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1.
Medicine (Baltimore) ; 99(40): e21503, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019382

RESUMO

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but HBV-HCC related prognosis signature remains rarely investigated. This study was to identify an integrated long non-coding RNAs-messenger RNAs (lncRNA-mRNA) signature for prediction of overall survival (OS) and explore their underlying functions.One RNA-sequencing dataset (training set, n = 95) and one microarray dataset E-TABM-36 (validation set, n = 44) were collected. Least absolute shrinkage and selection operator analysis was performed to identify an lncRNA-mRNA prognosis signature. The OS difference of patients in the high-risk and low-risk risk groups was evaluated by Kaplan-Meier curve. Area under the receiver operating characteristic curve (AUC), Harrell concordance index (C-index) calculation, and multivariate analyses with clinical characteristics were used to determine the prognostic ability. Furthermore, a coexpression network was constructed to interpret the functions.Nine signature genes (3 lncRNAs and 6 mRNAs) were selected to generate the risk score model. Patients belonging to the high-risk group showed a significantly shorter survival than those of the low-risk group. The prediction accuracy of the risk score for 5-year OS was 0.936 and 0.905 for the training set and validation set, respectively. Also, this risk score was independent of various clinical variables for the prognosis prediction. Incorporation of the risk score remarkably increased the predictive power of the routine clinical prognostic factors (vascular invasion status, tumor recurrence status) (AUC = 0.942 vs 0.628; C-index = 0.7997 vs 0.6908). Furthermore, LncRNA insulin-like growth factor 2 antisense RNA (IGF2-AS) and long intergenic non-protein coding RNA 342 (LINC00342) were predicted to exert tumor suppression effects by regulating homeobox D1 (HOXD1) and secreted frizzled related protein 5 (SFRP5), respectively; while lncRNA rhophilin Rho GTPase binding protein 1 antisense RNA 1 (RHPN1-AS1) may possess carcinogenic potential by promoting the transcription of chromobox 2 (CBX2), cell division cycle 20 (CDC20), matrix metallopeptidase 12 (MMP12), stratifin (SFN), tripartite motif containing 16 (TRIM16), and uroplakin 3A (UPK3A). These mRNAs may be associated with cell proliferation or apoptosis related pathways.This study may provide a novel, effective prognostic biomarker, and some therapeutic targets for HBV-HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Hepatite B/genética , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1053-1060, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051418

RESUMO

OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, especially in Asia and Africa. However, the underlying mechanism is still unclear. Consequently, it is important to explore its key genes and prognosis-related genes via bioinformatics. This study aimed to explore the molecular mechanism of HCC by using bioinformatics analysis for HCC gene chip data. METHODS: Microarray data of HCC genes were downloaded from public GEO database and screened for differentially expressed genes (DEGs) by GEO2R analysis. Then DAVID online tool was used for GO annotation and KEGG pathway enrichment analysis. STRING-DB online database and Cytoscape software were used for protein interaction network analysis.GEPIA and Ualcan were applied to evaluate prognosis and promoter methylation level. RESULTS: A total of 87 DEGs of HCC were screened, of which 15 genes were up-regulated and 72 genes were down-regulated. GO annotation indicated that most of the genes were involved in oxidation reduction,cellular amino acid derivative metabolic process, carboxylic acid catabolic process, and response to wounding. KEGG pathways were enriched in linoleic acid metabolism, retinol metabolism, complement and coagulation cascades,steroid hormone biosynthesis, drug metabolism, and other pathways. Two key modules and key genes AURKA and SPP2 were obtained by protein interaction network analysis. Prognostic analysis showed that the 2 genes were significantly correlated with the total survival time of patients with HCC. There was no significant difference in the methylation level of AURKA promoter between the primary tumor group and the normal group (P=0.296) and the methylation level of SPP2 promoter was significantly lower in the primary tumor group than that in the normal group (P<0.001). CONCLUSIONS: HCC-relevant AURKA and SPP2 are obtained via bioinformatics analysis, which are closely related to the prognosis of patients with HCC. Gene promoter methylation is not the main factor for AURKA and SPP2 expression levels.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoproteínas
3.
Rev Med Suisse ; 16(704): 1554-1559, 2020 Sep 02.
Artigo em Francês | MEDLINE | ID: mdl-32880111

RESUMO

Hepatocellular adenomas (HA) are rare benign liver tumors known to affect mainly women of reproductive age taking oral contraception. They can be complicated by hemorrhage or malignant transformation to hepatocellular carcinoma, especially when the size of the lesion exceeds 5 cm. Magnetic resonance imaging is the most specific tool for the non-invasive characterization of HA. The discovery of mutations underlying different specific HA phenotypes has allowed the establishment of a molecular classification that modified the management of this pathology.


Assuntos
Adenoma de Células Hepáticas , Neoplasias Hepáticas , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Adenoma de Células Hepáticas/terapia , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Imagem por Ressonância Magnética , Mutação
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(4): 365-371, 2020 Apr 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879059

RESUMO

OBJECTIVES: To investigate the roles of cytoskeleton-associated protein 2 (CKAP2) in proliferation, apoptosis, and migration in liver cancer cells and the potential mechanisms. METHODS: Human normal hepatocyte L02 and liver cancer cell lines HepG2, Huh7, and SMMC-7721 were cultured. The CKAP2 expression was detected by real-time PCR and Western blotting. HepG2 cells were randomly divided into a control group, a negative control (NC) group, and a CKAP2 silencing (siCKAP2) group. CCK-8 and BrdU assays were used to evaluate cell viability and proliferation, respectively. Transwell assay was employed to determine cell migration and invasion. The protein levels of cleaved-caspase 3, Bax, E-cadherin, N-cadherin, Vimentin, phosphorylated Janus kinase 2 (p-JAK2), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) were determined by Western blotting. RESULTS: Compared with normal hepatocyte L02, CKAP2 was highly expressed in liver cancer cell lines HepG2, Huh7, and SMMC-7721 (all P<0.05). Compared with the NC group, cell viability and proliferation rate of the siCKAP2 group were decreased (both P<0.05). The apoptotic rate, protein expression of cleaved-caspase 3 and Bax in the siCKAP2 group were significantly higher than those in the NC group (all P<0.05). Compared with the NC group, cell migration and invasion rates of the siCKAP2 group were significantly attenuated (both P<0.05). Compared with the NC group, E-cadherin protein expression in siCKAP2 group was increased, while protein expression levels of Vimentin, N-cadherin, p-JAK2, and p-STAT3 were decreased (all P<0.05). CONCLUSIONS: CKAP2 gene silence inhibits proliferation, migration, and invasion, and promotes apoptosis in liver cancer cells, while JAK2/STAT3 signaling pathway may be involved in these processes.


Assuntos
Apoptose , Neoplasias Hepáticas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Citoesqueleto , Humanos
5.
Nat Commun ; 11(1): 4489, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895384

RESUMO

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).


Assuntos
Biomarcadores Tumorais/isolamento & purificação , Carcinoma Hepatocelular/diagnóstico , Detecção Precoce de Câncer/métodos , Vesículas Extracelulares/genética , Neoplasias Hepáticas/diagnóstico , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Química Click/instrumentação , Química Click/métodos , Química Computacional , Simulação por Computador , Diagnóstico Diferencial , Dimetilpolisiloxanos/química , Progressão da Doença , Detecção Precoce de Câncer/instrumentação , Feminino , Células Hep G2 , Humanos , Dispositivos Lab-On-A-Chip , Biópsia Líquida/instrumentação , Biópsia Líquida/métodos , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Pessoa de Meia-Idade , Nanoestruturas/química , Nanofios/química , Estadiamento de Neoplasias , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa/instrumentação , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
6.
Anticancer Res ; 40(9): 5211-5219, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878809

RESUMO

BACKGROUND/AIM: CBP is a transcriptional coactivator in the Wnt/ß-catenin pathway that is related to cell kinetics and differentiation. This study aimed to characterize ß-catenin-activated hepatocellular carcinoma (HCC) and evaluate the direct effects of PRI-724 (a selective inhibitor of Wnt/ß-catenin/CBP signaling) on HCC. MATERIALS AND METHODS: Immunohistochemistry for ß-catenin was performed in 199 HCC resected samples. Moreover, using cultured HCC cell lines, cell kinetics and its related proteins were analyzed after treatment of cells with C-82 (active form of PRI-724). RESULTS: Nuclear ß-catenin expression was found in 18% of HCC cases and the tumor sizes in these positive samples were larger. In HCC cell lines with a constitutively activated ß-catenin, C-82 inhibited cell proliferation. C-82 led to an increase in the percentage of cells in the G0/G1 phase of the cell cycle. The percentage of cells in the sub-G1 phase also increased. Moreover, C-82 treatment significantly decreased the expression of cell proliferating markers and increased the expression of apoptosis-related proteins. CONCLUSION: PRI-724(C-82) may be a novel drug for ß-catenin-activated HCC therapy.


Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Pirimidinonas/farmacologia , beta Catenina/metabolismo , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores
7.
DNA Cell Biol ; 39(10): 1838-1849, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32876480

RESUMO

The breast cancer gene 1 (BRCA1) is a tumor suppressor, and mutations or epigenetic inactivation will increase the risk of breast cancer oncogenesis. The current research aimed to explore the relationship between BRCA1 expression, prognosis, and tumor immunity in hepatocellular carcinoma (HCC). In this study, BRCA1 expression was analyzed via multiple online databases and its association with clinical characteristics, prognosis and genetic alterations was identified using the original The Cancer Genome Atlas-liver hepatocellular carcinoma cohorts. DNA methylation sites and their prognostic values were analyzed using MethSurv. The correlations between BRCA1 and immune infiltration were investigated via Tumor Immune Estimation Resource. As results, BRCA1 was significantly upregulated in tumor tissues in multiple HCC cohorts. Besides, high BRCA1 expression was correlated with race, advanced T stage, clinical stage, poor tumor grade, MSI status, and worse prognosis. Notably, BRCA1 expression was positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. The current findings imply that BRCA1 is associated with prognosis and immune infiltration, laying foundations for in-depth research on the role of BRCA1 in HCC.


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Movimento Celular , Metilação de DNA , Células Dendríticas/imunologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Linfócitos/imunologia , Macrófagos/imunologia
8.
Nat Commun ; 11(1): 4383, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873799

RESUMO

Mongolia has the highest incidence of hepatocellular carcinoma (HCC) in the world, but its causative factors and underlying tumor biology remain unknown. Here, we describe molecular characteristics of HCC from 76 Mongolian patients by whole-exome and transcriptome sequencing. We present a comprehensive analysis of mutational signatures, driver genes, and molecular subtypes of Mongolian HCC compared to 373 HCC patients of different races and ethnicities and diverse etiologies. Mongolian HCC consists of prognostic molecular subtypes similar to those found in patients from other areas of Asia, Europe, and North America, as well as other unique subtypes, suggesting the presence of distinct etiologies linked to Mongolian patients. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which is associated with hepatitis D viral infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Hepatite D/genética , Neoplasias Hepáticas/genética , Idoso , Carcinogênese/genética , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Hepatectomia , Hepatite D/epidemiologia , Hepatite D/cirurgia , Hepatite D/virologia , Vírus Delta da Hepatite/isolamento & purificação , Humanos , Incidência , Fígado/patologia , Fígado/cirurgia , Fígado/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Mongólia/epidemiologia , Mutação , Prognóstico , Sequenciamento Completo do Exoma
9.
Medicine (Baltimore) ; 99(38): e22312, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957395

RESUMO

RATIONALE: Immunotherapy and targeted therapy have attracted widespread attention in current clinical research, which could be considered as a good therapeutic option for treatment of refractory liver cancer. PATIENT CONCERNS: The patient was a 37-year-old man with hepatitis B virus (HBV) infection. He was presented with hepatalgia and discomfort. DIAGNOSIS: The computed tomography showed multiple intrahepatic masses, indicating primary liver cancer with multiple intrahepatic metastases. INTERVENTIONS: After failed transarterial chemoembolization therapy, he was initially treated with immunotherapy pembrolizumab plus angiogenesis inhibitor lenvatinib, and after 3 months of treatment, the condition improved. However, the disease subsequently progressed. The next-generation sequencing identified a BRCA2 germline mutation in this patient. A poly (ADP-ribose) polymerase inhibitor, olaparib, plus nivolumab therapy was started and achieved stable disease. OUTCOMES: The patient achieved stable disease and improvement in hepatalgia for 3 months after the combination treatment of Olaparib and nivolumab. CONCLUSION: We identified a BRCA2 germline mutation in a patient with liver cancer. Our findings could offer an alternative management for patients with liver cancer harboring germline BRCA2 mutation.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Nivolumabe/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Evolução Fatal , Genes BRCA2 , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/genética , Masculino
10.
BMC Bioinformatics ; 21(1): 396, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894041

RESUMO

BACKGROUND: MicroRNAs are a class of important small noncoding RNAs, which have been reported to be involved in the processes of tumorigenesis and development by targeting a few genes. Existing studies show that the imbalance between cell proliferation and apoptosis is closely related to the initiation and development of cancers. However, the impact of miRNAs on this imbalance has not been studied systematically. RESULTS: In this study, we first construct a cell fate miRNA-gene regulatory network. Then, we propose a systematical method for calculating the global impact of miRNAs on cell fate genes based on the shortest path. Results on breast cancer and liver cancer datasets show that most of the cell fate genes are perturbed by the differentially expressed miRNAs. Most of the top-identified miRNAs are verified in the Human MicroRNA Disease Database (HMDD) and are related to breast and liver cancers. Function analysis shows that the top 20 miRNAs regulate multiple cell fate related function modules and interact tightly based on their functional similarity. Furthermore, more than half of them can promote sensitivity or induce resistance to some anti-cancer drugs. Besides, survival analysis demonstrates that the top-ranked miRNAs are significantly related to the overall survival time in the breast and liver cancers group. CONCLUSION: In sum, this study can help to systematically study the important role of miRNAs on proliferation and apoptosis and thereby uncover the key miRNAs during the process of tumorigenesis. Furthermore, the results of this study will contribute to the development of clinical therapy based miRNAs for cancers.


Assuntos
Apoptose/genética , Proliferação de Células/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Bases de Dados Genéticas , Feminino , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , MicroRNAs/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida
11.
Gene ; 761: 145028, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32763490

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies and inflicts high mortality worldwide. The effect of tumor microenvironment components on HCC oncogenesis remains unknown. In particular, the nonleukocyte portion of the stromal fraction (SF) is poorly understood. METHODS: We comprehensively evaluated the proportional cell counts and gene expression data from The Cancer Genome Atlas (TCGA) to examine the contributions of cell components to the tumor microenvironment. Single-cell sequencing data from the Gene Expression Omnibus (GEO) were also analyzed to verify the association between the nonleukocyte SF and genes. We classified HCC using a hierarchical clustering method based on diversity of nonleukocyte SF-related gene expression among different components, and we used an appropriate GEO dataset to verify the clusters with a support vector machine (SVM) model. The prognosis of subtypes and their relationship with tumor microenvironmental cell proportions, clinicopathogenesis factors, and other indicators were evaluated. RESULTS: Based on linear regression, 711 genes related to nonleukocyte SF were selected from the TCGA dataset. We classified HCC into three subtypes using genes related to the nonleukocyte SF. Additionally, the GEO single-cell sequencing data confirmed the relationship between genes and the nonleukocyte SF. The tumor microenvironment of Type 2 contained the most significant mutually reinforcing interaction between the nonleukocyte SF and tumor cells. Meanwhile, Type 2 patients had the poorest prognosis and the most severe tumor-node-metastasis (TNM) stages, histological grades, etc. The analysis based on the GEO dataset verified the classification results with an SVM model. Type 2 was associated with worse clinicopathological characteristics, including tumor grading and staging, than the other types. In addition, the pathway analysis revealed that signals related to the SF and cell proliferation were significantly enhanced in Type 2 compared to the other group, which consisted of Types 1 and 3. CONCLUSION: The nonleukocyte SF in the tumor microenvironment contributed greatly to HCC oncogenesis. We can use these HCC classification criteria to stratify patients into subtypes for personalized treatment.


Assuntos
Carcinoma Hepatocelular/genética , Células Estromais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genômica , Humanos , Neoplasias Hepáticas/genética , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral/genética
12.
Nat Commun ; 11(1): 3978, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770044

RESUMO

Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism, increases resistance to methionine restriction or sorafenib, promotes epithelial-mesenchymal transition, and induces cell migration. Conversely, genetic or metabolic restoration of the transsulfuration pathway in SAA metabolism significantly alleviates the outcomes induced by HNF4α deficiency in liver cancer cells. Our study identifies HNF4α as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.


Assuntos
Fator 4 Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Cisteína/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Camundongos , Sorafenibe/farmacologia , Transcrição Genética/efeitos dos fármacos
13.
PLoS Pathog ; 16(8): e1008346, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764824

RESUMO

Viruses subvert macromolecular pathways in infected host cells to aid in viral gene amplification or to counteract innate immune responses. Roles for host-encoded, noncoding RNAs, including microRNAs, have been found to provide pro- and anti-viral functions. Recently, circular RNAs (circRNAs), that are generated by a nuclear back-splicing mechanism of pre-mRNAs, have been implicated to have roles in DNA virus-infected cells. This study examines the circular RNA landscape in uninfected and hepatitis C virus (HCV)-infected liver cells. Results showed that the abundances of distinct classes of circRNAs were up-regulated or down-regulated in infected cells. Identified circRNAs displayed pro-viral effects. One particular up-regulated circRNA, circPSD3, displayed a very pronounced effect on viral RNA abundances in both hepatitis C virus- and Dengue virus-infected cells. Though circPSD3 has been shown to bind factor eIF4A3 that modulates the cellular nonsense-mediated decay (NMD) pathway, circPSD3 regulates RNA amplification in a pro-viral manner at a post-translational step, while eIF4A3 exhibits the anti-viral property of the NMD pathway. Findings from the global analyses of the circular RNA landscape argue that pro-, and likely, anti-viral functions are executed by circRNAs that modulate viral gene expression as well as host pathways. Because of their long half-lives, circRNAs likely play hitherto unknown, important roles in viral pathogenesis.


Assuntos
Carcinoma Hepatocelular/virologia , Hepacivirus/genética , Hepatite C/complicações , Neoplasias Hepáticas/virologia , Provírus/genética , RNA Circular/genética , RNA Viral/genética , Replicação Viral , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Perfilação da Expressão Gênica , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Degradação do RNAm Mediada por Códon sem Sentido , Proteínas Virais/genética , Proteínas Virais/metabolismo
14.
PLoS One ; 15(7): e0236491, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735635

RESUMO

Selenoprotein P (SEPP1) is a kind of secretory glycoproteins with an antioxidant effect during the development of some diseases. In this study, we attempted to observe the expression of SEPP1 in livers from the patients with hepatocellular carcinoma (HCC) and explore its effect on HCC cells. All the tissues from patients with HCC were obtained from Affiliated Hospital of Nantong University. Western blot and immunohistochemical results showed that SEPP1 was reduced in HCC liver tissues. Its expression was negatively correlated with Ki67 expression in tissues. The expression of SEPP1 in normal liver cell line was significantly higher than those in the liver cancer cell lines. Serum starvation and release experiment demonstrated that SEPP1 expression was reduced and PCNA expression was increased, when the serum was re-added into cell culture system and the cells were on a proliferation state. After SEPP1 over-expression plasmid was transfected into HepG2 cells, cell proliferation of HepG2 cells and PCNA expression level were all inhibited by SEPP1. Results obtained via 8-isoprostane ELISA further indicated that inhibited ROS level was found in HepG2 cells transfected with SEPP1 over-expression plasmid. In addition, RT-qPCR results demonstrated that GPX1 expression levels increased in HepG2 cells transfected with SEPP1 over-expression plasmid. In conclusion, SEPP1 may inhibit the proliferation of HCC cells, accompanied by the reduction of ROS production and the increasing of GPX1 expression.


Assuntos
Carcinoma Hepatocelular/genética , Glutationa Peroxidase/genética , Neoplasias Hepáticas/genética , Selenoproteína P/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Antígeno Ki-67/genética , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino
15.
DNA Cell Biol ; 39(9): 1621-1638, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32758021

RESUMO

Increasing evidence highlights the clinical significance of stromal cells and immune cells in the liver cancer microenvironment. However, reliable prognostic models have not been well established. This study aimed to develop a gene signature for liver cancer based on stromal and immune scores. Using the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, stromal and immune scores were estimated based on the transcriptome profile of The Cancer Genome Atlas (TCGA) liver cancer cohort. Stromal-/immune-related differentially expressed genes were identified, followed by functional enrichment analysis. The Cox regression model was used to select prognostic genes and construct a gene signature. Its predictive potential was evaluated by receiver operating characteristic (ROC). The correlation between the risk score and immune cell infiltration was analyzed using Tumor Immune Estimation Resource (TIMER). Three hundred sixty-four upregulated and 10 downregulated stromal-/immune-related genes were identified, were mainly enriched in immune-related processes and pathways. Through univariate and multivariate cox survival analysis, a five-gene risk score was constructed, composed of FABP3, HTRA3, OLFML2B, PDZD4 and SLAMF6. Patients with high score indicated a poorer prognosis than those with low risk score. The areas under the ROC curves of overall survival (OS), progression-free interval, 3-, 5-year, OS status were 0.68, 0.57, 0.72, 0.74 and 0.728, indicating its well performance on predicting patients' prognoses. Furthermore, the risk score and the five genes were significantly correlated with immune cell infiltration in the tumor microenvironment. In this study, we proposed a prognostic five-gene signature based on stromal/immune scores in the liver cancer microenvironment.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Hepáticas/genética , Microambiente Tumoral , Idoso , Biomarcadores Tumorais/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Proteína 3 Ligante de Ácido Graxo/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Transcriptoma
16.
J Cancer Res Clin Oncol ; 146(10): 2461-2477, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32685988

RESUMO

PURPOSE: The aim of this study was to investigate DNA methylation alterations in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinomas (HCCs). METHODS: Genome-wide DNA methylation analysis was performed using the Infinium Human Methylation 450 K BeadChip, and levels of mRNA expression were analyzed by quantitative reverse transcription-PCR. RESULTS: Compared to 36 samples of normal control liver tissue (C), DNA methylation alterations were observed on 19,281 probes in 22 samples of cancerous tissue (T) obtained from patients showing histological features compatible with NASH in their non-cancerous liver tissue (N). Among those probes, 1396 were located within CpG islands or their shores and shelves, designed around the transcription start sites of 726 genes. In representative genes, such as DCAF4L2, CKLF, TRIM4, PRC1, UBE2C and TUBA1B, both DNA hypomethylation and mRNA overexpression were observed in T samples relative to C samples, and the levels of DNA methylation and mRNA expression were inversely correlated with each other. DNA hypomethylation occurred even in N samples at the precancerous NASH stage, and this was inherited by or further strengthened in T samples. DNA hypomethylation of DCAF4L2, CKLF and UBE2C was observed in both NASH-related and viral hepatitis-related HCCs, whereas that of TRIM4, PRC1 and TUBA1B occurred in a NASH-related HCC-specific manner. DNA hypomethylation and/or mRNA overexpression of these genes was frequently associated with the necroinflammatory grade of NASH and was correlated with poorer tumor differentiation. CONCLUSION: DNA methylation alterations may occur under the necroinflammatory conditions characteristic of NASH and participate in NASH-related hepatocarcinogenesis through aberrant expression of tumor-related genes.


Assuntos
Carcinoma Hepatocelular/genética , Metilação de DNA , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Am J Chin Med ; 48(5): 1243-1261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668963

RESUMO

4-acetylantrocamol LT3 (4AALT3), a new ubiquinone from the mycelium of Antrodia cinnamomea (Polyporaceae), has been recently shown to possess anticancer activity. However, the detailed mechanisms of such action remain unclear. In this study, the molecular mechanisms of 4AALT3 on hepatocellular carcinoma cells (HCC) were investigated. Human hepatocellular carcinoma cell line HepG2 cells were treated with concentrations of 4AALT3. Cell viability, colony formation, and the underlying mechanisms were then analyzed by CCK-8, colony formation, qPCR, and Western blotting assays. We found that 4AALT3 significantly decreased cell viability and colony formation in a dose-dependent manner. Accordingly, 4AALT3 significantly decreased protein levels of cyclin B, E1, D1, and D3, thereby facilitating cell cycle arrest. In addition, 4AALT3 significantly suppressed the nuclear localization of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), mammalian target of rapamycin (mTOR), and WNT/[Formula: see text]-catenin signaling pathways, all of which are well-known signaling pathways that contribute to the malignant properties of HCC. These effects are associated with activation of 5' AMP-activated protein kinase (AMPK) and autophagy. Our findings indicate that 4AALT3 exerts inhibitory effects on HepG2 cell growth via multiple signaling pathways and may be a potential agent for HCC therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antrodia/química , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Antineoplásicos Fitogênicos , Autofagia/efeitos dos fármacos , Autofagia/genética , Células Hep G2 , Humanos , Ubiquinona/isolamento & purificação
18.
Environ Health Prev Med ; 25(1): 31, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703154

RESUMO

BACKGROUND: Various treatments for hepatocellular carcinoma (HCC) are utilized in clinical practice; however, the prognosis is still poor on account of high recurrence rates. DNA methylation levels of CpG islands around promoters (promoter CpGis) inversely regulate gene expression and closely involved in carcinogenesis. As a new strategy, several chemicals globally inhibiting DNA methylation have been developed aiming at reducing DNA methylation levels and maintaining the expression of tumor suppressor genes. On the other hand, since these drugs nonspecifically modify DNA methylation, they can cause serious adverse effects. In order to ameliorate the methods by targeting specific CpGs, information of cancer-related genes that are regulated by DNA methylation is required. METHODS: We searched candidate genes whose expressions were regulated by DNA methylation of promoter CpGi and which are involved in HCC cases. To do so, we first identified genes whose expression were changed in HCC by comparing gene expressions of 371 HCC tissues and 41 non-tumor tissues using the Cancer Genome Atlas (TCGA) database. The genes were further selected for poor prognosis by log-rank test of Kaplan-Meier plot and for cancer relevance by Pubmed search. Expression profiles of upregulated genes in HCC tissues were assessed by Gene Ontology (GO) analysis. Finally, using DNA methylation data of TCGA database, we selected genes whose promoter DNA methylation levels were inversely correlated with gene expression. RESULTS: We found 115 genes which were significantly up- or downregulated in HCC tissues and were associated with poor prognosis and cancer relevance. The upregulated genes were significantly enriched in cell division, cell cycle, and cell proliferation. Among the upregulated genes in HCC, we identified hypomethylation of CpGis around promoters of FANCB, KIF15, KIF4A, ERCC6L, and UBE2C. In addition, TCGA data showed that the tumor suppressor gene P16 is unexpectedly overexpressed in many types of cancers. CONCLUSIONS: We identified five candidate genes whose expressions were regulated by DNA methylation of promoter CpGi and associate with cancer cases and poor prognosis in HCC. Modification of site-specific DNA methylation of these genes enables a different approach for HCC treatment with higher selectivity and lower adverse effects.


Assuntos
Carcinoma Hepatocelular/genética , Ilhas de CpG/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Bases de Dados como Assunto , Humanos , Neoplasias Hepáticas/metabolismo , Regiões Promotoras Genéticas
19.
Anticancer Res ; 40(7): 3819-3830, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620621

RESUMO

BACKGROUND: Picrasma quassioides (PQ) is a traditional Asian herbal medicine with anti-tumor properties that can inhibit the viability of HepG2 liver cancer cells. H-Ras is often mutated in liver cancer, however, the effect of PQ treatment on H-Ras mutated liver cancer is unclear. This study aimed to investigate the role of PQ on ROS accumulation and mitochondrial dysfunction in H-ras mutated HepG2 (HepG2G12V) cells. MATERIALS AND METHODS: PQ ethanol extract-induced HepG2G12V apoptosis was analyzed by the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: PQ treatment affected cell migration and colony formation in HepG2G12V cells. Cleaved-caspase-3, cleaved-caspase-9 and BCL2 associated agonist of cell death (BAD) expression levels were increased, while the levels of B-cell lymphoma-extra large (Bcl-xL) were decreased with PQ treatment. PQ treatment led to a reduction of H-Ras expression levels in liver cancer cells, thus reducing their abnormal proliferation. Furthermore, it led to increased expression levels of Peroxiredoxin VI, which regulates the redox signal in cells. CONCLUSION: Taken together these results provide a new functional significance for the role of PQ in treating HepG2G12V liver cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias Hepáticas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Genes ras , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Picrasma/química , Proteínas Proto-Oncogênicas p21(ras)/biossíntese
20.
Life Sci ; 257: 118082, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32653519

RESUMO

AIMS: Hepatocellular carcinoma (HCC), one of the most common cancer, causes the fourth cancer-related deaths around the world. N6-methyladenosine (m6A) has been reported to mediate circRNA translation in cancer biology. However, the mechanisms by which m6A and circRNA in post-transcriptional in HCC progression remain poorly understood. This study aimed to explore the mechanisms by which m6A and circRNA in post-transcriptional in HCC progression. MAIN METHODS: circ_KIAA1429 (hsa_circ_0084922) expression profiles in matched normal and HCC tissues were detected using microarray analysis. The biological roles of circ_KIAA1429 in progression of HCCC were measured both in vitro and in vivo. KEY FINDINGS: In this study, we found hsa_circ_0084922, which came from KIAA1429, named circ_KIAA1429, was upregulated in HCC cells and tumor tissues. Overexpression of circ_KIAA1429 can facilitate HCC migration, invasion, and EMT process. However, knockdown of circ_KIAA1429 lead to the opposite results. Furthermore, it was demonstrated that Zeb1 was the downstream target of circ_KIAA1429. Up-regulation of Zeb1 led to HCC cells metastasis induced by circ_KIAA1429. In addition, YTHDF3 enhanced Zeb1 mRNA stability via an m6A dependent manner. SIGNIFICANCE: This study revealed that circ_KIAA1429 could accelerate HCC advancement, maintained the expression of Zeb1 through the mechanism of m6A-YTHDF3-Zeb1 in HCC. What's more, it might represent a potential therapeutic target in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas de Ligação a RNA/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Camundongos , Camundongos Nus , Análise em Microsséries , RNA Circular/genética , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
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