scholarly journals Opposing Roles of the Fork-head box genes FoxM1 and FoxA2 in Hepatocellular Carcinoma

2018 ◽  
Author(s):  
Vaibhav Chand ◽  
Akshay Pandey ◽  
Dragana Kopanja ◽  
Grace Guzman ◽  
Pradip Raychaudhuri
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Expression Patterns ◽  
Genetic Evidence ◽  
G1 Phase ◽  
Fork Head ◽  
Liver Cancers ◽  
Differentiation Gene ◽  
Pluripotency Genes

ABSTRACTThe fork-head box transcription factor FoxMl is essential for hepatocellular carcinoma (HCC) development and its overexpression coincides with poor prognosis. Here, we show that the mechanisms by which FoxM1 drives HCC progression involve overcoming the inhibitory effects of the liver differentiation gene FoxA2. First, the expression patterns of FoxM1 and FoxA2 in human HCC are opposite. We show that FoxM1 represses expression of FoxA2 in G1 phase, a phase in the cell cycle in which cells can undergo differentiation. Repression of FoxA2 in G1 phase is important, as it is capable of inhibiting expression of the pluripotency genes that are expressed mainly in S/G2 phases. Using a transgenic mouse model for oncogenic Ras-driven HCC, we provide genetic evidence for a repression of FoxA2 by FoxM1. Conversely, FoxA2 inhibits expression of FoxM1, and inhibits FoxM1-induced tumorigenicity of HCC cells. Moreover, expression of FoxA2 in mouse liver expressing activated Ras inhibits FoxM1 expression and inhibits HCC progression. The observations provide strong genetic evidence for an opposing role of FoxM1 and FoxA2 in HCC progression.AUTHOR SUMMARYLiver cancer remains untreatable because it is diagnosed at a stage when the cancer is aggressive and resistant to therapeutics. The mechanism that drives aggressive liver cancer is poorly understood. These cancers are made up of poorly differentiated cancer cells. Interestingly, the FoxM1 gene is overexpressed in the aggressive liver cancers. Although FoxM1 is important for expression of the proliferation genes, it does not explain why it is overexpressed mainly in the undifferentiated cancers. The current study addresses this puzzle. Our previous studies demonstrated that FoxM1 increases expression of the pluripotency genes that are expressed mainly in the stem-like cells. In the current manuscript we show that, in addition to activating the pluripotency genes, FoxM1 inhibits expression of the liver differentiation gene FoxA2. Overexpression of FoxM1 is important for this inhibition function, as it involves the retinoblastoma family of proteins, which are often inactivated in cancer cells, and thus, are of low-abundance. Moreover, the inhibition of FoxA2 is significant because FoxA2 could inhibit expression of the pluripotency genes as well as FoxM1. The observations provide new insights into how FoxM1 drives progression of aggressive liver cancer.

scholarly journals MicroRNAs as Diagnostic Tools in Hepatocellular Carcinoma

2021 ◽  
Vol 3 (4) ◽  
pp. 237-246
Author(s):  
Jessica Evangelista ◽  
Elisa Zaninotto ◽  
Annalisa Gaglio ◽  
Michele Ghidini ◽  
Lucrezia Raimondi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Sample Size ◽  
Expression Patterns ◽  
Critical Role ◽  
Measurement Techniques ◽  
Small Sample ◽  
Diagnostic Tools ◽  
Migration And Invasion ◽  
Altered Expression ◽  
Liver Cancers

Liver cancer is the fourth leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 80% of all liver cancers. The serum concentration of alpha-fetoprotein (AFP) is the only validated biomarker for HCC diagnosis. MicroRNAs (miRNAs) are small non-coding RNAs of 21–30 nucleotides playing a critical role in human carcinogenesis, with types of miRNAs with oncogenic (oncomiRs) or tumor suppressor features. The altered expression of miRNAs in HCC is associated with many pathological processes, such as cancer initiation, tumor growth, apoptosis escape, promotion of migration and invasion. Moreover, circulating miRNAs have been increasingly investigated as non-invasive biomarkers for HCC diagnosis. MiRNAs’ expression patterns are altered in HCC and several single miRNAs or miRNAs panels have been found significantly up or downregulated in HCC with respect to healthy controls or non-oncological patients (cirrhotic or with viral hepatitis). However, any of the investigated miRNAs or miRNAs panels has entered clinical practice so far. This has mostly to do with lack of protocols standardization, small sample size and discrepancies in the measurement techniques. This review summarizes the major findings regarding the diagnostic role of miRNAs in HCC and their possible use together with standard biomarkers in order to obtain an early diagnosis and easier differential diagnosis from non-cancerous liver disease.

scholarly journals Downexpression of HSD17B6 correlates with clinical prognosis and tumor immune infiltrates in hepatocellular carcinoma

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Lei Lv ◽  
Yujia Zhao ◽  
Qinqin Wei ◽  
Ye Zhao ◽  
Qiyi Yi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Immune Responses ◽  
Cancer Cells ◽  
Negative Regulator ◽  
Functional Enrichment ◽  
Migration And Invasion ◽  
Relative Reduction ◽  
Clinical Prognosis ◽  
Liver Cancer Cells

Abstract Background Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6), a key protein involved in synthetizing dihydrotestosterone, is abundant in the liver. Previous studies have suggested a role for dihydrotestosterone in modulating progress of various malignancies, and HSD17B6 dysfunction was associated with lung cancer and prostate cancer. However, little is known about the detailed role of HSD17B6 in hepatocellular carcinoma (HCC). Methods Clinical implication and survival data related to HSD17B6 expression in patients with HCC were obtained through TCGA, ICGC, ONCOMINE, GEO and HPA databases. Survival analysis plots were drawn with Kaplan–Meier Plotter. The ChIP-seq data were obtained from Cistrome DB. Protein–Protein Interaction and gene functional enrichment analyses were performed in STRING database. The correlations between HSD17B6 and tumor immune infiltrates was investigated via TIMER and xCell. The proliferation, migration and invasion of liver cancer cells transfected with HSD17B6 were evaluated by the CCK8 assay, wound healing test and transwell assay respectively. Expression of HSD17B6, TGFB1 and PD-L1 were assessed by quantitative RT-PCR. Results HSD17B6 expression was lower in HCC compared to normal liver and correlated with tumor stage and grade. Lower expression of HSD17B6 was associated with worse OS, PFS, RFS and DSS in HCC patients. HNF4A bound to enhancer and promoter regions of HSD17B6 gene, activating its transcription, and DNA methylation of HSD17B6 promoter negatively controlled the expression. HSD17B6 and its interaction partners were involved in androgen metabolism and biosynthesis in liver. HSD17B6 inhibited tumor cell proliferation, migration and invasion in liver cancer cells and low expression of HSD17B6 correlated with high immune cells infiltration, relative reduction of immune responses and multiple immune checkpoint genes expression in HCC, probably by regulating the expression of TGFB1. Conclusions This study indicate that HSD17B6 could be a new biomarker for the prognosis of HCC and an important negative regulator of immune responses in HCC.

scholarly journals ILF2 Directly Binds and Stabilizes CREB to Stimulate Malignant Phenotypes of Liver Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Hui Du ◽  
Yun Le ◽  
Fenyong Sun ◽  
Kai Li ◽  
Yanfeng Xu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Liver Cancer Cells ◽  
Binding Factor ◽  
Element Binding Protein

Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) is overexpressed and has an oncogenic role in hepatocellular carcinoma (HCC). Interleukin enhancer binding factor 2 (ILF2) has become research hotspot in liver cancer recently. However, it is still unclear whether and how CREB and ILF2 interact with each other. And how this interaction exerts its role in occurrence and development of liver cancer is still unclear. Here, we found that ILF2 directly bound with CREB, and this binding was essential for the malignant phenotypes of liver cancer cells. Moreover, we found that ILF2 acted as one of the upstream proteins of CREB and promoted CREB only in the protein level, whereas ILF2 expression was not regulated by CREB. Mechanistically, ILF2 bound to the pKID domain of CREB and stimulated its phosphorylation at Ser133. Taken together, our study finds a novel interaction between CREB and ILF2 in liver cancer, and this interaction might play a role in the diagnosis and remedy of liver cancer.

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 Immunotherapy for Hepatocellular Carcinoma: Current Advances and Future Expectations

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yingjun Xie ◽  
Yien Xiang ◽  
Jiyao Sheng ◽  
Dan Zhang ◽  
Xiaoxiao Yao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Primary Liver Cancer ◽  
Adoptive Cell Therapy ◽  
Oncolytic Viruses ◽  
Future Expectations ◽  
Digestive Cancers

Primary liver cancer is a common kind of digestive cancers with high malignancy, causing 745,500 deaths each year. Hepatocellular carcinoma is the major pathological type of primary liver cancer. Traditional treatment methods for patients with hepatocellular carcinoma have shown poor efficacy in killing residual cancer cells for a long time. In recent years, tumor immunotherapy has emerged as a promising method owing to its safety and efficacy with respect to delaying the progression of advanced tumors and protecting postoperative patients against tumor relapse and metastasis. Immune tolerance and suppression in tumor microenvironments are the theoretical basis of immunotherapy. Adoptive cell therapy functions by stimulating and cultivating autologous lymphocytes ex vivo and then reinfusing them into the patient to kill cancer cells. Cancer vaccination is performed using antigenic substances to activate tumor-specific immune responses. Immune checkpoint inhibitors can reactivate tumor-specific T cells and develop an antitumor effect by suppressing checkpoint-mediated signaling. Oncolytic viruses may selectively replicate in tumor cells and cause lysis without harming normal tissues. Here, we briefly introduce the mechanism of immunosuppression in hepatocellular carcinoma and summarize the rationale of the four major immunotherapeutic approaches with their current advances.

Highly fluorescent QD probes labeling hepatocellular carcinoma cells

RSC Advances ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 1841-1845 ◽  
Author(s):  
Baiqi Wang ◽  
Hetao Chen ◽  
Rui Yang ◽  
Fang Wang ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Carcinoma Cells ◽  
Hepatocellular Carcinoma Cells ◽  
Liver Cancer Cells ◽  
Hcc Cells

The red signals from the cytoplasm of HCC cells reveal that the QD probes can specifically label liver cancer cells.

scholarly journals Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

Toxins ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 719
Author(s):  
Mohammad Heiat ◽  
Hamid Hashemi Yeganeh ◽  
Seyed Moayed Alavian ◽  
Ehsan Rezaie
Keyword(s):  
Hepatocellular Carcinoma ◽  
Side Effects ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Treatment Strategy ◽  
High Efficiency ◽  
The Other ◽  
Cross Resistance ◽  
Chemotherapy Drugs ◽  
The World

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Therefore, fighting against such cancer is reasonable. Chemotherapy drugs are sometimes inefficient and often accompanied by undesirable side effects for patients. On the other hand, the emergence of chemoresistant HCC emphasizes the need for a new high-efficiency treatment strategy. Immunotoxins are armed and rigorous targeting agents that can purposefully kill cancer cells. Unlike traditional chemotherapeutics, immunotoxins because of targeted toxicity, insignificant cross-resistance, easy production, and other favorable properties can be ideal candidates against HCC. In this review, the characteristics of proper HCC-specific biomarkers for immunotoxin targeting were dissected. After that, the first to last immunotoxins developed for the treatment of liver cancer were discussed. So, by reviewing the strengths and weaknesses of these immunotoxins, we attempted to provide keynotes for designing an optimal immunotoxin against HCC.

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.

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