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1.
Aging (Albany NY) ; 122020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017706

RESUMO

This paper was originally published in Aging Advance Online Publications on February 2, 2020. In compliance with Aging's withdrawal policy, the paper was withdrawn in its entirety. It will not appear in Aging internal or any external indexes or archives.

2.
Am J Clin Oncol ; 43(1): 20-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31633514

RESUMO

OBJECTIVES: The objective of this study was to establish a reliable and effective nomogram for predicting prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with postoperative adjuvant transarterial chemoembolization (TACE). PATIENTS AND METHODS: A derivation cohort of 370 HCC patients treated with postoperative TACE in the Eastern Hepatobiliary Surgery Hospital from January 2009 to December 2012 were retrospectively analyzed. Univariate and multivariate analysis were performed by Cox regression and independent prognostic factors for overall survival were determined to construct the nomogram. Concordance index (C-index), calibration curve and decision curve analysis were performed to evaluate the capability of the nomogram and the established nomogram was compared with TNM stage and Barcelona Clinic Liver Cancer (BCLC) stage to identify the superior model. The results were validated in a validation cohort of 123 HCC patients in the same center. RESULTS: Multivariate analysis indicated that γ-glutamyl transferase, α-fetoprotein, tumor number, tumor size, satellite lesions, microvascular invasion, and HBV-DNA were independent prognostic factors for overall survival in the derivation cohort, and all these factors were selected into the nomogram. The C-index was 0.755 for survival prediction of the nomogram, which was significantly higher than the TNM stage (0.636, P<0.001) and BCLC stage (0.594, P<0.001). A fair uniformity and a superior net benefit with wide range threshold probabilities were showed in the calibration curves and decision curve analysis. In the validation cohort, the C-index of the nomogram (0.785) also had a higher predictive accuracy than TNM stage (0.744, P=0.019) and BCLC stage (0.616, P<0.001). CONCLUSIONS: The nomogram with accurate and reasonable performance was proposed for predicting survival of HBV-related HCC with postoperative adjuvant TACE.

3.
Mol Carcinog ; 58(10): 1897-1907, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313392

RESUMO

The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Tropomodulina/genética , Animais , Carcinoma Hepatocelular/patologia , Progressão da Doença , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética
4.
J Hepatol ; 70(5): 904-917, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30654066

RESUMO

BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. METHODS: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. RESULTS: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. CONCLUSION: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. LAY SUMMARY: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.

5.
Mol Oncol ; 12(6): 936-952, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29689643

RESUMO

We previously demonstrated that interleukin-17A (IL-17A) is associated with the progression of hepatocellular carcinoma (HCC). However, its role in the invasion-metastasis cascade of HCC and the efficacy of IL-17A-targeting therapeutics in HCC remain largely unknown. In this study, we found that IL-17A promoted intrahepatic and pulmonary metastasesis of HCC cells in an orthotopic implant model. Moreover, our results showed that IL-17A induced epithelial-mesenchymal transition (EMT) and promoted HCC cell colonization in vitro and in vivo, and the role of IL-17A in invasion-metastasis was dependent on activation of the AKT pathway. Remarkably, combined therapy using both secukinumab and sorafenib has better inhibition on tumour growth and metastasis compared to sorafenib monotherapy. Additionally, the combination of intratumoral IL-17A+ cells and E-cadherin predicted the outcome of patients with HCC at an early stage after hepatectomy based on tissue microarray and immunohistochemistry. In conclusion, our studies reveal that IL-17A induces early EMT and promotes late colonization of HCC metastasis by activating AKT signalling. Secukinumab is a promising candidate for clinical development in combination with sorafenib for the management of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Interleucina-17/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Hepatectomia , Humanos , Interleucina-6/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Resultado do Tratamento
7.
Nat Commun ; 7: 12992, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27703150

RESUMO

Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV integration between tumour and non-tumour tissues. HBV insertional sites are significantly enriched in the proximity of telomeres in tumours. Recurrent HBV target genes are identified with few that overlap. The overall HBV integration frequency is much higher in tumour genomes of males than in females, with a significant enrichment of integration into chromosome 17. Furthermore, a cirrhosis-dependent HBV integration pattern is observed, affecting distinct targeted genes. Our data suggest that HBV integration has a high potential to drive oncogenic transformation.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Transformação Celular Neoplásica , Ilhas de CpG , DNA Viral/genética , Feminino , Genoma Humano , Genoma Viral , Hepatite B Crônica/genética , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/genética , Cirrose Hepática/virologia , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Análise de Sequência de RNA , Integração Viral
8.
Oncotarget ; 7(43): 70045-70057, 2016 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-27661119

RESUMO

Paraoxonase 3 (PON3) exerts prominent anti-inflammation and anti-oxidation properties mainly at the cellular level, and is primarily expressed in the liver. However, its role in HCC remains unexplored. Here, we investigated the expression pattern, clinical significance, and function of PON3 in HCC. PON3 mRNA and protein levels were respectively determined in two large cohorts using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) of tissue microarray. We found that PON3 was downregulated in most HCCs. Kaplan-Meier and log-rank test showed that PON3 downregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in all HCC patients, especially early-stage HCC patients. Cox regression analysis revealed that the PON3 downregulation was an independent risk factor for RFS and OS. Gain- and loss-of-function experiments revealed that PON3 suppressed cell proliferation in vivo and in vitro, which was attributed to its cell-cycle arrest effect. In addition, microarray analysis showed that some pro-proliferative genes were elevated when PON3 was knockdown, and these genes possibly involved in the underlying mechanisms. In conclusion, our studies reveal the cell proliferation inhibitory function of PON3 and offer a potential prognostic predictor and therapeutic target for HCC.


Assuntos
Arildialquilfosfatase/fisiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Adulto , Idoso , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Análise Serial de Tecidos
9.
Surg Oncol ; 25(3): 171-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27566019

RESUMO

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC·In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Hepatectomia/efeitos adversos , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Complicações Pós-Operatórias , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Proteínas de Homeodomínio/genética , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
10.
Cancer Lett ; 379(2): 239-44, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-26282784

RESUMO

The epigenetic mechanism that incorporates DNA methylation alterations, histone modifications, and non-coding RNA expression has been identified as a major characteristic in distinguishing physiological and pathological settings of cancers including hepatocellular carcinoma (HCC), the third leading cause of mortality related cancer. The advance in methylation modification of chromatin elements (for both genomic DNA and histone tails) and the emerging roles of long noncoding RNA (lncRNA) have given us a better understanding of molecular mechanisms underlying HCC. Recently, methods like genome-wide lncRNA profiling and histone hallmark detection were reported to discover mass tumor-associated lncRNAs epigenetically deregulated by differential chromosome modification, mainly by genomic DNA and histone methylation. Therefore, aberrant methylation modification of certain particular lncRNA genes could be crucial events correlating with unfavorable outcomes in HCC. In addition, amount of lncRNAs could act as a manipulator for DNA methylation or a scaffold for histone modification to affect key signaling pathways in hepatocarcinogenesis. This suggests that methylation modification of chromatin elements may have functional crosstalk with lncRNA. Here, we aim to outline the emerging role of the methylation and lncRNA, and their crosstalk of molecular mechanism.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Metilação de DNA , Epigênese Genética , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , RNA Longo não Codificante/metabolismo , Transdução de Sinais
11.
Hepatology ; 63(2): 499-511, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25964079

RESUMO

UNLABELLED: Tumor cells with stemness (stem-cell) features contribute to initiation and progression of hepatocellular carcinoma (HCC), but involvement of long noncoding RNAs (lncRNAs) remains largely unclear. Genome-wide analyses were applied to identify tumor-associated lncRNA-DANCR. DANCR expression level and prognostic values of DANCR were assayed in two HCC cohorts (China and Korea, n = 135 and 223). Artificial modulation of DANCR (down- and overexpression) was done to explore the role of DANCR in tumorigenesis and colonization, and tumor-bearing mice were used to determine therapeutic effects. We found that lncRNA-DANCR is overexpressed in stem-like HCC cells, and this can serve as a prognostic biomarker for HCC patients. Experiments showed that DANCR markedly increased stemness features of HCC cells to promote tumorigenesis and intra-/extrahepatic tumor colonization. Conversely, DANCR knockdown attenuated the stem-cell properties and in vivo interference with DANCR action led to decreased tumor cell vitality, tumor shrinkage, and improved mouse survival. Additionally, we found that the role of DANCR relied largely on an association with, and regulation of, CTNNB1. Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)-214, miR-320a, and miR-199a on CTNNB1. This observation was confirmed in vivo, suggesting a novel mechanism of tumorigenesis involving lncRNAs, messenger RNAs, and microRNAs. CONCLUSIONS: These studies reveal a significance and mechanism of DANCR action in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/fisiologia , beta Catenina/fisiologia , Animais , Carcinogênese , Masculino , Camundongos , Camundongos Nus
12.
Hepatology ; 63(3): 850-63, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26663434

RESUMO

UNLABELLED: Systemic analyses using large-scale genomic profiles have successfully identified cancer-driving somatic copy number variations (SCNVs) loci. However, functions of vast focal SCNVs in "protein-coding gene desert" regions are largely unknown. The integrative analysis of long noncoding RNA (lncRNA) expression profiles with SCNVs in hepatocellular carcinoma (HCC) led us to identify the recurrent deletion of lncRNA-PRAL (p53 regulation-associated lncRNA) on chromosome 17p13.1, whose genomic alterations were significantly associated with reduced survival of HCC patients. We found that lncRNA-PRAL could inhibit HCC growth and induce apoptosis in vivo and in vitro through p53. Subsequent investigations indicated that the three stem-loop motifs at the 5' end of lncRNA-PRAL facilitated the combination of HSP90 and p53 and thus competitively inhibited MDM2-dependent p53 ubiquitination, resulting in enhanced p53 stability. Additionally, in vivo lncRNA-PRAL delivery efficiently reduced intrinsic tumors, indicating its potential therapeutic application. CONCLUSIONS: lncRNA-PRAL, one of the key cancer-driving SCNVs, is a crucial stimulus for HCC growth and may serve as a potential target for antitumor therapy.


Assuntos
Carcinoma Hepatocelular/genética , Variações do Número de Cópias de DNA , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Animais , Sequência de Bases , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , China/epidemiologia , Pontos de Quebra do Cromossomo , Feminino , Genes p53 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Sequências Repetidas Invertidas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Dados de Sequência Molecular , Prognóstico
13.
Medicine (Baltimore) ; 94(40): e1344, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26447993

RESUMO

Previous studies showed that suppressor of cytokine signaling 3 (SOCS3) protein is associated with incidence and progression of hepatocellular carcinoma (HCC); however, the association between the genetic polymorphism of SOCS3 gene and HCC remains unknown. A total of 254 HCC patients and 354 healthy controls were enrolled. All HCC patients underwent partial hepatectomy as initial treatment and were followed. Three SOCS3 gene polymorphisms, namely, rs4969170 A>G, rs8064821 C>T, and rs12953258 C>A were determined. Our data show that the rs4969170 A>G polymorphism dramatically affects the susceptibility to HCC in our cohorts. Logistic regression analyses revealed that the rs4969170 GG is a risk factor for HCC after the adjustment with confounding factors. The rs4969170A>G polymorphism is also associated with the clinical features of HCC patients and predicts the postoperative relapse-free survival and overall survival. The rs4969170GG genotype carrier had a worse prognosis than the rs4969170AG and rs4969170AA carrier. Our findings suggest that the rs4969170A>G polymorphism of SOCS3 gene may be used as a prognostic predictor for HCC patients who underwent surgical treatment.


Assuntos
Carcinoma Hepatocelular/genética , Hepatectomia , Neoplasias Hepáticas/genética , Polimorfismo Genético , Proteínas Supressoras da Sinalização de Citocina/genética , Western Blotting , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/terapia , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteína 3 Supressora da Sinalização de Citocinas
14.
Mol Cancer ; 14: 170, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26376879

RESUMO

BACKGROUND: Downregulation of Aldolase B (ALDOB) has been reported in hepatocellular carcinoma. However, its clinical significance and its role in pathogenesis of HCC remain largely unknown. METHODS: We analyzed the expression of ALDOB and its clinical features in a large cohort of 313 HCC patients using tissue microarray and immunohistochemistry. Moreover, the function of stably overexpressed ALDOB in HCC cells was explored in vitro and in vivo. Gene expression microarray analysis was performed on ALDOB-overexpressing SMMC7721 cells to elucidate its mechanism of action. RESULTS: ALDOB downregulation in HCC was significantly correlated with aggressive characteristics including absence of encapsulation, increased tumor size (>5 cm) and early recurrence. ALDOB downregulation was indicative of a shorter recurrence-free survival (RFS) and overall survival (OS) for all HCC patients and early-stage HCC patients (BCLC 0-A and TNM I stage patients). Multiple analyses revealed that ALDOB downregulation was an independent risk factor of RFS and OS. Stable expression of ALDOB in HCC cell lines reduced cell migration in vitro and inhibited lung metastasis, intrahepatic metastasis, and reduced circulating tumor cells in vivo. Mechanistically, we found that cells stably expressing ALDOB show elevated Ten-Eleven Translocation 1 (TET1) expression. Moreover, ALDOB expressing cells have higher levels of methylglyoxal than do control cells, which can upregulate TET1 expression. CONCLUSION: The downregulation of ALDOB could indicate a poor prognosis for HCC patients, and therefore, ALDOB might be considered a prognostic biomarker for HCC, especially at the early stage. In addition, ALDOB inhibits the invasive features of cell lines partly through TET1 expression.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/genética , Proteínas de Ligação a DNA/biossíntese , Frutose-Bifosfato Aldolase/biossíntese , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas/biossíntese , Idoso , Animais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Frutose-Bifosfato Aldolase/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Oxigenases de Função Mista , Metástase Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Ann Surg ; 261(1): 56-66, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25072444

RESUMO

OBJECTIVE: A randomized controlled trial was conducted to find out whether antiviral therapy in patients with hepatitis B-related hepatocellular carcinoma (HCC) improves long-term survival after hepatic resection. BACKGROUND: Despite advances in surgery and in multidisciplinary treatment, there is still no effective adjuvant treatment to prevent HCC recurrence after R0 resection for HCC. Whether antiviral therapy is useful in reducing postoperative HCC recurrence is unclear. METHODS: Between May 2007 and April 2008, patients who received R0 hepatic resection for HBV-related HCC were randomly assigned to receive no treatment (the control group, n = 100) or antiviral therapy (adefovir 10 mg/d, the antiviral group, n = 100). RESULTS: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.0%, 50.3%, 46.1% and 84.0%, 37.9%, 27.1%, respectively. The corresponding overall survival rates for the 2 groups were 96.0%, 77.6%, 63.1% and 94.0%, 67.4%, 41.5%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.026, P = 0.001). After adjusting for the confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.651 [95% confidence interval (CI): 0.451-0.938; P = 0.021] and 0.420 (95% CI: 0.271-0.651; P < 0.001). Antiviral therapy was an independent protective factor of late tumor recurrence (HR = 0.348, 95% CI: 0.177-0.687; P = 0.002) but not of early tumor recurrence [hazard ratio (HR) = 0.949, 95% CI: 0.617-1.459; P = 0.810]. CONCLUSIONS: In patients with hepatitis B-related HCC, adefovir antiviral therapy reduced late HCC recurrence and significantly improved overall survival after R0 hepatic resection.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Recidiva Local de Neoplasia/prevenção & controle , Organofosfonatos/uso terapêutico , Adenina/uso terapêutico , Adolescente , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , DNA Viral/sangue , Hepatite B/genética , Humanos , Falência Hepática/etiologia , Neoplasias Hepáticas/mortalidade , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida , Ativação Viral , Adulto Jovem
16.
J Cancer Res Clin Oncol ; 141(7): 1195-203, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25512078

RESUMO

PURPOSE: To investigate the expression of SRHC and the role of SRHC in the pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed HCC samples and matched non-tumor liver tissues (controls) collected from 81 patients who underwent hepatectomy in Shanghai, China. The expression levels of SRHC were determined by quantitative reverse-transcription polymerase chain reaction. Statistical analyses were used to associate the levels of SRHC with tumor features and patient outcomes. RESULTS: We found that a lower SRHC expression level was significantly more frequent in tissues with a high serum a-fetoprotein level (positive, >20 µg/L, P = 0.004) and a low degree of differentiated tumors (poorly differentiated, P = 0.017). Furthermore, we found that the promoter region of SRHC contains a CpG-rich island and that SRHC is down-regulated in tumors by DNA methylation. CONCLUSION: Here, we identified a new long noncoding RNA designated as SRHC that is capable of inhibiting cancer proliferation and is down-regulated in tumors at least partly by DNA methylation.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Inativação Gênica , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Metilação de DNA , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
17.
Mol Pharm ; 12(2): 644-52, 2015 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-25495890

RESUMO

Targeted delivery system would be an interesting platform to enhance the therapeutic effect and to reduce the side effects of anticancer drugs. In this study, we have developed lactobionic acid (LA)-modified chitosan-stearic acid (CS-SA) (CSS-LA) to deliver doxorubicin (DOX) to hepatic cancer cells. The average particle size of CSS-LA/DOX was ∼100 nm with a high entrapment efficiency of >95%. Drug release studies showed that DOX release from pH-sensitive micelles is significantly faster at pH 5.0 than at pH 7.4. The LA conjugated micelles showed enhanced cellular uptake in HepG2 and BEL-7402 liver cancer cells than free drug and unconjugated micelles. Consistently, CSS-LA/DOX showed enhanced cell cytotoxicity in these two cell lines. Annexin-V/FITC and PI based apoptosis assay showed that the number of living cells greatly reduced in this group with marked presence of necrotic and apoptotic cells. LA-conjugated carrier induced typical chromatic condensation of cells; membrane blebbing and apoptotic bodies began to appear. In vivo, CSS-LA/DOX showed an excellent tumor regression profile with no toxic side effects. The active targeting moiety, long circulation profile, and EPR effect contributed to its superior anticancer effect in HepG2 based tumor. Our results showed that polymeric micelles conjugated with LA increased the therapeutic availability of DOX in the liver cancer cell based solid tumor without any toxic side effects. The active targeting ligand conjugated nanoparticulate system could be a promising therapeutic strategy in the treatment of hepatic cancers.


Assuntos
Quitosana/química , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Neoplasias Hepáticas/tratamento farmacológico , Micelas , Polímeros/química , Ácidos Esteáricos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dissacarídeos/química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Células Hep G2 , Humanos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Carcinog ; 54(12): 1584-95, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25307746

RESUMO

Pioglitazone (PGZ), a synthetic PPARγ ligand, is known to have anti-tumor activity. However, it is unclear how it acts against hepatocellular carcinoma (HCC). We hypothesized that the pathological receptor for advanced glycation end products (RAGE) is involved in the PGZ anti-tumor process. To test this notion, human primary HCC tissues and corresponding adjacent non-cancerous tissues (ANCT) from 75 consecutive cases were analyzed. The expression and clinical significance of RAGE was assessed by immunohistochemical assay through tissue microarray. After HCC cells were pretreated with different concentrations of PGZ, cell proliferation, apoptosis, cell invasion, and cell cycle distribution were evaluated by multiple assays. The results showed that, the positive expression of RAGE was significantly higher in HCC tissues than in ANCT (66.7% vs. 36.0%, P < 0.001), and was closely associated with pathological staging (P = 0.014) and lymph-vascular space invasion (P = 0.003). Moreover, PGZ inhibited proliferative activity and invasive potential, and induced apoptosis and cell cycle arrest in HCC cells resulting in increased expression of PPARγ and decreased expression of RAGE, NF-κB, HMGB1, p38MAPK, Ki-67, MMP-2, and CyclinD1. Furthermore, knockdown of RAGE or NF-κB by siRNA effectively suppressed cell proliferation and invasion, and mediated the inhibitory effects of PGZ in HCC cells. Taken together, our findings suggest that, RAGE is overexpressed in human HCC tissues, and is closely associated with the pathological staging and tumor invasion of HCC. In addition, PGZ as a PPARγ agonist may inhibit growth and invasion of HCC cells via blockade of the RAGE signaling.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Invasividade Neoplásica/prevenção & controle , PPAR gama/agonistas , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Pioglitazona , Transdução de Sinais/efeitos dos fármacos
19.
Hepatology ; 60(4): 1278-90, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25043274

RESUMO

UNLABELLED: Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein we examined the expression profiles of long noncoding RNAs (lncRNAs) found in fetal and adult liver in mice. Many fetal hepatic lncRNAs were identified; one of these, lncRNA-mPvt1, is an oncofetal RNA that was found to promote cell proliferation, cell cycling, and the expression of stem cell-like properties of murine cells. Interestingly, we found that human lncRNA-hPVT1 was up-regulated in HCC tissues and that patients with higher lncRNA-hPVT1 expression had a poor clinical prognosis. The protumorigenic effects of lncRNA-hPVT1 on cell proliferation, cell cycling, and stem cell-like properties of HCC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Moreover, mRNA expression profile data showed that lncRNA-hPVT1 up-regulated a series of cell cycle genes in SMMC-7721 cells. By RNA pulldown and mass spectrum experiments, we identified NOP2 as an RNA-binding protein that binds to lncRNA-hPVT1. We confirmed that lncRNA-hPVT1 up-regulated NOP2 by enhancing the stability of NOP2 proteins and that lncRNA-hPVT1 function depends on the presence of NOP2. CONCLUSION: Our study demonstrates that the expression of many lncRNAs is up-regulated in early liver development and that the fetal liver can be used to search for new diagnostic markers for HCC. LncRNA-hPVT1 promotes cell proliferation, cell cycling, and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects on the treatment of HCC.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Proliferação de Células/fisiologia , Neoplasias Hepáticas/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Proteínas Nucleares/fisiologia , RNA Longo não Codificante/fisiologia , tRNA Metiltransferases/fisiologia , Animais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Ciclo Celular/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/fisiologia
20.
J Exp Clin Cancer Res ; 33: 61, 2014 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-25060425

RESUMO

BACKGROUND: Karyopherin alpha 2 (KPNA2) promotes tumor growth in hepatocellular carcinoma (HCC). We aimed to determine the content and clinical significance of mechanism underlying. METHODS: The association of transcriptional factor pleomorphic adenoma gene 1 (PLAG1) with KPNA2 was explored by co-immunoprecipitation. In vitro gain- and loss-of-function models were established to explore the functional interaction. Clinical samples from 314 HCC patients were applied to explore the clinical significance. RESULTS: We found that PLAG1 could associate with KPNA2 and be promoted into nucleus by KPNA2. The increment of proliferative and metastatic abilities by KPNA2 over-expression can be significantly retarded by PLAG1 inhibition. The co-enrichment of KPNA2 and PLAG1 in nucleus is observed in clinical samples and can distinguish patients with the worst prognosis. The positive PLAG1 expression is an independent risk factor of recurrence free survival (HR: 1.766, 1.315-2.371; P = 0.000) and overall survival (HR: 1.589, 1.138-2.220; P = 0.007). Especially for patients with positive KPNA2 staining (N = 152), the positive PLAG1 expression is the sole risk factor for both recurrence free survival (HR: 1.749, 1.146-2.670; P = 0.010) and overall survival (HR: 1.662, 1.007-2.744; P = 0.047). CONCLUSIONS: The nuclear import of PLAG1 by KPNA2 is essential for the role of KPNA2 in HCC cells and is significant to predict poor survival of HCC patients after hepatectomy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/metabolismo , alfa Carioferinas/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Núcleo Celular/metabolismo , Proliferação de Células/fisiologia , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Fatores de Risco , Análise de Sobrevida , Transfecção , alfa Carioferinas/genética
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