scholarly journals A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Hua Yang ◽  
Mu-Zi-he Zhang ◽  
Hui-wei Sun ◽  
Yan-tao Chai ◽  
Xiaojuan Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Antitumor Activity ◽  
Glucose Transporter ◽  
Epithelial Mesenchymal Transition ◽  
Aerobic Glycolysis ◽  
Related Factors ◽  
Clinical Role ◽  
Mesenchymal Transition ◽  
Advanced Hcc ◽  
Long Acting

BAY-876 is an effective antagonist of the Glucose transporter type 1 (GLUT1) receptor, a mediator of aerobic glycolysis, a biological process considered a hallmark of hepatocellular carcinoma (HCC) together with cell proliferation, drug-resistance, and metastasis. However, the clinical application of BAY-876 has faced many challenges. In the presence study, we describe the formulation of a novel microcrystalline BAY-876 formulation. A series of HCC tumor models were established to determine not only the sustained release of microcrystalline BAY-876, but also its long-acting antitumor activity. The clinical role of BAY-876 was confirmed by the increased expression of GLUT1, which was associated with the worse prognosis among advanced HCC patients. A single dose of injection of microcrystalline BAY-876 directly in the HCC tissue achieved sustained localized levels of Bay-876. Moreover, the single injection of microcrystalline BAY-876 in HCC tissues not only inhibited glucose uptake and prolonged proliferation of HCC cells, but also inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors. Thus, the microcrystalline BAY-876 described in this study can directly achieve promising localized effects, given its limited diffusion to other tissues, thereby reducing the occurrence of potential side effects, and providing an additional option for advanced HCC 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 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 miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma

2013 ◽  
Vol 210 (4) ◽  
pp. 789-803 ◽  
Author(s):  
Zhong-Hua Tao ◽  
Jin-Liang Wan ◽  
Ling-Yao Zeng ◽  
Lu Xie ◽  
Hui-Chuan Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Inhibitory Effects ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Advanced Hcc ◽  
Metastatic Cascade ◽  
First Time

MicroRNAs (miRNAs) play a critical role in tumor metastasis. In this study, we identified a set of 32 miRNAs involved in hepatocellular carcinoma (HCC) metastasis. Among them, miR-612 was shown for the first time to have inhibitory effects on HCC proliferation, migration, invasion, and metastasis. AKT2 was verified to be one of the direct targets of miR-612, through which the epithelial–mesenchymal transition (EMT) and metastasis were inhibited. The level of miR-612 in HCC patients was inversely associated with tumor size, stage, EMT, and metastasis. Of particular importance, miR-612 is involved in both the initial and final steps of the metastatic cascade, by suppressing local invasion and distant colonization. The pleiotropic roles of miR-612 in the HCC metastatic cascade suggest that it could be an effective target for both early and advanced HCC.

scholarly journals Molecular Mechanisms of Exercise on Cancer: A Bibliometrics Study and Visualization Analysis via CiteSpace

2022 ◽  
Vol 8 ◽  
Author(s):  
Dongling Zhong ◽  
Yuxi Li ◽  
Yijie Huang ◽  
Xiaojuan Hong ◽  
Juan Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Hot Spots ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Aerobic Glycolysis ◽  
Mesenchymal Transition ◽  
Productive Author ◽  
Stress Gene

Objective: To analyze the research hot spots and frontiers of molecular mechanisms of exercise on cancer via CiteSpace.Method: Related publications in the Web of Science Core Collection Science Citation Index Expanded were retrieved from inception to November 27th, 2021. Then we used CiteSpace to generate network maps and identify top authors, institutions, countries, keywords, co-cited authors, journals, references and research trends.Results: A total of 1,130 related publications were retrieved. The most productive author and journal were Lee W Jones and PLOS ONE. Hanahan D and Warburg O were the most cited authors. Fudan University and Shanghai Jiao Tong University were the leading institutions, while China was the leading country. Top-cited authors and references generally focused on the epidemiology and hallmarks of cancer. Top five keywords with both high frequency and high betweenness centrality were breast cancer, aerobic glycolysis, oxidative stress, gene expression, skeletal muscle. Keyword “warburg effect” ranked first with the highest citation burst, while “inflammation”, “hepatocellular carcinoma”, “epithelial mesenchymal transition”, and “adipose tissue” were emerging research foci.Conclusion: This study analyzed the research hot spots and frontiers of molecular mechanisms of exercise on cancer via CiteSpace. Based on the results, altered metabolism (aerobic glycolysis, insulin resistance, myokines), oxidative stress, gene expression and apoptosis were hot-research mechanisms of exercise on cancer. Emerging research foci of mechanisms were generally around inflammation, epithelial mesenchymal transition and adipokines. In addition, future studies could carry in-depth research of interactions between different mechanisms and try to elucidate the recommended doses and intensities of exercise for cancer, especially in breast, colorectal, prostate cancer and hepatocellular carcinoma.

scholarly journals Correction to: Forkhead box (FOX) G1 promotes hepatocellular carcinoma epithelial-Mesenchymal transition by activating Wnt signal through forming T-cell factor-4/Betacatenin/FOXG1 complex

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xingrong Zheng ◽  
Jiaxin Lin ◽  
Hewei Wu ◽  
Zhishuo Mo ◽  
Yunwen Lian ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
T Cell Factor ◽  
Forkhead Box ◽  
Wnt Signal

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Peng Xia ◽  
Hao Zhang ◽  
Kequan Xu ◽  
Xiang Jiang ◽  
Meng Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
P53 Protein ◽  
Rna Modifications ◽  
M Cell ◽  
Mesenchymal Transition ◽  
Akt Phosphorylation ◽  
Repeat Domain ◽  
Cell Cycle Transition

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.

scholarly journals FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition

Oncotarget ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 1703-1713 ◽  
Author(s):  
Tianxiu Dong ◽  
Yu Zhang ◽  
Yaodong Chen ◽  
Pengfei Liu ◽  
Tingting An ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition
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