TUG1 in hepatocellular carcinoma (HCC) remain largely unknown. Methods The expressions of TUG1, microRNA-216b-5p and distal-less homeobox 2 (DLX2) were detected by Quantitative real-time polymerase chain reaction (qRT-PCR). The target relationships were predicted by StarBase v.2.0 or TargetScan and confirmed by dual-luciferase reporter assay. The cell growth, apoptosis, migration and invasion were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow cytometry and Transwell assays, respectively. All protein expression levels were detected by western blot. Tumor xenografts were implemented to explore the role of TUG1 in vivo. Results We found that there was a marked rise in TUG1 expression in HCC tissues and cells, and knockdown of TUG1 repressed the growth and metastasis and promoted apoptosis of HCC cells. In particular, TUG1 could act as a ceRNA, effectively becoming a sink for miR-216b-5p to fortify the expression of DLX2. Additionally, repression of TUG1 impared the progression of HCC cells by inhibiting DLX2 expression via sponging miR-216b-5p in vitro. More importantly, TUG1 knockdown inhibited HCC tumor growth in vivo through upregulating miR-216b-5p via inactivation of the DLX2. Conclusion TUG1 interacting with miR-216b-5p contributed to proliferation, metastasis, tumorigenesis and retarded apoptosis by activation of DLX2 in HCC.

scholarly journals Reactive Oxygen Species-Mediated Cezanne Inactivation by Oxidation of its Catalytic Cysteine Residue in Hepatocellular Carcinoma

2019 ◽  
Vol 27 (9) ◽  
pp. 1069-1077
Author(s):  
Zhongyuan Yin ◽  
Lin Yang ◽  
Feng Wu ◽  
Jinshuo Fan ◽  
Juanjuan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Matrix Metalloproteinase 2 ◽  
Intercellular Adhesion Molecule ◽  
Oxygen Species ◽  
Cysteine Oxidation ◽  
Diphenylene Iodonium ◽  
Hcc Cells ◽  
Inflammatory Effect

Cysteine oxidation occurs at the active site of deubiquitinases (DUBs) during many biologic signaling cascades. Here we report that hepatocellular carcinoma cells (HCCs) generated higher levels of endogenous reactive oxygen species (ROS). This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in HCC cells. Moreover, we found that H2O2 could activate NF-κB-dependent inflammatory effect through increased induction of matrix metalloproteinase 2 (MMP2), MMP9, and intercellular adhesion molecule 1 (ICAM1) expression levels. In addition, we found that H2O2 could prolong NF-κB activation by suppressing the negative regulatory functions of Cezanne in HCC cells. Ubiquitin-derived thiol-reactive probe (HA-UbVME) assay and biotin-tagged 1,3-cyclohexadione derivative (DCP-Bio1) assay showed that H2O2 has the capacity to inhibit the catalytic activity of Cezanne, and the reducing agent, DTT, could reactivate the Cezanne deubiquitinating enzyme activity. Taken all together, these findings demonstrated an important role for oxidation of Cezanne by ROS in regulation of the inflammatory effect of hepatocellular carcinoma.

scholarly journals ILF2 Directly Binds and Stabilizes CREB to Stimulate Malignant Phenotypes of Liver Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Hui Du ◽  
Yun Le ◽  
Fenyong Sun ◽  
Kai Li ◽  
Yanfeng Xu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Liver Cancer Cells ◽  
Binding Factor ◽  
Element Binding Protein

Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) is overexpressed and has an oncogenic role in hepatocellular carcinoma (HCC). Interleukin enhancer binding factor 2 (ILF2) has become research hotspot in liver cancer recently. However, it is still unclear whether and how CREB and ILF2 interact with each other. And how this interaction exerts its role in occurrence and development of liver cancer is still unclear. Here, we found that ILF2 directly bound with CREB, and this binding was essential for the malignant phenotypes of liver cancer cells. Moreover, we found that ILF2 acted as one of the upstream proteins of CREB and promoted CREB only in the protein level, whereas ILF2 expression was not regulated by CREB. Mechanistically, ILF2 bound to the pKID domain of CREB and stimulated its phosphorylation at Ser133. Taken together, our study finds a novel interaction between CREB and ILF2 in liver cancer, and this interaction might play a role in the diagnosis and remedy of liver cancer.

scholarly journals LpCat1 Promotes Malignant Transformation of Hepatocellular Carcinoma Cells by Directly Suppressing STAT1

2021 ◽  
Vol 11 ◽  
Author(s):  
Weidan Ji ◽  
Zhangxiao Peng ◽  
Bin Sun ◽  
Lei Chen ◽  
Qin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Clinical Gene Therapy ◽  
First Time ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a malignant cancer with rapid proliferation and high metastasis ability. To explore the crucial genes that maintain the aggressive behaviors of cancer cells is very important for clinical gene therapy of HCC. LpCat1 was reported to be highly expressed and exert pro-tumorigenic effect in a variety of cancers, including HCC. However, its detailed molecular mechanism remained unclear. In this study, we confirmed that LpCat1 was up-regulated in HCC tissues and cancer cell lines. The overexpressed LpCat1 promoted the proliferation, migration and invasion of HCC cells, and accelerated cell cycle progression, while knocking down LpCat1 significantly inhibited cell proliferation, migration and invasion in vitro and in vivo, and arrested HCC cells at G0/G1 phase. Moreover, we proved for the first time that LpCat1 directly interacted with STAT1 which was generally recognized as a tumor suppressor in HCC. High levels of LpCat1 in HCC could inhibit STAT1 expression, up-regulate CyclinD1, CyclinE, CDK4 and MMP-9, and decrease p27kip1 to promote cancer progression. Conversely, down-regulation of LpCat1 would cause the opposite changes to repress the viability and motility of HCC cells. Consequently, we concluded that LpCat1 was a contributor to progression and metastasis of HCC by interacting with STAT1.

scholarly journals ORC6, Negatively Regulated by miR-1-3p, Promotes Proliferation, Migration, and Invasion of Hepatocellular Carcinoma Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Hu Chen ◽  
Lequn Bao ◽  
Jianhua Hu ◽  
Dongde Wu ◽  
Xianli Tong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Regulatory Function ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Hcc Cells

BackgroundIn recent years, microRNA-1-3p (miR-1-3p) has been linked to the progression of multiple cancers, whereas little is known about its role in hepatocellular carcinoma (HCC). Herein, we investigated the function of miR-1-3p in HCC, and its regulatory function on origin recognition complex subunit 6 (ORC6).MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) was performed for detecting the expression levels of miR-1-3p and ORC6 mRNA in HCC samples and cell lines. ORC6 expression at the protein level was quantified by Western blot. After gain-of-function and loss-of-function models were established, cell counting kit-8 (CCK-8) assays, Transwell assays, flow cytometry, and 5-Ethynyl-2′-deoxyuridine (EdU) assay were performed for examining cell proliferation, migration, invasion, cell cycle, and apoptosis. The targeting relationship between miR-1-3p and ORC6 was confirmed with bioinformatic analysis and dual-luciferase reporter assays.ResultsThe expression of miR-1-3p was reduced in HCC samples and cell lines. Overexpression of miR-1-3p suppressed the proliferation, migration, and invasion, and induced cell-cycle arrest and apoptosis of HCC cells, whereas the opposite effects were induced by miR-1-3p inhibition. ORC6 is identified as a novel target of miR-1-3p, the expression of which is negatively correlated with miR-1-3p expression in HCC tissues. ORC6 overexpression facilitated the proliferation, migration, invasion, and cell cycle progression, and reduced apoptosis of HCC cells, whereas the opposite effects were induced by ORC6 knockdown. What is more, ORC6 overexpression counteracted the biological functions of miR-1-3p in HCC cells.ConclusionMiR-1-3p targets ORC6 to suppress the proliferation, migration, invasion, and cell cycle progression, and promote apoptosis of HCC cells.

268 CYCLIC GUANOSINE MONOPHOSPHATE INHIBITS PHOSPHODIESTERASE 3 ACTIVITY IN PORCINE OOCYTES

2013 ◽  
Vol 25 (1) ◽  
pp. 282 ◽  
Author(s):  
F. G. Zaffalon ◽  
C. Guimmelette ◽  
C. L. V. Leal ◽  
F. J. Richard
Keyword(s):  
Critical Role ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Intracellular Camp ◽  
Activity Levels ◽  
Nuclear Maturation ◽  
Serum Gonadotropin

The level of cyclic adenosine monophosphate (cAMP) within oocytes has been shown to play a critical role in maintaining meiotic arrest. High levels of intracellular cAMP prevent spontaneous oocyte maturation in vitro, whereas a decrease in oocyte cAMP is associated with the resumption of meiosis. Another cyclic nucleotide that also was recently proposed as being involved in meiotic resumption is cyclic guanosine monophosphate (cGMP), which could be regulating phosphodiesterase (PDE) 3 activity. The aim of this study was to determine whether cGMP inhibits cAMP-PDE activity in porcine oocytes. With the method described previously by Sasseville et al. (2006 BMC Dev. Biol. 6, 47), PDE activity was measured in groups of 10 oocytes cultured in the absence (control) or presence of different concentrations of cGMP (1, 3, 10, 30, 100, 300, 1000, and 3000 nM) or with the PDE3 inhibitor cilostamide (10 µM). Before assaying PDE activity, the cumulus–oocyte complexes (COC) were matured in vitro for 24 h in the presence of pregnant mare serum gonadotropin (5 IU) and hCG (5 IU) at 38.5°C in 5% CO2. The COC were homogenised in a hypotonic buffer. Data were analysed using one-way ANOVA followed by Duncan’s post-hoc test. Differences with P < 0.05 were considered significant. Results showed that 300, 1000, and 3000 nM cGMP inhibited PDE3 activity (7.9, 5.1, and 4.1 fmol min–1 per COC; P < 0.05) at levels below the controls (13.2 fmol min–1 per COC) and were similar to the activity observed in the presence of (2.4 fmol min–1 per COC; P > 0.05). The other concentrations tested were similar to activity levels seen in the control (1 to 100 nM; 12.2, 11.3, 10.8, 11.5, and 10.4; P > 0.05). In conclusion, the results support the concept that increasing concentrations of cGMP inhibit PDE activity, suggesting the inhibition of the predominant form of cAMP-PDE present in porcine oocytes, PDE3. These results support the hypothesis that cGMP inhibits PDE activity in porcine oocytes. Further work is needed to determine the role this plays in maintaining high cAMP levels and inhibiting oocyte nuclear maturation. Financial support from FGZ FAPESP 2010/20188-6 and 2010/18023-9 is acknowledged.

scholarly journals Effects of Chlorpyrifos on Cholinesterase and Serine Lipase Activities and Lipid Metabolism in Brains of Rainbow Trout (Oncorhynchus mykiss)

2019 ◽  
Vol 172 (1) ◽  
pp. 146-154 ◽  
Author(s):  
Justin B Greer ◽  
Jason T Magnuson ◽  
Kirstin Hester ◽  
Marissa Giroux ◽  
Carey Pope ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Rainbow Trout ◽  
Lipid Metabolism ◽  
Organophosphorus Compounds ◽  
Fatty Acid Amide Hydrolase ◽  
Critical Role ◽  
Acid Amide ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Rainbow Trout Oncorhynchus Mykiss

Abstract Chlorpyrifos is an organophosphorus insecticide that elicits acute toxicity through inhibition of acetylcholinesterase (AChE), leading to acetylcholine accumulation and prolonged stimulation of cholinergic receptors throughout the central and peripheral nervous systems. Previous studies have indicated that neurodevelopment may also be impaired through alternative pathways, including reduction of cyclic adenosine monophosphate (cAMP)-catalyzed downstream events. The upstream initiating events that underlie noncholinergic neurological actions of chlorpyrifos and other organophosphorus compounds remain unclear. To investigate the potential role of fatty acid signaling disruption as a mechanism of toxicity, lipid metabolism and fatty acid profiles were examined to identify alterations that may play a critical role in upstream signaling in the central nervous system (CNS). Juvenile rainbow trout were treated for 7 days with nominal chlorpyrifos concentrations previously reported to diminish olfactory responses (10, 20, and 40 μg/l). Although lethality was noted higher in doses, measured chlorpyrifos concentrations of 1.38 μg/l (nominal concentration 10 μg/l) significantly reduced the activity of AChE and two serine lipases, monoacylglycerol lipase, and fatty acid amide hydrolase in the brain. Reductions in lysophosphatidylethanolamines (16:0, 18:0, 18:1, and 22:6) derived from the phosphatidylethanolamines and free fatty acids (palmitic acid 16:0, linolenic acid 18:3, eicosadienoic acid 20:2, arachidonic acid 20:4, and docosahexaenoic acid 22:6) were also noted, suggesting that chlorpyrifos inhibited the metabolism of select phospholipid signaling precursors at sublethal concentrations. These results indicate that in addition to AChE inhibition, environmentally relevant chlorpyrifos exposure alters serine lipase activity and lipid metabolites in the trout brain, which may compromise neuronal signaling and impact neurobehavioral responses in aquatic animals.

Systemic hypoxia potentiates anti-tumor effects of metformin in hepatocellular carcinoma in mice

2020 ◽  
Vol 52 (4) ◽  
pp. 421-429
Author(s):  
Hui Lin ◽  
Wenfang Zhou ◽  
Yonghong Huang ◽  
Min Ren ◽  
Fangyun Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Tumor Volume ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Inhibitory Effect ◽  
Whole Body ◽  
Matrix Metalloproteinase 2 ◽  
Systemic Hypoxia ◽  
Novel Strategy

Abstract Local hypoxia is a universal phenomenon in most solid tumors. The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established. However, the effect of acute systemic hypoxia (exposing the whole body to 10% O2 environment) on cancer has not yet been investigated. In this study, we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC. Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice. Interestingly, the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight. Moreover, acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression. More importantly, the expressions of hypoxia response genes including hypoxia-inducible factor-1 α, vascular endothelial growth factor, and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment. Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin. This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.

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