RESUMO
Liquid biopsies, based on cell free DNA (cfDNA) and proteins, have shown the potential to detect early stage cancers of diverse tissue types. However, most of these studies were retrospective, using individuals previously diagnosed with cancer as cases and healthy individuals as controls. Here, we developed a liquid biopsy assay, named the hepatocellular carcinoma screen (HCCscreen), to identify HCC from the surface antigen of hepatitis B virus (HBsAg) positive asymptomatic individuals in the community population. The training cohort consisted of individuals who had liver nodules and/or elevated serum α-fetoprotein (AFP) levels, and the assay robustly separated those with HCC from those who were non-HCC with a sensitivity of 85% and a specificity of 93%. We further applied this assay to 331 individuals with normal liver ultrasonography and serum AFP levels. A total of 24 positive cases were identified, and a clinical follow-up for 6-8 mo confirmed four had developed HCC. No HCC cases were diagnosed from the 307 test-negative individuals in the follow-up during the same timescale. Thus, the assay showed 100% sensitivity, 94% specificity, and 17% positive predictive value in the validation cohort. Notably, each of the four HCC cases was at the early stage (<3 cm) when diagnosed. Our study provides evidence that the use of combined detection of cfDNA alterations and protein markers is a feasible approach to identify early stage HCC from asymptomatic community populations with unknown HCC status.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Detecção Precoce de Câncer/métodos , Antígenos de Superfície da Hepatite B/sangue , Biópsia Líquida/métodos , Neoplasias Hepáticas/diagnóstico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Ácidos Nucleicos Livres , Vírus da Hepatite B , Hepatite B Crônica , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Sensibilidade e Especificidade , UltrassonografiaRESUMO
BACKGROUND AND AIMS: Somatic mutation R249S in TP53 is highly common in hepatocellular carcinoma (HCC). We aim to investigate the effects of R249S in ctDNA on the prognosis of HCC. METHODS: We analysed three cohorts including 895 HCC patients. TP53 mutation spectrum was examined by direct sequencing of genomic DNA from tissue specimens in HCC patients with hepatectomy (Cohort 1, N = 260). R249S and other recurrent missense mutations were assessed for their biological functions and associations with overall survival (OS) and progression-free survival (PFS) of HCC patients in Cohort 1. R249S within circulating tumour DNA (ctDNA) was detected through droplet digital polymerase chain reaction (ddPCR) and its association with OS and PRS was analysed in HCC patients with (Cohort 2, N = 275) or without (Cohort 3, N = 360) hepatectomy. RESULTS: In Cohort 1, R249S occupied 60.28% of all TP53 mutations. Overexpression of R249S induced more serious malignant phenotypes than those of the other three identified TP53 recurrent missense mutations. Additionally, R249S, but not other missense mutations, was significantly associated with worse OS (P = .006) and PFS (P = .01) of HCC patients. Consistent with the results in Cohort 1, HCC patients in Cohorts 2 and 3 with R249S had worse OS (P = 8.291 × 10-7 and 2.608 × 10-7 in Cohorts 2 and 3, respectively) and PFS (P = 5.115 × 10-7 and 5.900 × 10-13 in Cohorts 2 and 3, respectively) compared to those without this mutation. CONCLUSIONS: TP53 R249S mutation in ctDNA may serve as a promising prognosis biomarker for HCC patients with or without hepatectomy.
Assuntos
Carcinoma Hepatocelular , DNA Tumoral Circulante , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirurgia , DNA Tumoral Circulante/genética , Hepatectomia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genéticaRESUMO
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality in China, and the molecular mechanism of uncontrolled HCC progression remains to be explored. NK3 homeobox 1 (NKX3.1), an androgen-regulated prostate-specific transcription factor, suppresses tumors in prostate cancer, but its role in HCC is unknown, especially in hepatocellular carcinoma. In the present study, the differential expression analyses in HCC tissues and matched adjacent noncancerous liver tissues revealed that NKX3.1 is frequently down-regulated in human primary HCC tissues compared with matched adjacent noncancerous liver tissues. We also noted that NKX3.1 significantly inhibits proliferation and mobility of HCC cells both in vitro and in vivo Furthermore, NKX3.1 overexpression resulted in cell cycle arrest at the G1/S phase via direct binding to the promoter of forkhead box O1 (FOXO1) and up-regulation of expression. Of note, FOXO1 silencing in NKX3.1-overexpressing cells reversed the inhibitory effects of NKX3.1 on HCC cell proliferation and invasion. Consistently, both FOXO1 and NKX3.1 were down-regulated in human HCC tissues, and their expression was significantly and positively correlated with each other. These results suggest that NKX3.1 functions as a tumor suppressor in HCC cells through directly up-regulating FOXO1 expression.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/patologia , Fatores de Transcrição/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Ciclo Celular , Movimento Celular , Proteína Forkhead Box O1/genética , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Prognóstico , Taxa de Sobrevida , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Increasing evidence has shown that zinc-alpha2-glycoprotein (AZGP1) is associated with the progression and prognosis of several tumor types. However, little is known regarding the underlying molecular mechanisms of AZGP1 in hepatocellular carcinoma (HCC). In this study, we report that transcription factor Ikaros bound to the AZGP1 promoter and increased its expression in HCC cells. The downregulation of AZGP1 was associated with histone deacetylation in HCC. In addition, the positive feedback regulation via acetylation of histone H4-mediated transactivation of the Ikaros promoter and the Ikaros-mediated transactivation of the acetylation of histone H4 were crucial for regulating AZGP1 expression in HCC cells. Moreover, low serum AZGP1 level in HCC patients was associated with poor prognosis. The ectopic overexpression of AZGP1 or recombinant AZGP1 protein inhibited HCC cell proliferation, migration and invasion in vitro and in vivo, whereas silencing AZGP1 expression resulted in increased cell proliferation, migration and invasion in vitro. In addition, we found that AZGP1 inhibited cell migration and invasion through the regulation of the PTEN/Akt and CD44s pathways. Collectively, our findings revealed the molecular mechanism of AZGP1 expression in HCC, providing new insights into the mechanisms underlying tumor progression.
Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Transporte/biossíntese , Transição Epitelial-Mesenquimal/genética , Glicoproteínas/biossíntese , Neoplasias Hepáticas/genética , Adipocinas , Animais , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/genética , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Histona Desacetilases/genética , Humanos , Receptores de Hialuronatos/genética , Fator de Transcrição Ikaros/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteína Oncogênica v-akt/genética , PTEN Fosfo-Hidrolase/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
UNLABELLED: Cancer cells possess a unique metabolic phenotype that allows them to preferentially utilize glucose through aerobic glycolysis. This phenomenon is referred to as the "Warburg effect." Accumulating evidence suggests that microRNAs (miRNAs), a class of small noncoding regulatory RNAs, interact with oncogenes/tumor suppressors and induce such metabolic reprograming in cancer cells. To systematically study the metabolic roles of miRNAs in cancer cells, we developed a gain-of-function miRNA screen in HeLa cells. Subsequent investigation of the characterized miRNAs indicated that miR-199a-5p acts as a suppressor for glucose metabolism. Furthermore, miR-199a-5p is often down-regulated in human liver cancer, and its low expression level was correlated with a low survival rate, large tumor size, poor tumor differentiation status, high tumor-node-metastasis stage and the presence of tumor thrombus of patients. MicroRNA-199a-5p directly targets the 3'-untranslated region of hexokinase 2 (HK2), an enzyme that catalyzes the irreversible first step of glycolysis, thereby suppressing glucose consumption, lactate production, cellular glucose-6-phosphate and adenosine triphosphate levels, cell proliferation, and tumorigenesis of liver cancer cells. Moreover, HK2 is frequently up-regulated in liver cancer tissues and associated with poor patient outcomes. The up-regulation of hypoxia-inducible factor-1α under hypoxic conditions suppresses the expression of miR-199a-5p and promotes glycolysis, whereas reintroduction of miR-199a-5p interferes with the expression of HK2, abrogating hypoxia-enhanced glycolysis. CONCLUSION: miR-199a-5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients.
Assuntos
Glicólise , Hexoquinase/metabolismo , Ácido Láctico/biossíntese , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Tumorais CultivadasRESUMO
UNLABELLED: Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71) ≤ Pmeta ≤ 9.92 × 10(-7) ). CONCLUSION: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.
Assuntos
Antígenos CD40/genética , Fator B do Complemento/genética , Antígenos HLA-C/genética , Hepatite B Crônica/genética , Antígenos CD40/sangue , Fator B do Complemento/metabolismo , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-IdadeRESUMO
Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide, and its incidence continues to increase. However, the mechanism underlying the development and progression of HCC remains unknown. The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family and influences the carcinogenesis of multiple types of tumors, but the biological roles of SOCS2 in HCC remain unclear. In this study, we found that SOCS2 expression was reduced in HCC tissues compared with matched noncancerous liver tissues. Moreover, decreased SOCS2 expression was significantly associated with the presence of intrahepatic metastasis and high histological grade in HCC patients. Colony formation assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that overexpression of SOCS2 or knockdown of endogenous SOCS2 did not significantly affect cell proliferation and tumorigenicity in HCC cells in vitro and in vivo. However, SOCS2 overexpression significantly inhibited the migration and invasion of HCC cells in vitro and inhibited metastasis in vivo. Consistent with these findings, the knockdown of endogenous SOCS2 enhanced migration and invasion in HCC cells in vitro. Our study demonstrated that SOCS2 inhibited human HCC metastasis, and SOCS2 might provide a new potential therapeutic strategy for treating HCC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/secundário , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras da Sinalização de Citocina/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
Single-nucleotide polymorphisms (SNPs) of microRNAs (miRNAs) are considered potential markers of cancer risk and prognosis in various cancers. In the current study, the primary aim is to determine whether the miR-492G>C polymorphism (rs2289030) altered hepatocellular carcinoma (HCC) prognosis. The SNP rs2289030 of miR-492 was genotyped using DNA from blood samples of 362 HCC patients that had undergone surgical resection of a HCC tumor. The associations between overall survival and demographic characteristics, clinical features, and the SNP rs2289030 were estimated using the Cox proportional hazards model. Results showed that patients who carried the CG genotype (P = 0.015, hazard ratio [HR] = 0.704, 95 % confidence interval [CI] 0.530-0.934) and CG+GG genotype (P = 0.011, HR = 0.703, 95 % CI 0.536-0.924) had significantly decreased risk of death compared to those with the CC genotype. Similar results were found in the multivariate analysis adjusted by tumor size and venous invasion. Further stratification analysis indicated that the effect of rs2289030 had more prominence in patients ≤50 years old and that reported ever using alcohol, male gender, a family history of HCC, being HbsAg or alpha fetoprotein (AFP) positive, differentiation I + II, presence of venous invasion or cirrhosis, multiple tumors, and pTNM stage I + II. Results from this study illustrate the potential use of miR-492 rs2289030 as a prognostic marker for HCC patients that have undergone a surgical resection of the tumor.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Predisposição Genética para Doença/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Feminino , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto JovemRESUMO
Single nucleotide polymorphisms (SNPs) within microRNAs (miRNAs) are considered potential markers for risk and prognosis of various cancers. In the current study, we aimed to determine whether miR-608 rs4919510 affected hepatocellular carcinoma (HCC) prognosis. We genotyped rs4919510 using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. Associations between rs4919510 and overall survival (OS) and demographic characteristics and clinical features were estimated using the Cox proportional hazards model. Results showed that HCC patients who carried the rs4919510 CC genotype had a significantly longer OS compared to those who carried the GG genotype (P = 0.013, hazard ratio [HR] = 0.600, 95 % confidence interval [CI] 0.402-0.897) and the CG + GG genotype (P = 0.033, HR = 0.681, 95 % CI 0.479-0.970) in univariate analysis. Similar results were obtained in multivariate analysis. Further stratification analysis indicated that rs4919510 was significantly associated with OS in patients who were satisfied with one of the following criteria: male gender, HbsAg-positive, α-fetoprotein (AFP)-positive, tumor size >5 cm, cirrhosis, solitary tumor, I + II pTNM stage, or no tumor capsule. Finally, a significantly higher frequency of rs4919510 CC genotype was observed in patients with cirrhosis (22.9 %, 55/240) than those without cirrhosis (14.0 %, 17/121) (P = 0.047). In conclusion, our results illustrated the potential role of miR-608 rs4919510 as a prognostic marker for HCC patients undergoing surgical resection of the tumor.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Seguimentos , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Forkhead box P1 (FOXP1) belongs to a family of winged-helix transcription factors that are involved in the processes of cellular proliferation, differentiation, metabolism, and longevity. FOXP1 can affect cell proliferation and migratory ability in hepatocellular carcinoma (HCC) in vitro. However, little is known about the mechanism of FOXP1 in the proliferation of HCC cells. This study aimed to further explore the function of FOXP1 on the proliferation of HCC cells as well as the relevant mechanism involved. Western blot analysis, tumor xenograft models, and flow cytometry analysis were performed to elucidate the function of FOXP1 in the regulation of cell proliferation in human HCC. We observed that silencing FOXP1 significantly suppressed the growth ability of HCC cells both in vitro and in vivo. In addition, knockdown of FOXP1 induced G1/S phase arrest, and the expression of total and phosphorylated Rb (active type) as well as the levels of E2F1 were markedly decreased at 24 h; however, other proteins, including cyclin-dependent kinase (CDK) 4 and 6 and cyclin D1 did not show noticeable changes. In conclusion, downregulation of FOXP1 inhibits cell proliferation in hepatocellular carcinoma by inducing G1/S phase cell cycle arrest, and the decrease in phosphorylated Rb is the main contributor to this G1/S phase arrest.
Assuntos
Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Fatores de Transcrição Forkhead/genética , Pontos de Checagem da Fase G1 do Ciclo Celular , Neoplasias Hepáticas/metabolismo , Proteínas Repressoras/genética , Pontos de Checagem da Fase S do Ciclo Celular , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo , Fator de Transcrição E2F1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Repressoras/metabolismoRESUMO
A two stage study was conducted to explore new potential mutations in the full genome of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China. In stage 1, full genomes of HBV were compared between 30 HCC cases and 30 controls. In stage 2, an independent case-control study including 100 HCC cases and 100 controls was enrolled to verify the relationship between hot-spot mutations and HCC development. Furthermore, a longitudinal study was conducted on 11 HCC cases with serial serum samples available before HCC diagnosis. A total of 10 mutations (including pre-S2 start codon mutation and pre-S deletion in pre-S gene, G1613A, C1653T, A1762T, and G1764A mutations in X gene, A2159G, A2189Y, G2203W, and C2288R mutations in C gene) showed an increased risk of HCC. In the validation study, pre-S deletion, C1653T, A1762T/G1764A, A2159G, A2189Y, G2203W, and C2288R mutations were associated with increased HCC risk in univariate analysis. Multivariate analysis indicated that pre-S deletion, A1762T/G1764A, A2159G, and A2189Y mutations were independently related with HCC development. Moreover, a significant biological gradient of HCC risk by number of mutations in the C gene was observed. Longitudinal observation demonstrated a gradual combination of the above mutations accumulated during the progression of HCC.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Genes Virais/genética , Predisposição Genética para Doença , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Mutação , China , Genoma Viral , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Análise MultivariadaRESUMO
UNLABELLED: Ribonucleotide reductase (RR)M2B is an enzyme belonging to the ribonucleotide reductase enzyme family, which is essential for DNA synthesis and repair. RRM2B plays an important role in tumor progression and metastasis; however, little is known about the expression and underlying molecular mechanisms of RRM2B in hepatocellular carcinoma (HCC). In the present study, we report that down-regulation of RRM2B in HCC is negatively associated with intrahepatic metastasis, regardless of p53 status. Moreover, the ectopic overexpression of RRM2B decreased HCC cell migration and invasion in vitro, whereas silencing RRM2B expression resulted in increased migration and invasion in vitro and intrahepatic and lung metastasis in vivo. Additionally, knockdown of RRM2B by short hairpin RNA (shRNA) in HCC cells was associated with epithelial-mesenchymal transition (EMT), including the down-regulation of E-cadherin, and the concomitant up-regulation of N-cadherin and slug. A further experiment showed that RRM2B inhibited cell migration and spreading through regulation of the early growth response protein 1 (Egr-1)/phosphatase and tensin homolog (PTEN)/Akt1 pathway. Consistently, we also detected a significant correlation between RRM2B and E-cadherin protein expression in HCC tissues. Furthermore, Egr-1 also directly bound to the RRM2B promoter and repressed RRM2B transcription, thereby establishing a negative regulatory feedback loop. CONCLUSION: These findings indicate that RRM2B suppresses cell migration and spreading by way of modulation of the Egr-1/PTEN/Akt1 pathway.
Assuntos
Carcinoma Hepatocelular/fisiopatologia , Proteínas de Ciclo Celular/fisiologia , Movimento Celular/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Neoplasias Hepáticas/fisiopatologia , PTEN Fosfo-Hidrolase/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Ribonucleotídeo Redutases/fisiologia , Transdução de Sinais/fisiologia , Caderinas/fisiologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo/fisiologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/farmacologia , Fatores de Transcrição da Família Snail , Fatores de Transcrição/fisiologiaRESUMO
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death in developing countries, especially in East Asia and South Africa, and the identification of new biomarkers for early diagnosis and prognosis is needed. Delta-like 1 homologue (Drosophila) (DLK1) is expressed in malignancies and promotes cancer cell stemness and tumourigenicity, which makes this molecule a potential target for therapies directed against cancer stem/progenitor cells. Here, we aimed to assess the predictive value of DLK1 as a diagnostic and prognostic biomarker in HCC. With this purpose, serum DLK1 levels were detected using an enzyme-linked immunosorbent assay (ELISA) in serum specimens from 397 HCC patients, 114 healthy individuals, 43 patients with chronic hepatitis B virus (HBV) infection and 24 cirrhotic liver patients with HBV infection, and the correlation between DLK1 levels and clinical features was evaluated. Our data showed that the serum DLK1 level was significantly higher in HCC patients than in healthy individuals or patients with chronic HBV infection (HBV carriers) (P < 0.05). Moreover, the serum DLK1 levels were positively correlated with tumour size and α-fetoprotein (AFP) levels, but not with gender, age, histological grade, HBV infection, intrahepatic metastasis or cirrhosis in HCC patients. Kaplan-Meier analysis indicated that higher DLK1 levels were associated with shorter survival in HCC patients. These results suggest that the serum levels of DLK1 may serve as a prognostic biomarker for HCC patients.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Neoplasias Hepáticas/sangue , Proteínas de Membrana/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio , Carcinoma Hepatocelular/patologia , Feminino , Hepatite B Crônica/sangue , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/sangue , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND AND AIM: Angiopoietin-like protein 2 (ANGPTL2) plays various roles in metabolism, vascular biology, inflammation, and tumor metastasis, but little is known about its function in human hepatocellular carcinoma (HCC) metastasis. This study aimed to further explore the function of ANGPTL2 on migration and invasion of liver cancer cells. METHODS: Quantitative real-time polymerase chain reaction, Western blotting, immunohistochemistry, transwell migration, and invasion assays were performed to clarify the function of ANGPTL2 in the regulation of cell migration and invasion in human HCC. RESULTS: In HCC patients, ANGPTL2 expression was higher in HCC tissues compared with matched noncancerous liver tissues. And the ANGPTL2 levels of HCC tissues positively correlated with intrahepatic metastasis in HCC patients. Overexpression of ANGPTL2 significantly increased migration and invasion of HCC cells in vitro, and promoted intrahepatic and distal pulmonary metastasis in vivo, while knockdown of endogenous ANGPTL2 resulted in a reduced migration and invasion in vitro. Colony formation assay and 3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay showed ANGPTL2 did not affect cell proliferation in vitro, whereas overexpression of ANGPTL2 promoted tumor formation in xenograft animal model. CONCLUSIONS: Our findings show that ANGPTL2 drives human HCC metastasis and provides a potential therapeutic target for HCC treatment.
Assuntos
Angiopoietinas/fisiologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteína 2 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Masculino , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Transplante de NeoplasiasRESUMO
BACKGROUND: Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined. METHODS AND FINDINGS: The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10-14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996-2000 and 2008-2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%-97%), 70% (95% CI 15%-89%), and 69% (95% CI 34%-85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%-30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%-75%). Receiving a booster at age 10-14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR]â = 0.68, 95% CI 0.47-0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up. CONCLUSIONS: Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series. Please see later in the article for the Editors' Summary.
Assuntos
Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Hepatopatias/epidemiologia , Neoplasias Hepáticas/epidemiologia , China , Hepatite B/imunologia , Humanos , Recém-Nascido , Vacinação/estatística & dados numéricosRESUMO
UNLABELLED: Nuclear factor kappa B (NF-κB) is an important factor linking inflammation and tumorigenesis. In this study we experimentally demonstrated through a high-throughput luciferase reporter screen that NF-κB signaling can be directly targeted by nearly 29 microRNAs (miRNAs). Many of these miRNAs can directly target NF-κB signaling nodes by binding to their 3' untranslated region (UTR). miR-195, a member of the miR-15 family, is frequently down-regulated in gastrointestinal cancers, especially in hepatocellular carcinoma (HCC). The expression level of miR-195 is inversely correlated with HCC tumor size. We further show that miR-195 suppresses cancer cell proliferation and migration in vitro and reduces tumorigenicity and metastasis in vivo. Additionally, miR-195 may exert its tumor suppressive function by decreasing the expression of multiple NF-κB downstream effectors by way of the direct targeting of IKKα and TAB3. CONCLUSION: Multiple miRNAs are involved in the NF-κB signaling pathway and miR-195 plays important inhibitory roles in cancer progression and may be a potential therapeutic target.
Assuntos
Carcinoma Hepatocelular/fisiopatologia , Quinase I-kappa B/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neoplasias Hepáticas/fisiopatologia , MicroRNAs/fisiologia , NF-kappa B/fisiologia , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Regiões 3' não Traduzidas/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Carcinogênese , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células , Progressão da Doença , Regulação para Baixo/fisiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Based on data from the population-based Qidong Cancer Registry, we report a survival analysis for female breast cancer patients diagnosed during 1972-2011 in order to assess the long-term trends for the prognosis of this cancer. METHODS: The last follow-up for survival status of the 3,398 registered female breast cancer cases was April, 2012. Cumulative observed survival (OS) and relative survival (RS) rates were calculated using Hakulinen's method performed by the SURV3.01 Software developed at the Finnish Cancer Registry. RESULTS: The one-, three-, five-, ten-, fifteen-, twenty-, thirty-, and forty- year OS rates were 83.61%, 67.53%, 58.75%, 48.56%, 42.57%, 38.30%, 29.19%, 19.35%; and the RS rates were 84.76%, 70.45%, 63.12%, 56.81%, 55.26%, 56.36%, 62.59%, 84.00%, respectively. Five-year RS rates of age groups 15-34, 35-44, 45-54, 55-64, 65-74, and 75+ were 60.17%, 68.27%, 67.79%, 56.03%, 55.50%, and 57.28%; 10-year RS rates were 54.16%, 59.59%, 61.34%, 47.78%, 51.30%, and 59.28%, respectively. There were statistical differences among the age groups (RS: χ2 = 152.15, P = 0.000). Remarkable improvement could be seen for the 5-year RS rates from 52.08% in 1972 to 69.26% in 2003-2007, and the 10-year RS rates from 43.16% in 1972 to 60.85% in 1998-2002, respectively. CONCLUSIONS: Survival outcomes from Qidong registered cases with breast cancer have shown gradual progress during the past 40 years. The disparities between survival rates of this area and developed countries are getting narrower, but there is still great need for improving survival in Qidong.
Assuntos
Neoplasias da Mama/mortalidade , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , China/epidemiologia , Feminino , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde , Humanos , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo , Adulto JovemRESUMO
AIM: To investigate the roles of mutations in enhancer II (Enh II), basal core promoter (BCP) and precore (PC) regions of hepatitis B virus (HBV) in the progression of hepatocellular carcinoma (HCC) in Qidong, China. METHODS: We conducted a case-control study within a cohort of 2387 male HBV carriers who were recruited between August and September 1996. The HBV DNA sequence was determined in 152 HCC and 131 chronic hepatitis patients. Mutation exchanges during follow up in 115 cases were compared with 108 controls with serum samples taken during a similar length of follow up. In addition, a longitudinal study was conducted in 22 cases in which serial serum samples were available before HCC. RESULTS: After adjustment for age, history of cigarette smoking and alcohol consumption, hepatitis B e-antigen positivity, T1653, V1753 and T1762/A1764 double mutations were associated with risk of HCC. Multivariate analysis showed that T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. Moreover, a significant biological gradient of HCC risk by number of mutations in Enh II/BCP regions was observed. Paired samples analysis indicated that the increased HCC risk for at-risk sequence mutations were attributable to the persistence of these mutations, but not a single time point mutation. The longitudinal observation demonstrated a gradual combination of mutations in Enh II/BCP regions accumulated during the development of HCC. CONCLUSION: T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. The effect of combined mutations in Enh II/BCP regions increased the risk and persistence of at-risk sequence mutations and was critical for HCC development.
RESUMO
OBJECTIVE: To evaluate whether first-degree family history of liver cancer plays a role in liver cancer incidence by prospective evaluation of a patient cohort in Qidong, China over a 20-year period. METHODS: In May 1992, 708 hepatitis B surface antigen (HBsAg) carriers and 730 HBsAg-negadve controls from Qidong city were enrolled for participation in a prospective cohort study ending in November 2012.Follow-up was carried out every 6 to 12 months, and evaluations included serum assays to measure concentrations of alpha fetoprotein (AFP), HBsAg and alanine aminotransferase (ALT), as well as abdominal ultrasound to assess liver disease.The relationship between baseline (study entry) information of patients with first-degree family history of liver cancer and liver cancer incidence during the two decades of study was statistically assessed. RESULTS: There were 172 newly diagnosed liver cancer cases in the cohort during 25 753 person-years (py) of follow-up, representing an incidence of 667.88/100 000 py.The incidence rates of liver cancer among participants with or without liver cancer family history were 1 244.36/100 000 py and 509.70/100 000 py respectively, and the between-group difference reached the threshold for statistical significance (P less than 0.01, Relative Risk (RR):2.44, 95% Confidence Interval (CI):1.80-3.31).The incidence rates of liver cancer among participants who had a sibling with liver cancer and participants who had a parent with liver cancer were not significantly different (P > 0.05), but the liver cancer incidence among participants who had a mother with liver cancer was significantly higher than that of participants who had a father with liver cancer (P < 0.05, RR:1.86, 95% CI:1.03-3.36). Among the participants with liver cancer family history, 56.52% (39/69) were diagnosed before 50 years old, and this rate was significantly higher than that of participants without a family history of liver cancer (40.78%, 42/103, P less than 0.05).The incidence rate of liver cancer among the participants who were family history-positive and HBsAg-positive was significantly higher than that of participants who were family history-negative but HBsAg-positive (P < 0.01, RR:1.75, 95% CI:1.29-2.38), and was 59.59 times higher than for participants who were family history-negative and HBsAgnegative.Subgroup analysis of liver cancer incidence among participants who were family history-positive but HBsAg-negative and participants who were family history-negative and HBsAg-negative produced anRR of 2.60, but there was no statistically significant difference between the two subgroups (P > 0.05).At the study's end, the incidence rates of liver cancer for the different subgroups were 32.21% for the family history-positive and HBsAgpositive participants, 19.80% for the family history-negative and HBsAg-positive participants, 1.71% for the family history-positive and HBsAg-negative participants, and 0.65% for the family history-negative and HBsAg-negative participants. CONCLUSION: First-degree family history of liver cancer is a risk factor of liver cancer in Chinese patients from Qidong, and exhibits synergism with HBsAg-positivity for incidence of liver cancer.