Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Clin Med Insights Oncol ; 16: 11795549221090186, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35509769

RESUMO

Background: Pancreatic acinar cell carcinoma (PACC) is rare, and its appropriate treatment remains unknown. We aim to explore the characteristics and optimal treatment of it. Methods: The data on clinicopathologic characteristics, molecular alteration, treatment, and survival of patients diagnosed with PACC at the Sun Yat-sen University Cancer Center from 2005 to 2020 were collected. The optimal treatment was explored by co-analyzing our results and published literatures. Results: Twenty-two PACC patients were enrolled. Eight of 17 non-metastatic patients received adjuvant chemotherapy. The patients receiving fluoropyrimidine-based regimen (n = 3) had a better median disease-free survival (mDFS) than those with gemcitabine-based regimen (n = 5) (unreached vs 27 months). Eight metastatic patients received first-line chemotherapy. Four patients received second-line chemotherapy. The objective response rate (ORR) of the fluoropyrimidine-based regimen was 85.7% (6/7), much better than that of the gemcitabine-based regimen (0/5). One patient who had responded to the first-line FOLFIRINOX (5-fluorouracil + oxaliplatin + leucovorin + irinotecan) regimen received olaparib as maintenance treatment for 5 months with good tolerance. Thirty-one published literatures, with a total of 86 cases, were included in the co-analysis. The ORR of the first-line fluoropyrimidine-based regimen (n = 47) was higher than that of gemcitabine-based regimen (n = 39) (59.6% vs 15.3%, P < .001). Eight of 11 patients treated with the FOLFIRINOX regimen achieved partial response (PR). Conclusions: For patients with metastasis, a fluorouracil-based regimen such as FOLFIRINOX may be preferred, and maintenance treatment of poly ADP-ribose polymerase (PARP) inhibitors after effective platinum-containing treatment for breast cancer susceptibility gene (BRCA) mutation patients must be assessed.

2.
Cancer Lett ; 526: 236-247, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34767927

RESUMO

Nuclear pore complex (NPC) embedded in the nuclear envelope, is the only channel for macromolecule nucleocytoplasmic transportation and has important biological functions. However, the deregulation of specific nucleoporins (Nups) and NPC-Nup-based mechanisms and their function in tumour progression remain poorly understood. Here, we aimed to identify the Nups that contribute to HCC progression and metastasis in 729 primary hepatocellular carcinoma (HCC) cases using molecular, cytological, and biochemical techniques. Our results revealed elevated Nup93 expression in HCC tissues, especially in cases with metastasis, and was linked to worse prognosis. Furthermore, Nup93 knockdown suppressed HCC cell metastasis and proliferation, while Nup93 overexpression promoted these activities. We observed that Nup93 promotes HCC metastasis and proliferation by regulating ß-catenin translocation. In addition, we found that Nup93 interacted with ß-catenin directly, independent of importin. Furthermore, LEF1 and ß-catenin facilitated the Nup93-mediated metastasis and proliferation in HCC via a positive feedback loop. Thus, our findings provide novel insights into the mechanisms underlying the Nup93-induced promotion of HCC metastasis and suggest potential therapeutic targets in the LEF1-Nup93-ß-catenin pathway for HCC therapeutics.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , beta Catenina/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Metástase Neoplásica , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Fosforilação , Transdução de Sinais , Transcrição Genética
3.
Am J Cancer Res ; 11(10): 5006-5015, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765307

RESUMO

Gastric cancer (GC) patients with Epstein-Barr virus (EBV) positivity have demonstrated promising response with immunotherapy. We assessed the efficacy and safety of camrelizumab as salvage treatment in EBV-positive mGC. In this single-arm, phase 2 prospective clinical trial (NCT03755440), stage IV EBV-positive GC patients who failed/could not tolerate previous lines of chemotherapy were given intravenous camrelizumab 200 mg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response, and toxicity. Exploratory analysis included the associations between treatment response and tumor mutation burden (TMB), programmed cell death ligand-1 (PD-L1) expression. Six eligible patients were enrolled in the first stage of the study. No patient achieved an objective response; thus, the study did not proceed to the second stage. The DCR was 67% (4/6). The median PFS rate was 2.2 months (95% CI: 1.5-not reached [NR]) and median OS was 6.8 months (95% CI: 1.7-NR). All treatment-related adverse events were grade 1-2, with reactive cutaneous capillary endothelial proliferation (n=4 [67%]) being the most commonly observed event. The only patient with PD-L1 combined positive score >1 had disease progression. Two stable disease and one disease progression were observed in three patients with TMB >10 Mut/Mb. EBV positivity may not be a good predictor for response to camrelizumab in mGC. Newer biomarkers are needed to identify EBV-positive mGC respondents who might benefit from immunotherapy.

4.
Br J Cancer ; 124(12): 1988-1996, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824478

RESUMO

BACKGROUND: Pathologic diagnosis of hepatocellular carcinoma (HCC) can be challenging in differentiating from benign and non-hepatocytic malignancy lesions. The aim of this study was to investigate the potential utility of α-fetoprotein (AFP) mRNA RNAscope, a sensitive and specific method, in the diagnosis of HCC. METHODS: Three independent retrospective cohorts containing 2216 patients with HCC, benign liver lesions, and non-hepatocytic tumours were examined. AFP was detected using ELISA, IHC (Immunohistochemistry), and RNAscope. Glypican3 (GPC3), hepatocyte paraffin-1 (HepPar-1), and arginase-1 (Arg-1) proteins were detected using IHC. RESULTS: AFP RNAscope improved the HCC detection sensitivity by 24.7-32.7% compared with IHC. In two surgical cohorts, a panel of AFP RNAscope and GPC3 provided the best diagnostic value in differentiating HCC from benign hepatocytic lesions (AUC = 0.905 and 0.811), and a panel including AFP RNAscope, GPC3, HepPar-1, and Arg-1 yielded the best AUC (0.971 and 0.977) when distinguishing HCC from non-hepatocytic malignancies. The results from the liver biopsy cohort were similar, and additional application of AFP RNAscope improved the sensitivity by 18% when distinguishing HCC from benign hepatocytic lesions. CONCLUSIONS: AFP mRNA detected by RNAscope is highly specific for hepatocytic malignancy and may serve as a novel diagnostic biomarker for HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , alfa-Fetoproteínas/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Estudos de Coortes , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Hibridização In Situ , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Valor Preditivo dos Testes , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade , Análise Serial de Tecidos , alfa-Fetoproteínas/metabolismo
5.
Ther Adv Med Oncol ; 12: 1758835920937434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670421

RESUMO

BACKGROUND: Epstein-Barr virus-associated gastric cancer (EBVaGC) has unique clinicopathologic features and our present understanding of its treatment outcome is limited. Here, we investigated the clinical outcomes of resectable and metastatic EBVaGC cases with regards to their respective treatment. METHODS: We retrieved the data of EBVaGC patients treated at our center from October 2014 to June 2019. The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) for stage I-III patients, progression-free survival (PFS) and objective response rate (ORR) for stage IV patients. RESULTS: Patients classified as stage I-III accounted for 83.7% of the total 197 cases analyzed. Two patients had mismatched repair-deficiency. The 5-year OS rate of the entire cohort was 63.51% [95% (confidence interval (CI): 52.31-72.76%]. Tumor-node-metastasis (TNM) stage and gastric stump cancer were identified as independent prognostic factors for OS. The 3- and 5-year DFS rate for stage I-III patients were 83.72% (95% CI: 75.86-89.19%) and 73.83% (95% CI: 60.39-83.32%), respectively. TNM stage III, neural invasion, lymphovascular invasion, and baseline plasma EBV-DNA positive were correlated with shorter DFS. The ORR and disease control rate (DCR) for metastatic EBVaGC patients to first-line therapy were 29.0% and 90.3% (median PFS: 9.8 months), respectively, and to second-line therapy were 25.0% and 75.0%, respectively. Seven patients received anti-PD1 therapy and had an ORR of 28.5% and a median PFS of 2.8 months. CONCLUSIONS: EBVaGC patients have few metastases, long DFS, and high DCR. TNM stage and gastric stump cancer were independent prognostic factors for OS.

6.
Clin Transl Med ; 10(1): 353-362, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32508039

RESUMO

PURPOSE: To identify how Epstein-Barr virus (EBV) status combined with molecular profiling predicts the prognosis of gastric cancer patients and their associated clinical actionable biomarkers. EXPERIMENTAL DESIGN: A next-generation sequencing assay targeting 295 cancer-related genes was performed in 73 EBV-associated gastric cancer (EBVaGC) and 75 EBV-negative gastric cancer (EBVnGC) specimens and these results were compared with overall survival (OS). RESULTS: PIK3CA, ARID1A, SMAD4, and PIK3R1 mutated significantly more frequently in EBVaGC compared with their corresponding mutation rate in EBVnGC. As the most frequently mutated gene in EBVnGC (62.7%), TP53 also displayed a mutation rate of 15.1% in EBVaGC. PIK3R1 was revealed as a novel mutated gene (11.0%) associated almost exclusively with EBVaGC. PIK3CA, SMAD4, PIK3R1, and BCOR were revealed to be unique driver genes in EBVaGC. ARID1A displayed a significantly large proportion of inactivated variants in EBVaGC. A notable finding was that integrating the EBV status with tumor mutation burden (TMB) and large genomic instability (LGI) categorized the tumors into four distinct molecular subtypes and optimally predicted patient prognosis. The corresponding median OSs for the EBV+/TMB-high, EBV+/TMB-low, EBV-/LGI-, and EBV-/LGI+ subtypes were 96.2, 75.3, 44.4, and 20.2 months, respectively. The different subtypes were significantly segregated according to distinct mutational profiles and pathways. CONCLUSIONS: Novel mutations in PIK3R1 and TP53 genes, driver genes such as PIK3CA, SMAD4, PIK3R1, BCOR, and ARID1A, and distinguished genomic profiles from EBVnGC were identified in EBVaGC tumors. The classification of gastric cancer by EBV, TMB, and LGI could be a good prognostic indicator, and provides distinguishing, targetable markers for treatment.

7.
Int J Cancer ; 146(1): 272-280, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162842

RESUMO

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.


Assuntos
DNA Viral/sangue , Herpesvirus Humano 4/isolamento & purificação , Neoplasias Gástricas/virologia , Carga Viral , Idoso , Feminino , Herpesvirus Humano 4/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
8.
Mol Oncol ; 14(2): 373-386, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31670863

RESUMO

Hepatocellular carcinoma (HCC), with its ineffective therapeutic options and poor prognosis, represents a global threat. In the present study, we show that RAD52 motif 1 (RDM1), a key regulator of DNA double-strand break repair and recombination, is downregulated in HCC tissues and suppresses tumor growth. In clinical HCC samples, low expression of RDM1 correlates with larger tumor size, poor tumor differentiation, and unfavorable survival. In vitro and in vivo data demonstrate that knockdown of RDM1 increases HCC cell proliferation, colony formation, and cell population at G2/M phase, whereas RDM1 overexpression results in the opposite phenotypes. Mechanistically, RDM1 binds to the tumor suppressor p53 and enhances its protein stability. In the presence of p53, RDM1 suppresses the phosphorylation of Raf and ERK. Overexpression of p53 or treatment with ERK inhibitor significantly abolishes cell proliferation induced by the depletion of RDM1. In addition, overexpression of methyltransferase-like 3 markedly induces N6-methyladenosine modification of RDM1 mRNA and represses its expression. Taken together, our study indicates that RDM1 functions as a tumor suppressor and may be a potential prognostic and therapeutic factor for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Metiltransferases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Metilação , Metiltransferases/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/metabolismo
9.
Mod Pathol ; 32(11): 1646-1656, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31231126

RESUMO

Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28-8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells [tumor proportion score] together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28-8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28-8 and SP263 assays. In conclusion, the 22C3, 28-8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/imunologia , Imuno-Histoquímica/métodos , Neoplasias Hepáticas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes
10.
J Mol Med (Berl) ; 97(8): 1213-1214, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203376

RESUMO

In Figure 7f the panel for c-myc of MDA-MB-468 was erroneously duplicated. The corrected version of the figure is shown in this paper. This correction does not influence the conclusion of the study and we sincerely apologize for this oversight.

11.
Hepatology ; 69(1): 179-195, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30028541

RESUMO

Deregulation of alternative splicing contributes to the malignant progression of cancer. Little is known about the significant alternative splicing events in hepatocellular carcinoma (HCC). High-throughput sequencing revealed that coiled-coil domain containing 50 (CCDC50) pre-mRNA is aberrantly spliced in 50% of our HCC cases. A BaseScope assay was performed to examine the expression of CCDC50S (a truncated oncogenic splice variant) in HCC tissues. Compared with benign liver tumors and several other types of solid tumors, CCDC50S mRNA was up-regulated in HCC, with a diagnostic potential (sensitivity, 0.711; specificity, 0.793). High expression of CCDC50S mRNA in HCC was significantly correlated with poor tumor differentiation, advanced tumor node metastasis (TNM) stage, and unfavorable prognosis. Overexpression of CCDC50S exerted tumorigenic activities that promoted HCC growth and metastasis by activation of Ras/forkhead box protein O4 (Foxo4) signaling. Either suppression of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation or overexpression of Foxo4 markedly attenuated CCDC50S-mediated phenotypes. Furthermore, serine- and arginine-rich splicing factor 3 (SRSF3) directly bound to CCDC50S mRNA to maintain its stability in the cytoplasm. The cytosolic retention of SRSF3 was mediated by the interaction of hepatitis B virus-encoded X protein (HBx) and 14-3-3ß. Ectopic HBx expression induced expression of cytosolic SRSF3 and CCDC50S. Conclusion: Our study provided compelling evidence that up-regulation of CCDC50S was modulated by HBx/SRSF3/14-3-3ß complex and enhanced oncogenic progression of HCC through the Ras/Foxo4 signaling pathway. These data suggest that CCDC50S may serve as a diagnostic and prognostic biomarker and probably a promising therapeutic target in HCC.


Assuntos
Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Fatores de Processamento de Serina-Arginina/fisiologia , Transdução de Sinais/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C
12.
Cancer Res ; 79(3): 534-545, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30584071

RESUMO

Hepatocellular carcinogenesis is attributed to the reprogramming of cellular metabolism as a consequence of the alteration in metabolite-related gene regulation. Identifying the mechanism of aberrant metabolism is of great potential to provide novel targets for the treatment of hepatocellular carcinoma (HCC). Here, we demonstrated that glycogen synthase 2 (GYS2) restricted tumor growth in hepatitis B virus-related HCC via a negative feedback loop with p53. Expression of GYS2 was significantly downregulated in HCC and correlated with decreased glycogen content and unfavorable patient outcomes. GYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 expression. GYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation. Furthermore, GYS2 enhanced the p300-induced acetylation of p53 at K373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex. In summary, our findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC. SIGNIFICANCE: We elucidated the clinical significance, biological function, and regulation of the HBx/GYS2/p53 axis, which supplement the understanding of tumor glycogen metabolism and provide potential prognostic and therapeutic targets for HCC treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/3/534/F1.large.jpg.


Assuntos
Carcinoma Hepatocelular/metabolismo , Glicogênio Sintase/metabolismo , Hepatite B Crônica/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Retroalimentação Fisiológica , Células Hep G2 , Vírus da Hepatite B , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Análise Serial de Tecidos
13.
Cancer Manag Res ; 10: 2241-2248, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30100755

RESUMO

Introduction: Prenylated Rab acceptor 1 domain family member 2 (PRAF2), a novel oncogene, has been shown to be essential for the development of several human cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. Materials and methods: PRAF2 mRNA and protein expressions were examined in fresh tissues by quantitative reverse transcription-polymerase chain reaction and Western blot, respectively, and in 518 paraffin-embedded HCC samples by immunohistochemistry. The correlation of PRAF2 expression and clinical outcomes was determined by the Student's t-test, Kaplan-Meier test, and multivariate Cox regression analysis. The role of PRAF2 in HCC was investigated by cell viability, colony formation, and migration assays in vitro and with a nude mouse model in vivo. Results: In our study, the PRAF2 expression was noticeably increased in HCC tissues at both the mRNA and protein levels compared with that of the nontumorous tissues. Kaplan-Meier analysis indicated that high PRAF2 expression was correlated with worse overall survival in a cohort of 518 patients with HCC. The prognostic implication of PRAF2 was verified by stratified survival analysis. The multivariate Cox regression model revealed PRAF2 as an independent poor prognostic factor for overall survival (hazard ratio = 1.244, 95% CI: 1.039-1.498, P<0.017) in HCC. The in vitro data demonstrated that PRAF2 overexpression markedly enhanced cell viability, colony formation, and cell migration. Moreover, ectopic expression of PRAF2 promoted tumor growth and metastasis in vivo. Conclusion: Collectively, we conclude that PRAF2 is increased in HCC and is a novel unfavorable biomarker for prognostic prediction for patients with HCC.

14.
Neoplasia ; 20(5): 411-424, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29573636

RESUMO

The ubiquitin-proteasome system is implicated in cell apoptosis that is frequently dysregulated in human cancers. POH1/rpn11/PSMD14, as a part of the 19S proteasomal subunit, contributes to the progression of malignancy, but its role in apoptosis remains unclear. Here, we showed that POH1 expression was increased and associated with poor outcomes in three independent cohorts of patients with hepatocellular carcinoma (HCC), esophageal cancer (EC), and colorectal cancer (CRC). The knockdown of POH1 significantly inhibited tumor cell proliferation and induced apoptosis mediated by the mitochondrial pathway in vitro. Intratumoral injection of POH1 small interfering RNA (siRNA) significantly reduced the progression of tumor growth and induced apoptosis in vivo. Furthermore, p53 or Bim siRNA markedly attenuated the apoptosis induced by POH1 depletion. POH1 depletion resulted in cell apoptosis by increasing the stability of p53 and Bim and inhibiting their ubiquitination. Overall, POH1 knockdown induced cell apoptosis through increased expression of p53 and Bim via enhanced protein stability and attenuated degradation. Thus, POH1 may serve as a potential prognostic marker and therapeutic target in human cancers.


Assuntos
Apoptose/genética , Proteína 11 Semelhante a Bcl-2/genética , Proliferação de Células/genética , Neoplasias/genética , Complexo de Endopeptidases do Proteassoma/genética , Transativadores/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/genética , Ubiquitina/genética , Ubiquitinação/genética
15.
Transl Oncol ; 11(1): 125-131, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29248802

RESUMO

Liver is a major contributor of protein production physiologically. The aberrant state of protein synthesis leads to tumor progression. Eukaryotic elongation factor 1 alpha 1 (eEF1A1) is a major member of the eukaryotic elongation factor family that regulates protein synthesis. Although eEF1A1 plays an essential role in controlling the cell fate, its clinical significance in tumor development and progression has not been reported. Here, we aimed to uncover the expression and prognostic significance of eEF1A1 in hepatocellular carcinoma (HCC). Our data indicated that eEF1A1 expression was elevated in HCC cell lines and clinical samples at both the mRNA and protein levels. Immunohistochemistry revealed that eEF1A1 expression was upregulated in HCC samples compared with corresponding non-tumorous tissues. In 50 HCC cases with portal vein embolus, higher eEF1A1 immunoreactivity was detected in tumor metastases compared with the primary lesions. Kaplan-Meier analysis indicated that increased eEF1A1 expression was closely associated with unfavorable post-surgical overall and disease-free survival in 453 HCC patients. Moreover, multivariate analysis indicated eEF1A1 as an independent predictor for overall and disease-free survival. Collectively, our study suggests eEF1A1 as a novel prognostic biomarker and potential therapeutic target for HCC patients.

16.
Sci Rep ; 7(1): 16043, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29167471

RESUMO

Approximately 30% of locally advanced rectal cancer patients might not benefit from chemoradiotherapy; however, the response to neoadjuvant chemoradiotherapy in these cases is difficult to predict. Pim-3 is a member of the provirus integration site for a moloney murine leukemia virus family of proteins that contributes to cell proliferation, survival, and chemotherapy resistance. Therefore, the relationship between Pim-3 expression and response to neoadjuvant chemoradiotherapy in rectal cancer patients is important to evaluate. 175 rectal cancer patients who underwent neoadjuvant treatment enrolled in this study. The relationship between Pim-3 expression on immunohistochemical analysis of rectal cancer tissue, which was obtained before treatment, the response to chemoradiotherapy and survival was investigated. The patients with no Pim-3 expression were more likely to achieve a pathologic complete response to chemoradiotherapy than patients with Pim-3 expression (P = 0.001). Cox multivariate analysis showed that the significant prognostic factors were Pim-3 expression (P = 0.003) and the number of neoadjuvant chemotherapy cycles (P = 0.005) for overall survival. Neoadjuvant chemotherapy cycles (P = 0.007), adjuvant chemotherapy cycles (P = 0.004) and pathology types (P = 0.049) were significant prognostic factors for disease-free survival. Pim-3 is a potential predictive biomarker for the response of rectal cancer to chemoradiotherapy.


Assuntos
/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/terapia , Adulto , Capecitabina/uso terapêutico , Quimiorradioterapia , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Oxaliplatina/uso terapêutico , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Resultado do Tratamento
17.
Therap Adv Gastroenterol ; 10(10): 761-771, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29051787

RESUMO

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. METHODS: A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan-Meier analysis was conducted to assess the prognostic value of P2-HNF4α. RESULTS: The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression (p = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC (p = 0.002) and vascular invasion (p = 0.017). Kaplan-Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group (p = 0.01), validation group (p = 0.034), and overall group of patients with HCC (p < 0.001). CONCLUSIONS: Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

18.
Cancer Lett ; 402: 71-80, 2017 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28577975

RESUMO

The dysregulation of transcription factors contributes to the unlimited growth of cancer cells. Zic2 has been shown to be crucial to the progression of human cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. Our data showed that Zic2 expression gradually increased from normal to cancer to metastatic tissues. Zic2 overexpression promoted, whereas Zic2 knockdown inhibited, cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Gene microarray results indicated that PAK4 was a potential target of Zic2. The knockdown of Zic2 decreased, whereas Zic2 re-expression increased, the expression of PAK4. ChIP and luciferase assays indicated that Zic2 directly bound to the PAK4 promoter and modulated its activity. PAK4 interference attenuated Zic2-mediated cell growth via modulating the Raf/MEK/ERK pathway. In a cohort of 615 patients, Zic2 was positively correlated with PAK4 and associated with worse overall and disease-free survival. Multivariate analyses revealed that Zic2 and PAK4 were independent indicators of a poor outcome in HCC. In addition, Zic2 expression was inversely correlated with miR-1271 expression. Re-introduction of miR-1271 attenuated Zic2-promoted cell proliferation and migration. Taken together, our findings suggest that the newly identified miR-1271/Zic2/PAK4 axis plays an important role in HCC progression and may serve as a potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Movimento Celular , Proliferação de Células , Neoplasias Hepáticas/enzimologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Sítios de Ligação , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/secundário , Linhagem Celular Tumoral , Progressão da Doença , Intervalo Livre de Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Análise Multivariada , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Fatores de Transcrição/genética , Transcrição Genética , Ativação Transcricional , Transfecção , Carga Tumoral , Regulação para Cima , Quinases Ativadas por p21/genética , Quinases raf/metabolismo
19.
Mol Oncol ; 11(9): 1225-1240, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28580773

RESUMO

Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post-translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial-mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx-induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus-related HCC, as well as a possible therapeutic target for tumor metastasis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Transativadores/metabolismo , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Regulação para Baixo/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Transição Epitelial-Mesenquimal/genética , Fibronectinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Metástase Neoplásica , Ligação Proteica/genética , Proteólise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resultado do Tratamento , Ubiquitinação/genética , Proteínas Virais Reguladoras e Acessórias
20.
J Mol Med (Berl) ; 95(8): 873-886, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28523467

RESUMO

Cystatin SN (CST1) belongs to the type 2 cystatin (CST) superfamily, which restricts the proteolytic activities of cysteine proteases. CST1 has been recently considered to be involved in the development of several human cancers. However, the prognostic significance and function of CST1 in breast cancer remains unknown. In the current study, we found that CST1 was generally upregulated in breast cancer at both mRNA and protein level. Furthermore, overall survival (OS) and disease-free survival (DFS) in the low CST1 expression subgroup were significantly superior to the high CST1 expression subgroup (OS, p < 0.001; DFS, p < 0.001), which indicated that CST1 expression level was closely correlated to the survival risk of these patients. Univariate and multivariate analyses demonstrated that CST1 expression was an independent prognostic factor, the same as ER status and nodal status. Next, CST1 overexpression promoted breast cancer cell proliferation, clonogenicity, migration, and invasion abilities. By contrast, knockdown of CST1 attenuated these malignant characteristics in breast cancer cells. Collectively, our study indicates that CST1 cannot only serve as a significant prognostic indicator but also as a potential therapeutic target for breast cancer. KEY MESSAGES: High CST1 expression is negatively correlated with survival of breast cancer patients. CST1 promotes cell proliferation, clone formation, and metastasis in breast cancer cells. CST1 is a novel potential prognostic biomarker and therapeutic target for breast cancer.


Assuntos
Neoplasias da Mama/patologia , Cistatinas Salivares/genética , Cistatinas Salivares/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Feminino , Humanos , Prognóstico , RNA Interferente Pequeno/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...