scholarly journals Des-Gamma-Carboxy Prothrombin (DCP) Antagonizes the Effects of Gefitinib on Human Hepatocellular Carcinoma Cells

2015 ◽  
Vol 35 (1) ◽  
pp. 201-212 ◽  
Author(s):  
Yu-Sheng Zhang ◽  
Jia-Hui Chu ◽  
Zhi-Yu Song ◽  
Shu-Xiang Cui ◽  
Xian-Jun Qu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Growth Inhibition ◽  
Growth Factor Receptor ◽  
Annexin V ◽  
Inhibition Of Proliferation ◽  
Diphenyl Tetrazolium Bromide ◽  
Induced Apoptosis ◽  
Dependent Pathway ◽  
Hcc Cells

Background/Aims: Des-gamma-carboxy prothrombin (DCP), an aberrant prothrombin produced by hepatocellular carcinoma (HCC) cells, is known as a marker for HCC. Recent studies indicated that high levels of DCP are associated with the malignant potential of HCC. In this study, we aimed to investigate the association of DCP with gefitinib treatment failure in HCC and whether DCP counteracts gefitinib-induced growth inhibition and apoptosis of HCC. Methods: The experiments were performed in HCC cell lines HepG2 and PLC/PRF/5. The effects of gefitinib on HCC in the presence or absence of DCP were evaluated by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Apoptotic cells were identified by Annexin V-FITC/PI staining. Western blotting was performed to analyze the expressions of molecules related to the apoptotic caspase-dependent pathway and epidermal growth factor receptor (EGFR) pathway. Results: Gefitinib inhibited HCC cell proliferation and induced apoptosis in HCC cells. The effects of gefitinib on HCC cells were antagonized by DCP. In the presence of DCP, HCC cells were resistant to the gefitinib-induced inhibition of proliferation and stimulation of apoptosis. DCP prevented the activation of the apoptotic caspase-dependent pathway induced by gefitinib. These antagonistic effects of DCP also arose from its ability to up-regulate EGFR, c-Met and hepatocyte growth factor (HGF) in HCC cells. Conclusion: DCP antagonized gefitinib-induced HCC cell growth inhibition by counteracting apoptosis and up-regulating the EGFR pathway. High levels of DCP might thus lead to low response rates or possibly no response to gefitinib in patients with HCC.

scholarly journals PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiao Wang ◽  
Chao Liang ◽  
Xin Yao ◽  
Ruo-Han Yang ◽  
Zhan-Sheng Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Histone H3 ◽  
Growth Factor Receptor ◽  
Transcriptional Level ◽  
Mrna And Protein Expression ◽  
Normal Rat ◽  
Epidermal Growth ◽  
Hcc Cells

High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser37 site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr11 phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr11 phosphorylation. Furthermore, mutation of Thr11 of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr11 phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr11 phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr11 phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.

scholarly journals Deguelin Induces Apoptosis by Targeting Both EGFR-Akt and IGF1R-Akt Pathways in Head and Neck Squamous Cell Cancer Cell Lines

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Yuh Baba ◽  
Masato Fujii ◽  
Toyonobu Maeda ◽  
Atsuko Suzuki ◽  
Satoshi Yuzawa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cell Lines ◽  
Squamous Cell ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Annexin V ◽  
Akt Activation ◽  
Igf1r Signaling ◽  
Induced Apoptosis

Deguelin, a rotenoid compound from the African plantMundulea sericea(Leguminosae), has been shown to possess antitumor activities but the exact role for the growth factor receptor mediated signaling pathway in head and neck squamous cell carcinoma (HNSCC) is currently still unclear. In the present study, we investigated the effect of deguelin on epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF1R) pathways in HNSCC cell lines. Flowcytometric analysis revealed accumulation of annexin V positivity in deguelin-treated cells, showing that deguelin induced apoptosis. The deguelin-induced apoptosis was accompanied by the reduction of constitutive phosphorylated levels of IGF1R, Akt, and extracellular signal-regulated kinase1/2 (ERK1/2). LY294002-mediated inhibition of phosphatidylinositol-3 kinase, which is an upstream effector for Akt activation, increased cleavage of poly(ADP-ribosyl) polymerase (PARP) but ERK inhibition by U0126 did not. Deguelin inhibited both IGF-1- and EGF-induced Akt activation. These results showed that deguelin possessed antitumor effect by targeting Akt in dual axis such as EGFR and IGF1R signaling pathways and suggested that it provides an applicable therapeutic strategy for HNSCC patients.

scholarly journals Amphiregulin impairs apoptosis-stimulating protein 2 of p53 overexpression–induced apoptosis in hepatoma cells

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769502 ◽  
Author(s):  
Kai Liu ◽  
Dongdong Lin ◽  
Yabo Ouyang ◽  
Lijun Pang ◽  
Xianghua Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Hepg2 Cells ◽  
Apoptotic Cell ◽  
Growth Factor Receptor ◽  
Hepatoma Cells ◽  
Epidermal Growth ◽  
Induced Apoptosis

Overexpression of apoptosis-stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway impairs the pro-apoptotic role of ASPP2. In this study, in recombinant adenovirus-ASPP2-infected HepG2 cells, ASPP2 overexpression induces amphiregulin expression in a p53-dependent manner. Although amphiregulin initially contributes to ASPP2-induced apoptosis, it eventually impairs the pro-apoptotic function of ASPP2 by activating the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway, leading to apoptosis resistance. Moreover, blocking soluble amphiregulin with a neutralizing antibody also significantly increased apoptotic cell death of HepG2 cells due to treatment with methyl methanesulfonate, cisplatin, or a recombinant p53 adenovirus, suggesting that the function of amphiregulin involved in inhibiting apoptosis may be a common mechanism by which hepatoma cells escape from stimulus-induced apoptosis. Thus, our data elucidate an apoptosis-evasion mechanism in hepatocellular carcinoma and have potential implications for hepatocellular carcinoma therapy.

scholarly journals Lobaplatin promotes 125I-induced apoptosis and inhibition of proliferation in hepatocellular carcinoma by upregulating PERK-eIF2α-ATF4-CHOP pathway

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Dong Li ◽  
Wu-jie Wang ◽  
Yong-zheng Wang ◽  
Yi-biao Wang ◽  
Yu-liang Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Model ◽  
Absolute Quantification ◽  
Inhibition Of Proliferation ◽  
Isobaric Tag ◽  
Cellular Apoptosis ◽  
Radioactive Seed ◽  
Induced Apoptosis ◽  
Different Doses ◽  
Hcc Cells

Abstract We investigated the mechanism underlying the effect of a combination treatment of 125I radioactive seed implantation and lobaplatin (LBP) in hepatocellular carcinoma. The effects of administration of HCC cells and subcutaneous tumor model of mice with different doses of 125I or a sensitizing concentration of LBP alone, or in combination, on cellular apoptosis and proliferation were analyzed and it was confirmed that LBP promotes 125I-induced apoptosis and inhibition of proliferation of HCC. Furthermore, isobaric tag for relative and absolute quantification labeling analyses suggested that 125I promoted the apoptosis and inhibition of proliferation of HCC cells by upregulating the expression of PERK-eIF2α-ATF4-CHOP pathway, a well-known apoptosis-related pathway. Moreover, LBP was found to boost the 125I-induced upregulation of this pathway and increase the apoptosis. Our data indicate that LBP promotes the apoptotic and anti-proliferative effects of 125I and provide a firm foundation for better clinical application of this combination therapy.

scholarly journals Mir-455-3p Inhibits Hepatocellular Carcinoma Tumorigenesis, Lymphangiogenesis and Angiogenesis via Regulating Vascular Endothelial Growth Factor C as well as Vascular Endothelial Growth Factor Receptor-2

2021 ◽  
Author(s):  
Xiaoyun Bin ◽  
Jianchu Wang ◽  
Libai Lu ◽  
Guanbin Ye ◽  
Sufang Zhou
Keyword(s):  
Hepatocellular Carcinoma ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Vascular Endothelial ◽  
Factor C ◽  
Endothelial Growth Factor ◽  
Hcc Cells

Abstract Background: MicroRNAs (miRNAs), functioning as tumor suppressors or oncogenes, exert a considerable regulative influence in biological processes. Previous studies showed that miR-455-3p was significantly down-regulated in hepatocellular carcinoma (HCC), while the specific role of miR-455-3p in HCC is unclear. Methods: QRT-PCR was used to detect miR-455-3p expression levels in HCC cells and tissues. We adopted colony formation, EdU, CCK-8, transwell assays and wound-healing to identify the influences of miR-455-3p on proliferation, invasion and migration in HHCC and HuH-7 cells. Western blot analysis, angiogenesis assays, dual-luciferase reporter gene assay and bioinformatics analysis were also adopted to investigate the underlying molecular mechanisms. Results: MiR-455-3p was down-regulated in HCC tissues and cells. In vitro experiments identified miR-455-3p overexpression inhibited HCC cell proliferation, migration and invasion. Interestingly, it was identified that vascular endothelial growth factor C (VEGFC) was the downstream target gene of miR-455-3p. Additionally, overexpression of miR-455-3p in HCC cells and human umbilical vein endothelial cells (HUVECs) cells led to decreased expression of VEGFC, vascular endothelial growth factor receptor (VEGFR)-2, and subsequently decreased phosphatidylinositol 3-kinase (AKT) signaling pathway. Furthermore, in vivo restoration of miR-455-3p significantly suppressed tumorigenicity of HuH-7 cells in nude mice and inhibited both angiogenesis and lymphangiogenesis of tumor xenografts. Conclusions: Our findings suggest that miR-455-3p could play a role in HCC tumorigenesis at least in part by modulation of angiogenesis and lymphangiogenesis through targeting VEGFC, and could simultaneously block AKT signaling pathways.

scholarly journals Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival

2021 ◽  
Author(s):  
Andreas Schmidt ◽  
Angela Armento ◽  
Ovidio Bussolati ◽  
Martina Chiu ◽  
Verena Ellerkamp ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Growth Inhibition ◽  
Cell Viability ◽  
Cell Lines ◽  
Prognostic Significance ◽  
Asparagine Synthetase ◽  
Inhibition Of Proliferation ◽  
Its Gene ◽  
Glutamine Synthesis

Abstract Purpose Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival. Methods We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations. Results High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival. Conclusion Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.

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