scholarly journals Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

2017 ◽  
Vol 44 (5) ◽  
pp. 1856-1868 ◽  
Author(s):  
Zhikui Liu ◽  
Kangsheng Tu ◽  
Yufeng Wang ◽  
Bowen Yao ◽  
Qing Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Migration And Invasion ◽  
Ros Production ◽  
Mesenchymal Transition ◽  
Gli1 Expression ◽  
Hh Signaling ◽  
Hcc Cells

Background/Aims: Hypoxic microenvironment, a common feature of hepatocellular carcinoma (HCC), can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, the underlying molecular mechanisms have not fully elucidated. Methods: HCC cells were cultured under controlled hypoxia conditions or normoxic conditions. Transwell assays were used to examine the migration and invasion capacity. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. Results: In present study, we first observed a strongly positive correlation between HIF-1α and GLI1 expression in HCC tissues. Then, we showed that hypoxia significantly promoted EMT process and invasion of HCC cells, associated with activating the non-canonical Hh pathway without affecting SHH and PTCH1 expression. HIF-1α knockdown mitigated hypoxia-induced SMO and GLI1 expression, EMT invasion of HCC cells. Moreover, the SMO inhibitor or GLI1 siRNA also reversed the hypoxia-driven EMT and invasion of HCC cells under hypoxia condition. Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in HCC cells. In addition, we found that hypoxia increased ROS production and that ROS inhibitors (NAC) blocked GLI1-dependent EMT process and invasion under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is involved in hypoxia-induced ROS production. NOX4 expression was found to be increased at both mRNA and protein levels in hypoxic HCC cells. Furthermore, siRNA-mediated knockdown of NOX4 expression abolished hypoxia induced ROS generation and GLI1-dependent activation and invasion of HCC cells. Conclusion: Our findings indicate that hypoxia triggers ROS-mediated GLI1-dependent EMT progress and invasion of HCC cells through induction of NOX4 expression. Thus, hypoxia-driven ROS mediated non-canonical Hh signaling may play an important role in the initiation of EMT and provides a potential marker for cancer prevention and treatment.

scholarly journals Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism

2021 ◽  
Vol 22 (11) ◽  
pp. 5543
Author(s):  
Jitka Soukupova ◽  
Andrea Malfettone ◽  
Esther Bertran ◽  
María Isabel Hernández-Alvarez ◽  
Irene Peñuelas-Haro ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Lipid Metabolism ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Metabolic Switch ◽  
Mesenchymal Transition ◽  
Hcc Cells

(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial–mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-β in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-β when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-β in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.

scholarly journals Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis

2020 ◽  
Vol 117 (9) ◽  
pp. 4770-4780 ◽  
Author(s):  
Hao Jiang ◽  
Hui-Jun Cao ◽  
Ning Ma ◽  
Wen-Dai Bao ◽  
Jing-Jing Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chromatin Remodeling ◽  
Epithelial Mesenchymal Transition ◽  
Positive Association ◽  
Mechanistic Study ◽  
Migration And Invasion ◽  
Metastasis Suppressor ◽  
Mesenchymal Transition ◽  
Hcc Cells

Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial–mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.

scholarly journals RETRACTED ARTICLE: Sorcin Predicts Poor Prognosis and Promotes Metastasis by Facilitating Epithelial-mesenchymal Transition in Hepatocellular Carcinoma

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiong Lei ◽  
Yahang Liang ◽  
Jian Chen ◽  
Shuai Xiao ◽  
Jian Lei ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Significant Risk ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Liver Tissues

Abstract Metastasis-associated recurrence is the main cause for the poor prognosis of hepatocellular carcinoma (HCC). However, the detailed molecular mechanisms underlying HCC metastasis remain elusive. Though some data indicated the oncogenic role of Sorcin in tumors, the prognostic value and biological role of Sorcin in HCC is still unknown. In this study, it demonstrated that Sorcin expression levels were significantly upregulated in HCC tumor tissues compared with matched adjacent nontumorous liver tissues and normal liver tissues, and such expression level correlated with HCC metastasis. High Sorcin expression was significantly correlated with aggressive clinicopathological characteristics such as multiple tumor nodules, high Edmondson-Steiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05). HCC patients with high Sorcin expression had both shorter survival and higher recurrence than those with low Sorcin expression (all P < 0.05). Sorcin expression was an independent and significant risk factor for survival and recurrence of HCC patients. Results of functional experiments showed that Sorcin could promote HCC cell proliferation, migration, and invasion in vitro, and facilitate HCC growth and metastasis in vivo. Mechanistically, Sorcin exerted its role by activating extracellular signal-regulated kinase (ERK) pathway and promoted metastasis by facilitating epithelial-mesenchymal transition (EMT) in 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.

scholarly journals B-Cell Receptor-Associated Protein 31 Promotes Metastasis via AKT/β-Catenin/Snail Pathway in Hepatocellular Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Tengfei Liu ◽  
Junming Yu ◽  
Chao Ge ◽  
Fangyu Zhao ◽  
Chunxiao Miao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Migration And Invasion ◽  
Related Factor ◽  
Akt Inhibitor ◽  
Mesenchymal Transition ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is one of the most lethal cancer worldwide, characterized with high heterogeneity and inclination to metastasize. Emerging evidence suggests that BAP31 gets involved in cancer progression with different kinds. It still remains unknown whether and how BAP31 plays a role in HCC metastasis. Epithelial–mesenchymal transition (EMT) has been a common feature in tumor micro-environment, whose inducer TGF-β increased BAP31 expression in this research. Elevated expression of BAP31 was positively correlated with tumor size, vascular invasion and poor prognosis in human HCC. Ectopic expression of BAP31 promoted cell migration and invasion while BAP31 knockdown markedly attenuated metastatic potential in HCC cells and mice orthotopic xenografts. BAP31 induced EMT process, and enhanced the expression level of EMT-related factor Snail and decreased contents and membrane distribution of E-cadherin. BAP31 also activated AKT/β-catenin pathway, which mediated its promotional effects on HCC metastasis. AKT inhibitor further counteracted the activated AKT/β-catenin/Snail upon BAP31 over-expression. Moreover, silencing Snail in BAP31-overexpressed cells impaired enhanced migratory and invasive abilities of HCC cells. In HCC tissues, BAP31 expression was positively associated with Snail. In conclusion, BAP31 promotes HCC metastasis by activating AKT/β-catenin/Snail pathway. Thus, our study implicates BAP31 as potential prognostic biomarker, and provides valuable information for HCC prognosis and treatment.

scholarly journals ASIC1a Stimulates the Resistance of Human Hepatocellular Carcinoma by Promoting Epithelial-mesenchymal Transition via the AKT/GSK3β/Snail Signaling Pathway

2021 ◽  
Author(s):  
Yinci Zhang ◽  
Niandie Cao ◽  
Jiafeng Gao ◽  
Jiaojiao Liang ◽  
Yong Liang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Migration ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cell Migration And Invasion ◽  
Gsk 3Β ◽  
Hcc Cells

Abstract Background: The main obstacle to the cure of hepatocellular carcinoma (HCC) is multidrug resistance. Acid sensing ion channel 1a (ASIC1a) acts as a critical roles in all stages of cancer progression, especially invasion and metastasis as well as in resistance to therapy. Epithelial to mesenchymal transition (EMT) is a phenomenon in which epithelial cells transform into mesenchymal cells after being stimulated by extracellular factors and is closely related to tumor infiltration and resistance. Methods: Western blotting assay, Immunofluorescence (IF) staining, Immunohistochemistry (IHC) staining, MTT and colony formation assay and scratch healing assay were used to detect the level of ASIC1a and the cell proliferation, migration and invasion capabilities in this research.Results: In this research, we found that the protein of ASIC1a is overexpressed in HCC cancer tissues. In addition, we identified that the levels of ASIC1a are highly expressed in resistant HCC cells. Compared with the parental cells, EMT occurred more frequently in drug-resistant cells. Functional studies demonstrated that inactivation of ASIC1a restrained cell migration and invasion and enhanced the chemosensitivity of cells through EMT. In HCC cells, the overexpression of ASIC1a stimulates the up-regulation of EMT characterization molecular level and proliferation, migration and invasion capabilities and further induces drug resistance, while knocking down ASIC1a with short hairpin RNA (shRNA) has the opposite effect. Further investigations found that ASIC1a increased cell migration and invasion through EMT by regulating α and β-catenin, vimentin and fibronectin expression via AKT/GSK-3β/Snail pathway. Conclusions: Our study demonstrated that ASIC1a acts an important assignment in drug resistance of HCC through EMT via AKT/GSK-3β/Snail pathway, thereby lending a latent therapeutic objective and new ideas regarding to HCC.

Therapeutic inhibition of phospholipase D1 suppresses hepatocellular carcinoma

2016 ◽  
Vol 130 (13) ◽  
pp. 1125-1136 ◽  
Author(s):  
Junjie Xiao ◽  
Qi Sun ◽  
Yihua Bei ◽  
Ling Zhang ◽  
Jasmina Dimitrova-Shumkovska ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Modality ◽  
Migration And Invasion ◽  
Critical Pathways ◽  
Mesenchymal Transition ◽  
Phospholipase D1 ◽  
And Migration ◽  
Hcc Cells ◽  
Novel Therapeutic

Hepatocellular carcinoma (HCC) represents a leading cause of deaths worldwide. Novel therapeutic targets for HCC are needed. Phospholipase D (PD) is involved in cell proliferation and migration, but its role in HCC remains unclear. In the present study, we show that PLD1, but not PLD2, was overexpressed in HCC cell lines (HepG2, Bel-7402 and Bel-7404) compared with the normal human L-02 hepatocytes. PLD1 was required for the proliferation, migration and invasion of HCC cells without affecting apoptosis and necrosis, and PLD1 overexpression was sufficient to promote those effects. By using HCC xenograft models, we demonstrated that therapeutic inhibition of PLD1 attenuated tumour growth and epithelial–mesenchymal transition (EMT) in HCC mice. Moreover, PLD1 was found to be highly expressed in tumour tissues of HCC patients. Finally, mTOR (mechanistic target of rapamycin) and Akt (protein kinase B) were identified as critical pathways responsible for the role of PLD1 in HCC cells. Taken together, the present study indicates that PLD1 activation contributes to HCC development via regulation of the proliferation, migration and invasion of HCC cells, as well as promoting the EMT process. These observations suggest that inhibition of PLD1 represents an attractive and novel therapeutic modality for HCC.

scholarly journals KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3

2021 ◽  
Vol 23 (1) ◽  
pp. 104
Author(s):  
Yanhong Wang ◽  
Na Li ◽  
Yanping Zheng ◽  
Anqing Wang ◽  
Chunlei Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Adaptor Protein ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Macromolecular Protein ◽  
Carcinoma Metastasis

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/β-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.

MiR-9-5p promotes cell proliferation and migration of hepatocellular carcinoma by targeting CPEB3

2021 ◽  
Vol 15 (2) ◽  
pp. 97-108
Author(s):  
Zheyue Shu ◽  
Feng Gao ◽  
Qi Xia ◽  
Min Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Transition Process ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Promote Cell Proliferation ◽  
Growth Activity ◽  
And Migration ◽  
Hcc Cells

Objective: This study aimed to observe the effect of miR-9-5p and CPEB3 on hepatocellular carcinoma (HCC) cells, and investigate the underlying targeting regulatory mechanism. Materials & methods: Various experiments like CCK-8, colony formation assay, wound healing assay and Transwell were performed for cancer cell activities detection, including cell proliferation, growth activity, migration and invasion. Results: MiR-9-5p was found to be highly expressed in HCC cells, while CPEB3 was poorly expressed (p < 0.05). The overexpression of miR-9-5p and the silencing of CPEB3 both could significantly promote cell proliferation, migration and invasion (p < 0.05). In addition, miR-9-5p could target to downregulate CPEB3 expression, thus accelerating cell proliferation, migration, invasion and epithelial-mesenchymal transition process in HCC. Conclusion: MiR-9-5p can target CPEB3, thereby promoting cell proliferation, migration and invasion in HCC. The axis of miR-9-5p/CPEB3 is expected to become a potential therapeutic target beneficial for HCC patients.

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