scholarly journals N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yanying Wang ◽  
Jing Wang ◽  
Xiaoyu Li ◽  
Xushen Xiong ◽  
Jianyi Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Hedgehog Signaling ◽  
Cholesterol Synthesis ◽  
Patient Survival ◽  
Potent Inhibitor ◽  
Cholesterol Metabolism ◽  
Self Renewal ◽  
Advanced Hcc ◽  
Liver Cancers

AbstractHepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer.

scholarly journals Inhibition of β‑catenin protein expression by triptolide affects self-renewal of liver cancer stem cells

2015 ◽  
Vol 10 (2) ◽  
pp. 455 ◽  
Author(s):  
Jian-Bo Zhou ◽  
Gang Peng ◽  
Yu-Cheng Jia ◽  
Jun Li ◽  
Jia Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Inhibitory Concentration ◽  
The Self ◽  
Tripterygium Wilfordii ◽  
Self Renewal ◽  
Liver Cancer Stem Cells ◽  
Novel Agent

<p>The present study demonstrates the effects of triptolide, one of the constituents from Tripterygium wilfordii, on the self‑renewal capacity of human hepatocellular carcinoma. The investigation revealed that triptolide markedly prevented the proliferation of liver cancer stem cells (LCSCs). For the LCSCs the minimum inhibitory concentration of triptolide was 0.6 μM. There was a significant and obvious decrease in the capacity of LCSCs to form self-sphere. Furthermore, triptolide reduced the sphere-forming capacity of LCSCs along with inhibition of β‑catenin expression. However, the exposure of triptolide-treated cells to lithium chloride, an activator the Wnt/β-catenin signaling pathway, reversed the triptolide-induced inhibition of β-catenin expression and inhibited the self-renewal capacity. Therefore, triptolide effectively eradicates LCSCs through the inhibition of β-catenin protein and may act as a novel agent for the treatment of hepatocellular carcinoma.</p><p> </p>

scholarly journals Tumor-Intrinsic Mechanisms Regulating Immune Exclusion in Liver Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Katherine E. Lindblad ◽  
Marina Ruiz de Galarreta ◽  
Amaia Lujambio
Keyword(s):  
Liver Cancer ◽  
Rational Design ◽  
Immune Escape ◽  
Current Knowledge ◽  
Treatment Options ◽  
Health Concern ◽  
Patient Stratification ◽  
Tumor Immune Evasion ◽  
Advanced Hcc ◽  
Liver Cancers

Representing the fourth leading cause of cancer-related mortality worldwide, liver cancers constitute a major global health concern. Hepatocellular carcinoma (HCC), the most frequent type of liver cancer, is associated with dismal survival outcomes and has traditionally had few treatment options available. In fact, up until 2017, treatment options for advanced HCC were restricted to broad acting tyrosine kinase inhibitors, including Sorafenib, which has been the standard of care for over a decade. Since 2017, a multitude of mono- and combination immunotherapies that include pembrolizumab, nivolumab, ipilumumab, atezolizumab, and bevacizumab have been FDA-approved for the treatment of advanced HCC with unprecedented response rates ranging from 20 to 30% of patients. However, this also means that ~70% of patients do not respond to this treatment and currently very little is known regarding mechanisms of action of these immunotherapies as well as predictors of response to facilitate patient stratification. With the recent success of immunotherapies in HCC, there is a pressing need to understand mechanisms of tumor immune evasion and resistance to these immunotherapies in order to identify biomarkers of resistance or response. This will enable better patient stratification as well as the rational design of combination immunotherapies to restore sensitivity in resistant patients. The aim of this review is to summarize the current knowledge to date of tumor-intrinsic mechanisms of immune escape in liver cancer, specifically in the context of HCC.

scholarly journals Dietary Agents and Phytochemicals in the Prevention and Treatment of Hepatocellular Carcinoma: Review Article

Med Phoenix ◽  
2017 ◽  
Vol 2 (1) ◽  
pp. 52-62
Author(s):  
Mohammad Ahmad ◽  
Anuradha Mishra ◽  
Afreen Usmani ◽  
Md. Parwez Ahmad
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Epigallocatechin Gallate ◽  
Cancer Chemoprevention ◽  
Scientific Data ◽  
Anticancer Properties ◽  
Treatment And Prevention ◽  
Liver Cancers ◽  
Prevention And Treatment ◽  
Dietary Agents

Amongst all types of primary liver cancers, hepatocellular carcinoma (HCC) is the commonest form of liver cancer in the world. Cancer chemoprevention using dietary supplements and phytochemicals has attracted increasing attention in recent years. Numerous study reports suggest the role of phytochemicals and dietary compounds in the prevention and treatment of liver cancer. Certain dietary agents and related phytochemicals present in grapes, pomegranate, vegetables, beans, turmeric, soy, rice bran, and fish oils are reported to have chemopreventive potentials against hepatocellular carcinoma. Phytochemicals such as Carotenoids, Epigallocatechin gallate (EGCG), Curcumin, Resveratrol, Rutoside, Quercetin, Chrysin and Silibinin have possible therapeutic importance in tumor suppression during the initial phases of carcinogenesis. Many phytochemicals which are still under investigation lack the scientific data in support of anticancer properties of these compounds rather than anti-oxidant mechanism. So, emphasis should be given on the investigation of plausible molecular mechanism behind anticancer activity. This review summarizes the use of these dietary agents and phytochemicals in the treatment and prevention of HCC and also highlights the mechanisms responsible for their effects.Med Phoenix Vol.2(1) July 2017, 52-62

scholarly journals A gene-based risk score model for predicting recurrence-free survival in patients with hepatocellular carcinoma

2020 ◽  
Author(s):  
WENHUA WANG ◽  
LINGCHEN WANG ◽  
XINSHENG XIE ◽  
YEHONG YAN ◽  
YUE LI ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Risk Score ◽  
Prognostic Model ◽  
Validation Dataset ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Liver Cancers ◽  
Score Model ◽  
Robust Likelihood

Abstract BackgroundHepatocellular carcinoma (HCC) remains the most frequent liver cancer, accounting for approximately 90% of primary liver cancers worldwide. The recurrence-free survival (RFS) of HCC patients is a critical factor in devising a personal treatment plan. Thus, it is necessary to accurately forecast the prognosis of HCC patients in clinical practice.MethodsUsing The Cancer Genome Atlas (TCGA) dataset, we identified genes associated with RFS. A robust likelihood-based survival modeling approach was used to select the best genes for the prognostic model. Then, the GSE76427 dataset was used to evaluate the prognostic model’s effectiveness.ResultsWe identified 1331 differentially expressed genes associated with RFS. Seven of these genes were selected to generate the prognostic model. The validation in both the TCGA cohort and GEO cohort demonstrated that the 7-gene prognostic model can predict the RFS of HCC patients. Meanwhile, the results of the multivariate Cox regression analysis showed that the 7-gene risk score model could function as an independent prognostic factor. In addition, according to the time-dependent ROC curve, the 7-gene risk score model performed better in predicting the RFS of the training set and the external validation dataset than the classical TNM staging and BCLC. Furthermore, these seven genes were found to be related to the occurrence and development of liver cancer by exploring three other databases.ConclusionOur study identified a seven-gene signature for HCC RFS prediction that can be used as a novel and convenient prognostic tool. These seven genes might be potential target genes for metabolic therapy and the treatment of HCC.

scholarly journals FBXL6 governs c-MYC to promote hepatocellular carcinoma through ubiquitination and stabilization of HSP90AA1

2020 ◽  
Author(s):  
Weidong Shi ◽  
Lanyun Feng ◽  
Shu Dong ◽  
Zhouyu Ning ◽  
Yongqiang Hua ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Mrna Expression ◽  
Biological Effects ◽  
Xenograft Model ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Liver Cancers ◽  
F Box Protein

Abstract BACKGROUND: Heat shot protein 90 (HSP90) AA1 functions as an onco-protein to regulate the assembly, manipulation, folding and degradation of its client proteins, including c-MYC. However, the mechanisms underlying the regulation of HSP90AA1 are poorly understood.METHODS: Transcriptome RNA-sequencing data of Liver hepatocellular carcinoma (LIHC) samples were used to detect the mRNA expression of FBXL6. Immunoprecipitation/Mass Spectrum (IP/MS) method was used to identify the interacting proteins of FBXL6. The co-immunoprecipitation assay was used to determine the interaction between FBXL6 and HSP90AA1. The in vivo ubiquitination assay was performed to determine the regulation of HSP90AA1 by FBXL6. Luciferase reporter and chromatin immunoprecipitation assays were used to determine the transcriptional regulation of FBXL6 by c-MYC. Cell counting and colony formation assays were implemented to detect the biological effects of FBXL6 on the growth of HCC cells in vitro. The effect of FBXL6 on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. RESULTS: Here, we identified the orphan F-box protein FBXL6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin ligase for HSP90AA1. FBXL6 promoted K63-dependent ubiquitination of HSP90AA1 to stabilize it. Through analysis of TCGA dataset, we found that FBXL6 was significantly increased in liver cancer tissues and positively correlated with c-MYC pathway. FBXL6 accumulation in liver cancers causes the stabilization and activation of c-MYC by preventing HSP90AA1 degradation. Activated c-MYC, which in turn directly bound to the promoter region of FBXL6 to induce its mRNA expression.CONCLUSION: Collectively, our data revealed an unknown FBXL6-HSP90AA1-c-MYC axis which might contribute to the oncogenesis of liver cancer, and we propose that inhibition of FBXL6 might represent an effective therapeutic strategy for liver cancer treatment.

scholarly journals A prognostic model for predicting recurrence-free survival in hepatocellular carcinoma patients

2020 ◽  
Author(s):  
Wenhua Wang ◽  
Lingchen Wang ◽  
Xinsheng Xie ◽  
Yehong Yan ◽  
Yue Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Prognostic Model ◽  
Treatment Plan ◽  
External Validation ◽  
Validation Dataset ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Liver Cancers ◽  
Robust Likelihood

Abstract Hepatocellular carcinoma (HCC) remains the most frequent liver cancer, accounting for approximately 90% of primary liver cancers worldwide. The recurrence-free survival (RFS) of HCC patients is a critical factor in devising a personal treatment plan. Thus, it is necessary to accurately forecast the prognosis of HCC patients in clinical practice. Using the The Cancer Genome Atlas （TCGA） dataset, we identified genes that are associated with RFS. A robust likelihood-based survival modeling approach was used to select the best genes for the prognostic model. Then, the GSE76427 dataset was used to evaluate the prognostic model’s effectiveness. We identified 1331 differentially expressed genes associated with RFS. Seven of these genes were selected to generate the prognostic model. Validation in both the TCGA cohort and the GEO cohort demonstrated that the 7-gene prognostic model has the capability of predicting the RFS of HCC patients. Meanwhile, the result of multivariate Cox regression showed that the 7-gene prognostic model could work as an independent prognostic factor. In addition, according to the time dependent ROC curve, the 7-gene prognostic model performed better in predicting the RFS of the training set and the external validation dataset than the classical TNM staging and BCLC. What’s more, these seven genes were found to be related to the occurrence and development of liver cancer by exploring other three databases. Our study identified a seven-gene signature for HCC RFS prediction that is a novel and convenient prognostic tool. The seven genes might provide potential target genes for metabolic therapy and the treatment of HCC.

scholarly journals FBXL6 governs c-MYC to promote hepatocellular carcinoma through ubiquitination and stabilization of HSP90AA1

2020 ◽  
Author(s):  
Weidong Shi ◽  
Lanyun Feng ◽  
Shu Dong ◽  
Zhouyu Ning ◽  
Yongqiang Hua ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Mrna Expression ◽  
Biological Effects ◽  
Xenograft Model ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Liver Cancers ◽  
F Box Protein

Abstract BackgroundHeat shot protein 90 (HSP90) AA1 functions as an onco-protein to regulate the assembly, manipulation, folding and degradation of its client proteins, including c-MYC. However, the mechanisms underlying the regulation of HSP90AA1 are poorly understood.MethodsTranscriptome RNA-sequencing data of Liver hepatocellular carcinoma (LIHC) samples were used to detect the mRNA expression of FBXL6. Immunoprecipitation/Mass Spectrum (IP/MS) method was used to identify the interacting proteins of FBXL6. The co-immunoprecipitation assay was used to determine the interaction between FBXL6 and HSP90AA1. The in vivo ubiquitination assay was performed to determine the regulation of HSP90AA1 by FBXL6. Luciferase reporter and chromatin immunoprecipitation assays were used to determine the transcriptional regulation of FBXL6 by c-MYC. Cell counting and colony formation assays were implemented to detect the biological effects of FBXL6 on the growth of HCC cells in vitro. The effect of FBXL6 on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. ResultsHere, we identified the orphan F-box protein FBXL6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin ligase for HSP90AA1. FBXL6 promoted K63-dependent ubiquitination of HSP90AA1 to stabilize it. Through analysis of multiple public liver cancer GEO data, we found that FBXL6 was significantly increased in liver cancer tissues and positively correlated with c-MYC pathway. FBXL6 accumulation in liver cancers causes the stabilization and activation of c-MYC by preventing HSP90AA1 degradation. Activated c-MYC, which in turn directly binds to the promoter region of FBXL6 to induce its mRNA expression.ConclusionCollectively, our data revealed an unknown axis of FBXL6-HSP90AA1-c-MYC which might contribute to the oncogenesis of liver cancer, and we propose that inhibition of FBXL6 might represent an effective therapeutic strategy for liver cancer treatment.

scholarly journals A gene-based risk score model for predicting recurrence-free survival in patients with hepatocellular carcinoma

2020 ◽  
Author(s):  
WENHUA WANG ◽  
LINGCHEN WANG ◽  
XINSHENG XIE ◽  
YEHONG YAN ◽  
YUE LI ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Risk Score ◽  
Prognostic Model ◽  
Validation Dataset ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Liver Cancers ◽  
Score Model ◽  
Robust Likelihood

Abstract BackgroundHepatocellular carcinoma (HCC) remains the most frequent liver cancer, accounting for approximately 90% of primary liver cancers worldwide. The recurrence-free survival (RFS) of HCC patients is a critical factor in devising a personal treatment plan. Thus, it is necessary to accurately forecast the prognosis of HCC patients in clinical practice. MethodsUsing The Cancer Genome Atlas (TCGA) dataset, we identified genes associated with RFS. A robust likelihood-based survival modeling approach was used to select the best genes for the prognostic model. Then, the GSE76427 dataset was used to evaluate the prognostic model’s effectiveness. ResultsWe identified 1331 differentially expressed genes associated with RFS. Seven of these genes were selected to generate the prognostic model. The validation in both the TCGA cohort and GEO cohort demonstrated that the 7-gene prognostic model can predict the RFS of HCC patients. Meanwhile, the results of the multivariate Cox regression analysis showed that the 7-gene risk score model could function as an independent prognostic factor. In addition, according to the time-dependent ROC curve, the 7-gene risk score model performed better in predicting the RFS of the training set and the external validation dataset than the classical TNM staging and BCLC. Furthermore, these seven genes were found to be related to the occurrence and development of liver cancer by exploring three other databases. ConclusionOur study identified a seven-gene signature for HCC RFS prediction that can be used as a novel and convenient prognostic tool. These seven genes might be potential target genes for metabolic therapy and the treatment of HCC.

scholarly journals Wnt/β-Catenin Signaling in Liver Cancers

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 926 ◽  
Author(s):  
Wenhui Wang ◽  
Ron Smits ◽  
Haiping Hao ◽  
Chaoyong He
Keyword(s):  
Hepatocellular Carcinoma ◽  
Environmental Factors ◽  
Liver Cancer ◽  
Precancerous Lesion ◽  
Biologic Agents ◽  
High Morbidity ◽  
Future Perspectives ◽  
Liver Cancers ◽  
Cancer Studies ◽  
Shed Light

Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. Liver cancer consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and several other rare tumors. Progression has been witnessed in understanding the interactions between etiological as well as environmental factors and the host in the development of liver cancers. However, the pathogenesis remains poorly understood, hampering the design of rational strategies aiding in preventing liver cancers. Accumulating evidence demonstrates that aberrant activation of the Wnt/β-catenin signaling pathway plays an important role in the initiation and progression of HCC, CCA, and HB. Targeting Wnt/β-catenin signaling potentiates a novel avenue for liver cancer treatment, which may benefit from the development of numerous small-molecule inhibitors and biologic agents in this field. In this review, we discuss the interaction between various etiological factors and components of Wnt/β-catenin signaling early in the precancerous lesion and the acquired mechanisms to further enhance Wnt/β-catenin signaling to promote robust cancer formation at later stages. Additionally, we shed light on current relevant inhibitors tested in liver cancers and provide future perspectives for preclinical and clinical liver cancer studies.

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