scholarly journals MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Liang Ren ◽  
Yongshan Yao ◽  
Yang Wang ◽  
Shengqiang Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Glucose Transporter ◽  
Lactate Production ◽  
Growth Factor Receptor ◽  
Mechanism Study ◽  
Down Regulation ◽  
Critical Function ◽  
Insulin Growth Factor ◽  
Huh7 Cells ◽  
Hcc Cells

Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers globally. An increasing body of evidence has demonstrated the critical function of microRNAs (miRNAs) in the initiation and progression of human cancers. Here, we showed that miR-505 was down-regulated in HCC tissues and cell lines. Reduced expression of miR-505 was significantly correlated with the worse prognosis of HCC patients. Overexpression of miR-505 suppressed the proliferation, colony formation and induced apoptosis of both HepG2 and Huh7 cells. Further mechanism study uncovered that miR-505 bound the 3′-untranslated region (3′-UTR) of the insulin growth factor receptor (IGF-1R) and inhibited the expression of IGF-1R in HCC cells. The down-regulation of IGF-1R by miR-505 further suppressed the phosphorylation of AKT at the amino acid S473. Consistently, the abundance of glucose transporter (GLUT) 1 (GLUT1) was reduced with the overexpression of miR-505. Down-regulation of GLUT1 by miR-505 consequently attenuated the glucose uptake, lactate production and ATP generation of HCC cells. Collectively, our results demonstrated the tumor suppressive function of miR-505 possibly via inhibiting the glycolysis of HCC cells. These findings suggested miR-505 as an interesting target for designing anti-cancer strategy in HCC.

scholarly journals Nujiangexanthone A Inhibits Hepatocellular Carcinoma Metastasis via Down Regulation of Cofilin 1

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Zhang ◽  
Zongtao Chai ◽  
Siyuan Kong ◽  
Jiling Feng ◽  
Man Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Malignant Tumors ◽  
Disease Free Survival ◽  
Mechanism Study ◽  
Down Regulation ◽  
Free Survival ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is one of the malignant tumors with poor prognosis. High expression level of cofilin 1 (CFL1) has been found in many types of cancers. However, the role of CFL1 in HCC hasn’t been known clearly. Here, we found that CFL1 was up regulated in human HCC and significantly associated with both overall survival and disease-free survival in HCC patients. Nujiangexanthone A (NJXA), the caged xanthones, isolated from gamboge plants decreased the expression of CFL1, which also inhibited the migration, invasion and metastasis of HCC cells in vitro and in vivo. Down regulation of CFL1 inhibited aggressiveness of HCC cells, which mimicked the effect of NJXA. Mechanism study indicated that, knockdown of CFL1 or treatment with NJXA increased the level of F-actin and disturbed the balance between F-actin and G-actin. In conclusion, our findings reveal the role of CFL1 in HCC metastasis through the CFL1/F-actin axis, and suggest that CFL1 may be a potential prognostic marker and a new therapeutic target. NJXA can effectively inhibit the metastasis of HCC cells by down regulating the expression of CFL1, which indicates the potential of NJXA for preventing metastasis in 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 MiR-376a and Histone Deacetylation 9 Form A Regulatory Circuitry in Hepatocellular Carcinoma

2015 ◽  
Vol 35 (2) ◽  
pp. 729-739 ◽  
Author(s):  
Yongxia Zheng ◽  
Huan Chen ◽  
Manxiang Yin ◽  
Xiaoqian Ye ◽  
Guiqian Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Histone Deacetylation ◽  
Differentially Methylated Region ◽  
Down Regulation ◽  
Acetylation Level ◽  
Histone 3 ◽  
Huh7 Cells ◽  
As Effects

Background/Aims: Our previous study has demonstrated that down-regulation of miR-376a might contribute to the development of hepatocellular carcinoma (HCC), but the mechanism underlying this down-regulation remains obscure. Methods/Results: histone deacetylase (HDAC) inhibitor increased the level of miR-376a in L02 and Huh7 cells by up-regulating the acetylation level of histone 3 at the Maternally expressed 3 (Meg3) differentially methylated region (DMR). Interestingly, HDAC9, a histone deacetylase responsible for deacetylating lysine 18 of histone 3 (H3K18), was identified as the target of miR-376a. In addition, HDAC9 siRNA increased the expression of miR-376a by up-regulating the global histone H3K18 acetylation level, with Meg3 DMR included. Finally, miR-376a and HDAC9 were inversely correlated in HCC. Conclusion: HDAC9 plays an important role both as effects and targets of miR-376a.

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 Down-Regulation of C3aR/C5aR Inhibits Cell Proliferation and EMT in Hepatocellular Carcinoma

2020 ◽  
Vol 19 ◽  
pp. 153303382097066
Author(s):  
Bendong Chen ◽  
Wenyan Zhou ◽  
Chaofeng Tang ◽  
Genwang Wang ◽  
Peng Yuan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Down Regulation ◽  
Ki 67 ◽  
Small Interference Rna ◽  
Mesenchymal Transition ◽  
Functional Roles ◽  
G1 Phase Arrest ◽  
Hcc Cells

Complement 3a (C3a) and complement 5a (C5a), small cleavage fragments generated by complement activation, has been previously shown to be obviously up-regulated in highly metastatic hepatocellular carcinoma (HCC) cells. However, their functional roles in HCC cells remains unclear. Here, we investigated the biological function of G protein-coupled receptor C3aR/C5aR using small interference RNA in HCC cells. Our data showed that C3aR and C5aR knockdown significantly inhibited the proliferation, migration and invasion of HCC cells using CCK-8, colony formation and transwell assays. Flow cytometry assay showed C3aR and C5aR knockdown induced cell cycle G0/G1 phase arrest and apoptosis in HCC cells. Moreover, we found down-regulation of C3aR/C5aR obviously down-regulated the expression of PCNA, Ki-67 and suppressed the epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) in HCC cells. Collectively, our data demonstrated that targeting C3aR/C5aR may hold promise for the treatment of HCC.

Functional analysis of miR-101-3p and Rap1b involved in hepatitis B virus-related hepatocellular carcinoma pathogenesis

2014 ◽  
Vol 92 (2) ◽  
pp. 152-162 ◽  
Author(s):  
Yanrui Sheng ◽  
Shijia Ding ◽  
Ke Chen ◽  
Juan Chen ◽  
Sen Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Promoter Activity ◽  
Down Regulation ◽  
B Virus ◽  
And Migration ◽  
Hcc Cells ◽  
Proliferation And Migration

MicroRNA-101(miR-101) has been shown to be down-regulated in hepatocellular carcinoma (HCC). The hepatitis B virus (HBV) is a major risk factor in the development and progression of HCC. However, the correlation between HBV and miR-101 has not yet been fully elucidated. In this study, we reported that HBV could repress miR-101-3p by inhibiting its promoter activity and identified the potential effects of miR-101-3p on some important biological properties of HCC cells by targeting Rap1b. Dual-luciferase reporter assays showed that HBV down-regulated miR-101-3p by inhibiting its promoter activity. Down-regulation of miR-101-3p promoted cell proliferation, migration, and reduced apoptosis, and resulted in up-regulation of Rap1b, while overexpression of miR-101-3p inhibited these processes. Moreover, overexpression of Rap1b was able to reverse the suppressed cell proliferation and migration mediated by miR-101-3p. Our data showed that HBV down-regulated miR-101-3p expression by inhibiting its promoter activity, which resulted in up-regulation of Rap1b, and down-regulation of miR-101-3p or up-regulation of Rap1b promoted proliferation and migration of HCC cells. This provides a new understanding of the mechanism of HBV-related HCC pathogenesis and the potential application of miR-101-3p in cancer therapy.

scholarly journals Inhibiting p21-activated kinase (PAK7) enhances radiosensitivity in hepatocellular carcinoma

2021 ◽  
pp. 096032712110279
Author(s):  
Y-F Gu ◽  
L-T Kong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Inhibitory Effect ◽  
Sulforhodamine B ◽  
Huh7 Cells ◽  
M Phase ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
P21 Activated Kinase ◽  
Hcc Cells

Objective: In light of the upregulation of p21-activated kinase (PAK7) in a variety of cancers, including hepatocellular carcinoma (HCC), we aimed to investigate the effect of PAK7 on the sensitivity of HCC cells to radiotherapy. Methods: PAK7 expression was determined in normal adult liver epithelial THLE-2 and human HCC cell lines. The effect of ionizing radiation (IR) on the HCC cell viability was evaluated by Sulforhodamine B (SRB) assay. HCC cell lines Mahlavu and Huh7 were chosen to assess the effect of PAK7 shRNAs on the viability, clone formation, apoptosis, cycle distribution and γ-H2AX expression after exposure to IR. Results: As compared to THLE-2 cells, PAK7 was upregulated in poorly differentiated Mahlavu and SK-Hep-1 cells, but moderately or lowly expressed in well-differentiated Huh7 and HepG2 cells. HCC cells with moderate or low expression of PAK7 presented a decreased viability at 2 Gy IR, which had no significant effect on PAK7high HCC cells. Mahlavu and Huh7 cells transfected with PAK7 shRNAs showed increased inhibitory effect of IR on viability. In addition, PAK7 shRNAs reduced clone formation, facilitated the cell apoptosis, arrested cells at G2/M phase, and increased γ-H2AX expression. Moreover, changes above were more evident in the HCC cells co-treated with IR and PAK7 shRNAs. Conclusion: PAK7 downregulation could inhibit the viability, promote the apoptosis, arrest cells in G2/M phase, and induce the DNA damage in HCC cells, thereby enhancing the radiosensitivity in HCC.

scholarly journals Upregulation of PD-L1 expression promotes epithelial-to-mesenchymal transition in sorafenib-resistant hepatocellular carcinoma cells

2020 ◽  
Vol 8 (5) ◽  
pp. 390-398
Author(s):  
Gui-Li Xu ◽  
Cai-Fang Ni ◽  
Han-Si Liang ◽  
Yun-Hua Xu ◽  
Wan-Sheng Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Regulatory Element ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Knock Down ◽  
Huh7 Cells ◽  
Element Binding Protein ◽  
Hcc Cells ◽  
E Cadherin

Abstract Background The epithelial-to-mesenchymal transition (EMT) status is associated with programmed death-1 ligand 1 (PD-L1) expression in various cancers. However, the role and molecular mechanism of PD-L1 in the EMT of sorafenib-resistant hepatocellular carcinoma (HCC) cells remain elusive. In this study, we aimed to investigate the regulation of PD-L1 on the EMT in sorafenib-resistant HCC cells. Methods Initially, the sorafenib-resistant HCC cell lines HepG2 SR and Huh7 SR were established. Western-blot assays were used to detect the expression of PD-L1, E-cadherin, and N-cadherin. The intervention and overexpression of PD-L1 were used to explore the role of PD-L1 in the regulation of EMT in HepG2 SR and Huh7 SR cells. Cell migration and invasion were assessed by transwell assays. PD-L1 or Sterol regulatory element-binding protein 1 (SREBP-1) overexpression and knock-down were performed in order to study the mechanism of PD-L1 in sorafenib-resistant HCC cells. Results PD-L1 expression was upregulated, whereas E-cadherin levels were downregulated and N-cadherin expression was increased in HepG2 SR and Huh7 SR cells. The cell viabilities of HepG2 and Huh7 cells were lower than those of HepG2 SR and Huh7 SR cells. PD-L1 overexpression reduced E-cadherin expression and increased N-cadherin levels, whereas PD-L1 knock-down increased E-cadherin expression and decreased N-cadherin expression. PD-L1 expression promoted EMT and the migratory and invasive abilities of HepG2 SR and Huh7 SR cells. PD-L1 promoted the EMT of sorafenib-resistant HCC cells via the PI3K/Akt pathway by activating SREBP-1 expression in HepG2 SR and Huh7 SR cells. Conclusions The findings reveal that PD-L1 expression promotes EMT of sorafenib-resistant HCC cells.

scholarly journals Hypoxia-induced lncRNA -NEAT1 sustains the growth of hepatocellular carcinoma via regulation of miR-199a-3p/UCK2: integrative bioinformatics analysis and experimental validation

2020 ◽  
Author(s):  
Qiangnu Zhang ◽  
Qian Cheng ◽  
Mengting Xia ◽  
Xiaotao Huang ◽  
Xiaoyan He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Noncoding Rna ◽  
Bioinformatics Analysis ◽  
Luciferase Reporter ◽  
Qrt Pcr ◽  
Hypoxic Conditions ◽  
Huh7 Cells ◽  
Lncrna Neat1 ◽  
Hcc Cells

Abstract Background: The long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) has emerged as a novel player in hepatocellular carcinoma (HCC). Hypoxia is a common characteristic of the microenvironment of HCC. However, it remains unclear whether lncRNA-NEAT1 is induced by hypoxia in HCC, and the mechanism that underlies LncRNA-NEAT1 function is not well characterized. Methods: The expression changes of lncRNA-NEAT1 in HCC cell lines under hypoxic conditions were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The regulatory effect of HIF-1α on lncRNA-NEAT1 was confirmed with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The function of lncRNA-NEAT1 on HCC cell growth under hypoxic conditions was determined by CCK-8 assay and flow cytometry. lncRNA -NEAT1 was predicted to serve as a competing endogenous RNA (ceRNA) within microRNA (miRNA)/mRNA axes based on microarray data, public HCC-related datasets and integrative bioinformatics analysis, and the miR-199a-3p/UCK2 axis was selected and validated by qRT-PCR, western blotting, RNA immunoprecipitation, and luciferase reporter analyses. The role of miR-199a-3p/UCK2 in HCC and its functional association with lncRNA-NEAT1 were assessed both in vitro and in vivo . Results : LncRNA-NEAT1 expression was significantly induced by hypoxia in SNU-182 and HUH7 cells. HIF-1α was shown to regulate lncRNA-NEAT1 transcription. Under hypoxic conditions, lncRNA-NEAT1 maintained the growth of HCC cells and inhibited apoptosis and cell cycle arrest. LncRNA-NEAT1 was predicted to regulate a panel of HCC-associated miRNA-mRNA pairs consisting of 8 miRNAs and 13 mRNAs. Furthermore, lncRNA-NEAT1 was demonstrated to serve as a miR-199a-3p sponge that regulates UCK2 expression and to play a tumor-suppressive role in HCC, while UCK2 promotes cell growth. LncRNA-NEAT1 was shown to function as a ceRNA of miR-199a-3p/UCK2 both in HCC cells under hypoxic conditions and in an animal model. Conclusion: LncRNA-NEAT1 is a hypoxia-responsive lncRNA in HCC that sustains the growth of HCC cells by regulating HCC-associated mRNAs that interact with tumor-suppressive miRNAs. The lncRNA-NEAT1/miR-199a-3p/UCK2 pathway may contribute to the progression of HCC in a hypoxic microenvironment and therefore may represent a novel therapeutic target for HCC.

scholarly journals MicroRNA-2392 Functions as a Tumor Suppressor Gene and Inhibits Malignant Progression of Hepatocellular Carcinoma via Directly Targeting JAG2

2021 ◽  
Author(s):  
Chunying Liu ◽  
Bin Sun ◽  
Weidan Ji ◽  
Xuejing Lin ◽  
Lei Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Malignant Progression ◽  
Spheroid Formation ◽  
Down Regulation ◽  
Potential Target ◽  
Target Mrnas ◽  
Hcc Cells

Abstract Background Dysregulation of microRNA (miRNA) expression in various cancers and their vital roles in malignant progression of cancers are well investigated. Our previous studies have analyzed miRNAs that promote malignant progression of hepatocellular carcinoma (HCC), this study aim to systematically elucidate metastasis suppressor miRNAs in HCC. Methods High-throughput RNA sequencing analysis was used to identify anti-metastatic miRNAs of HCC. The relative expression levels of miRNAs were confirmed by qRT-PCR. The biological functions of miRNAs were studied by CCK8, wound-healing, transwell, colony formation in HCC cells. Circulating tumor cells were enriched from blood samples of HCC patients and cultured by three-dimensional (3D) system. The potential target mRNAs of miRNAs were analyzed by bioinformatics analysis and confirmed by luciferase reporter assay. Liver metastasis model via tail vein injection was further examined in nude mice. Kaplan-Meier and Cox regression were used to analyze the value of potential target mRNAs on overall survival. Results miR-2392 was significantly down-regulated in HCC. Overexpression of miR-2392 suppressed proliferation, mobility, spheroid formation and maintenance of cancer stem cells (CSC)-like characteristics in HCC cell lines, whereas down-regulation of miR-2392 led to the opposite results. CTCs from HCC patients with lower serum miR-2392 level had stronger cell spheroid formation ability. A negative correlation between the content of miR-2392 in serum and the number of CTC spheroids had been found. We identified Jagged2 (JAG2) as a direct target of miR-2392, miR-2392 inhibited the expression and nuclear accumulation of JAG2 by targeting 3’-UTR of JAG2. HCC cells were treated with LV-miR-2392 inhibitor and JAG2-siRNA to explore the mechanism of miR-2392 and JAG2 on HCC. Down-regulation of JAG2 inhibited the overexpression effects of miR-2392 in vitro and in vivo. JAG2 is highly expressed in HCC and is closely related to poor prognosis and survival of patients. Conclusions Our findings indicated a significant role of the miR-2392/JAG2 axis in suppressing HCC cell growth and aggressiveness, miR-2392 may play a role as a tumor suppressor gene to guide the individualized precise treatment of HCC.

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