scholarly journals Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Hui Chen ◽  
Qing Wu ◽  
Liu Peng ◽  
Ting Cao ◽  
Man-Ling Deng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Oxidative Phosphorylation ◽  
Tumor Cells ◽  
Clinical Significance ◽  
Warburg Effect ◽  
Noncoding Rna ◽  
Immune Escape ◽  
Migration And Invasion ◽  
Hcc Cells ◽  
The Warburg Effect

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the third leading cause of cancer death worldwide. The incidence of HCC accounts for more than 90% of primary HCC. Like most solid malignancies, the occurrence and development of HCC are closely related to the Warburg effect. The Warburg effect of HCC is mainly manifested as increased glucose uptake by HCC cells, increased glycolysis, restricted mitochondrial oxidative phosphorylation, increased pentose phosphate pathway in HCC cells, and increased glutamine decomposition. As the contribution of glycolysis to the total ATP of tumor cells generally does not exceed 50% to 60%, oxidative phosphorylation (OXPHOS) still makes a considerable contribution to the ATP of tumor cells. In some cases, there will be an anti-Warburg effect. HCC Warburg effect is closely related to HCC cell proliferation, apoptosis, immune escape, migration and invasion, chemotherapy resistance, and treatment failure. The mechanism of the Warburg effect in HCC is complex, involving the expression of stimulating the key glycolysis enzymes by hypoxia-inducible factor-1(HIF-1), the activation of oncogenes and the inactivation of tumor suppressor genes, the continuous activation of related signaling pathways, the participation of noncoding RNA, and the rate of metabolism gene mutation of enzyme. This article synthetically discusses the characteristics of glucose metabolism in HCC cells, the mechanism of Warburg effect, clinical significance, and corresponding treatment strategies and provides new perspectives for the prevention and treatment of HCC.

scholarly journals lncENST Suppress the Warburg Effect Regulating the Tumor Progress by the Nkx2-5/ErbB2 Axis in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Geng Chen ◽  
Jiayun Jiang ◽  
Xiaofei Wang ◽  
Kai Feng ◽  
Kuansheng Ma
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Cells ◽  
Warburg Effect ◽  
Noncoding Rna ◽  
Early Stage ◽  
Lactic Acid Production ◽  
Residual Tumor ◽  
Regulatory Relationship ◽  
In Vivo Models ◽  
The Warburg Effect

The therapeutic efficacy of radiofrequency ablation (RFA) against liver cancer is often limited by proliferation and metastasis of residual tumor cells. These phenomena are closely associated with the Warburg effect, wherein ErbB2 is activated. While RFA inhibits the Warburg effect of residual tumor cells at the early stage, the specific mechanisms remain unclear. We explored the regulatory relationship between the long noncoding RNA ENST00000570843.1 (lncENST) and ErbB2 using lentiviral transfection of lncENST and ErbB2 overexpression/interference vectors in in vitro and in vivo models of hepatocellular carcinoma in the presence of sublethal heat at 50°C. ErbB2-mediated Warburg effect was suppressed by lncENST, as manifested by reduced glucose uptake and lactic acid production in SMMC-7721 cells. lncENST also increased tumor apoptosis and inhibited tumor progression in nude Balb/c mice for up to 28 days after RFA. Additionally, we predicted through bioinformatic analysis that the promoter of ErbB2 binds to the transcription factor Nkx2-5, resulting in a negative regulatory effect. This speculation was confirmed by chromatin immunoprecipitation of the Nkx2-5 protein and ErbB2, indicating that ErbB2 transcription was curbed by Nkx2-5. We propose that lncENST downplays the Warburg effect in residual tumor cells by downregulating ErbB2 via Nkx2-5 activation. This study is aimed at providing molecular targets that can prevent residual tumor cell proliferation after RFA, with clinical significance in hepatocellular carcinoma treatment.

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 Long noncoding RNA CASC2c inhibited cell proliferation in hepatocellular carcinoma by inactivated ERK1/2 and Wnt/β-catenin signaling pathway

2019 ◽  
Vol 22 (3) ◽  
pp. 302-310 ◽  
Author(s):  
Q. Y. Li ◽  
K. Yang ◽  
F. G. Liu ◽  
X. G. Sun ◽  
L. Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cancer Susceptibility ◽  
Vital Role ◽  
Migration And Invasion ◽  
Tumor Tissues ◽  
Hcc Cells

Abstract Purpose Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumorigenesis, but their biological functions and the underlying molecular mechanisms remain unclear. Alternative splicing of five exons results in three transcript variants of cancer susceptibility 2 (CASC2): the lncRNAs CASC2a, CASC2b, and CASC2c. CASC2a/b have been found to have crucial regulatory functions in a number of malignancies, but few studies have examined the effects of CASC2c in cancers. The objective of the study was to investigate the role of CASC2c in the proliferation and apoptosis of hepatocellular carcinoma (HCC) cells. Methods This study first investigated the expression levels of CASC2c in tumor tissues, corresponding non-tumor tissues and cells using quantitative real-time polymerase chain reaction. The function and underlying molecular mechanism of CASC2c in human HCC were investigated in QGY-7703 cell line, as well as in gastric cancer (GC) cell and colorectal cancer (CRC) cell. Results In the present work, we observed that CASC2c was significantly down-regulated in HCC tissues and cells. Moreover, its overexpression remarkably inhibited the growth, migration, and invasion of HCC cells in vitro and promoted their apoptosis. Furthermore, we demonstrated that CASC2c overexpression decreased p-ERK1/2 levels in HCC, GC, and CRC cells. Interestingly, while overexpression of CASC2c decreased β-catenin expression in HCC and GC cells, it increased that in CRC cells. Conclusion The lncRNA–CASC2c has a vital role in tumorigenesis and cancer progression, and may serve as a biomarker or therapeutic target in cancer treatment via down-regulation of the ERK1/2 and Wnt/β-catenin signaling pathways.

scholarly journals Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 320 ◽  
Author(s):  
Chin-Chuan Chen ◽  
Chi-Yuan Chen ◽  
Shu-Huei Wang ◽  
Chau-Ting Yeh ◽  
Shih-Chi Su ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Repair ◽  
Noncoding Rna ◽  
Migration And Invasion ◽  
Tumor Growth Inhibition ◽  
Loss Of Function ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Repair Mechanisms ◽  
Hcc Cells

DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC.

scholarly journals Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

2021 ◽  
Vol 11 ◽  
Author(s):  
Juan Liu ◽  
Chao Yang ◽  
Xiao-Mei Huang ◽  
Pan-Pan Lv ◽  
Ya-Kun Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Warburg Effect ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cells ◽  
Targeted Agents ◽  
Related Factors ◽  
Mesenchymal Transition ◽  
Molecular Targeted Agents ◽  
Hcc Cells ◽  
The Warburg Effect

The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial–mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3′-untranslated region (3′-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway’s activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial–mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.

scholarly journals ROS-triggered AMPK de-SUMOylation promotes Warburg effect in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
Shutian Zhang
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Nuclear Translocation ◽  
High Recurrence Rate ◽  
Extracellular Flux ◽  
Mesenchymal Transformation ◽  
Hcc Cells ◽  
The Warburg Effect

AbstractHepatocellular carcinoma (HCC) is the most common malignant tumor of the liver characterized by high recurrence rate and high mortality. The interaction of oxidative stress tolerance and glycometabolism reprogramming in cancer cells results in metastasis and drug resistance in HCC. AMP-activated protein kinase (AMPK) is the master switch of cellular energy metabolism, which regulates the expression of glycolytic rate-limiting enzymes at multiple levels. SUMO Specific Peptidases (SENPs) respond to oxidative stress and modulate AMPK activity. Key scientific issues of this project: Activation of SENP5 by reactive oxygen species (ROS) triggered AMPKα2 de-SUMOylation and cytoplasmic retention to promote the Warburg effect in HCC cells. The human HCC cell lines SMMC-7721 and HepG2 were used in this project. H2O2 (200μM) was used to simulates oxidative stress in HCC cells. Glycolysis flow was monitored by Seahorse XF Extracellular Flux Analyzers. Western blot and immunofluorescence were used to evaluate expression and localization of AMPKα2. Data from TCGA database validated the correlation between SENP5 and glycolysis limiting enzymes. Results: (1) ROS-activated SNEP5 promoted Warburg effect; (2) SENP5 inhibited SUMO2/3 modification and nuclear translocation of AMPKα2; (3) Nuclear localized AMPKα2 activated FOXO3 to inhibit the Warburg effect mediated by c-Myc/Hif-α; (4) ROS activated SENP5 induced sorafenib resistance and epithelial mesenchymal transformation in HCC cells. Conclusion: SENP5 modifies the activation and localization of AMPK to promote glycometabolism reprogramming in HCC. This project provides a new theoretical bases for the treatment of HCC.Graphic abstractROS activation of SENP5 mediates AMPKα2 de-SUMOylation and cytoplasmic retention, which promotes Warburg effect of liver cancer cells

scholarly journals Methionine Dependence of Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 568 ◽  
Author(s):  
Peter Kaiser
Keyword(s):  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Rapid Growth ◽  
Warburg Effect ◽  
Metabolic Flux ◽  
Metabolic Changes ◽  
Normal Cells ◽  
Methionine Dependence ◽  
The Warburg Effect

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed.

scholarly journals Long Noncoding RNA MIR100HG Knockdown Attenuates Hepatocellular Carcinoma Progression by Regulating MicroRNA-146b-5p/Chromobox 6

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Fushun Li ◽  
Xianghua Sun ◽  
Qing Liu ◽  
Xilu Liu ◽  
Jia Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Viability ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Primary Liver Cancer ◽  
Tumor Stage ◽  
Migration And Invasion ◽  
Potential Therapeutic Target ◽  
Cell Behaviors ◽  
Hcc Cells

Purpose. Hepatocellular carcinoma (HCC) accounts for approximately ninety percent of primary liver cancer. This study attempted to investigate the effects of the long noncoding RNA MIR100HG (MIR100HG) in HCC and the underlying molecular mechanism. Materials and Methods. qRT-PCR was implemented to analyze the expression of MIR100HG, microRNA-146b-5p (miR-146b-5p), and Chromobox 6 (CBX6). The correlation between MIR100HG and clinicopathological features of HCC patients was assessed. Additionally, the effects of MIR100HG knockdown on HCC cell viability, migration, and invasion were explored. The interactions among MIR100HG, miR-146b-5p, and CBX6 were confirmed. Furthermore, rescue experiments were conducted to investigate whether MIR100HG knockdown modulates HCC cell behaviors through modulating the miR-146b-5p/CBX6 axis. Results. The expression of MIR100HG and CBX6 was enhanced, while miR-146b-5p was inhibited in HCC cells. High MIR100HG expression was positively associated with the TNM tumor stage and Edmondson-Steiner grading in HCC patients. MIR100HG knockdown considerably reduced the HCC cell viability, migration, and invasion. In addition, MIR100HG directly targeted miR-146b-5p, and miR-146b-5p directly targeted CBX6 in HCC cells. Moreover, miR-146b-5p suppression or CBX6 elevation evidently rescued the suppressed viability, migration, and invasion of HCC cells caused by MIR100HG knockdown. Conclusions. Knockdown of MIR100HG inhibited the viability, migration, and invasion of HCC cells by targeting the miR-146b-5p/CBX6 axis, offering a potential therapeutic target for HCC therapy.

scholarly journals The long noncoding RNA lncPARP1 contributes to progression of hepatocellular carcinoma through up-regulation of PARP1

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Heqiang Qi ◽  
Yuyan Lu ◽  
Jie Lv ◽  
Huita Wu ◽  
Jing Lu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Human Cancer ◽  
Noncoding Rnas ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Mechanistic Investigation ◽  
Induced Apoptosis ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) accounts for a large proportion of cancer-associated mortality worldwide. The functional impact of long noncoding RNAs (lncRNAs) in human cancer is not fully understood. Here, we identified a novel oncogenic lncRNA termed as lncPARP1, which was significantly up-regulated in HCC. Increase in lncPARP1 expression was associated with age, α-fetoprotein (AFP) levels, tumor size, recurrence, and poor prognosis of HCC patients. Loss-of-function approaches showed that knockdown of lncPARP1 inhibited proliferation, migration, and invasion, while induced apoptosis in HCC cells. Moreover, mechanistic investigation demonstrated that PARP1 was an underlying target of lncPARP1 in HCC. In summary, we provide the first evidence that lncPARP1 exerts an oncogene to promote HCC development and progression, at least in part, by affecting poly (ADP-ribose) (PAR) polymerase 1 (PARP1) expression.

scholarly journals Sirtuin 1 Protects the Mitochondria in Hepatocellular Carcinoma Cells via Suppressing Hypoxia-induced Factor-1 Alpha Expression

2022 ◽  
Author(s):  
Zun-Qiang Zhou ◽  
Jiao Guan ◽  
Shi-Geng Chen ◽  
Jian-Hua Sun ◽  
Zheng-Yun Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Warburg Effect ◽  
Sirtuin 1 ◽  
Luciferase Reporter ◽  
Tumor Xenografts ◽  
Mitochondrial Functions ◽  
Hcc Cells ◽  
The Warburg Effect

Abstract Background: We hypothesized that Sirtuin 1 (SIRT1) might attenuate the Warburg effect in tumor cells by modulating hypoxia-induced factor-1 alpha (HIF-1α) expression. This study aimed to explore the role and the underlying mechanism of SIRT1 in protecting the mitochondrial functions in hepatocellular carcinoma (HCC) cells. Methods: Quantitative real-time PCR and western blot analysis were conducted to determine gene expression in HCC cells. Co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays were performed to examine DNA-protein interactions. Colony formation and MTT assays were carried out to explore the role of SIRT1 in HCC cell proliferation in vitro. PLC5 and Huh7 tumor xenografts were generated in mice to investigate the role of SIRT1–HIF-1α signaling in HCC development in vivo. Results: In different HCC cell lines, overexpression of SIRT1 promoted oxidative phosphorylation-associated gene expressions, ATP production, cell proliferation, and apoptotic protein expression while attenuating VEGF expression. In mice, overexpression of SIRT1 resulted in significant reductions in the weights of PLC5 and Huh7 tumor xenografts. Knockdown of SIRT1 exhibited opposite effects. Mechanistically, overexpression of SIRT1 promoted HIF-1α deacetylation, VHL-mediated HIF-1α degradation, and AMPK expression. Furthermore, SIRT1 interfered with the HIF-1α–c-Myc interaction to stimulate the transcription of a mitochondrial biogenesis enhancer mitochondrial transcription factor A (TFAM). Overexpression of HIF-1α completely reversed the effects of SIRT1.Conclusions: SIRT1 protects the mitochondria of HCC cells via suppressing HIF-1α expression, suggesting that SIRT1 may exert antitumor activity in HCC by reducing the Warburg effect.

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