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1.
J Hepatol ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34509526

RESUMO

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with high aggressiveness and extremely poor prognosis. The role of circular RNAs (circRNAs) in ICC carcinogenesis and progression remains to be determined. METHODS: CircRNA microarray was performed to screen significantly up-regulated circRNAs in paired ICC and non-tumor tissues. Colony formation, transwell, and xenograft models were used to examine the role of circRNAs in ICC proliferation and metastasis. RNA pulldown, mass spectrometry, chromatin immunoprecipitation, RNA binding protein immunoprecipitation, chromatin isolation by RNA purification, electrophoretic mobility shift assay, and luciferase reporter assays were used to explore the molecular sponge role of the circRNA via binding to miRNAs, and the interaction between circRNA and RNA-binding proteins. RESULTS: Hsa_circ_0050898, which originated from exon 1 to exon 20 of the ACTN4 gene (named as circACTN4), was significantly upregulated in ICC. High circACTN4 expression was associated with enhanced tumor proliferation and metastasis in vitro and in vivo, as well as a worse prognosis following ICC resection. In addition, circACTN4 upregulated Yes-associated protein1 (YAP1) expression by sponging miR-424-5p. More importantly, circACTN4 also recruited Y-box binding protein 1 (YBX1) to stimulate Frizzled-7 (FZD7) transcription. Furthermore, circACTN4 overexpression in ICC cells enhanced the interaction between YAP1 and ß-catenin, which are the core components of the Hippo and Wnt signaling pathways, respectively. CONCLUSIONS: CircACTN4 was upregulated in ICC and promoted ICC proliferation and metastasis by acting as a molecular sponge of miR-424-5p, as well as by interacting with YBX1 to transcriptionally activate FZD7. These results suggested that circACTN4 is a potential prognostic marker and therapeutic target for ICC. LAY SUMMARY: A circular RNA (circACTN4) was highly expressed in intrahepatic cholangiocarcinoma (ICC). The expression level of circACTN4 was positively associated with tumor growth and metastasis through both the Hippo and Wnt signaling pathways.

2.
Cancer Med ; 10(20): 6985-6997, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34405567

RESUMO

OBJECTIVE: We explored the impact of clinically significant portal hypertension (CSPH) on short- and long-term outcomes of intrahepatic cholangiocarcinoma (ICC) after liver resection (LR). METHODS: Data of 352 ICC patients with cirrhosis who underwent LR were extracted from the Primary Liver Cancer Big Data (PLCBD) between 2005 and 2015 and reviewed. A nomogram based on logistic analyses was developed to illustrate the influencing factors of post-hepatectomy liver failure (PHLF). The impact of CSPH on long-term survival was explored through propensity score matching (PSM) analysis, log-rank test, Cox proportional hazards model, and Kaplan-Meier curves. RESULTS: A total of 106 patients had CSPH, and 246 patients did not. A nomogram established based on GGT level, CSPH, intraoperative blood loss, and multiple tumors had an area under the receiver operating characteristic curve of 0.721 (95% confidence interval [CI] = 0.630-0.812), which displayed a better PHLF predictive value than the MELD score (0.639, 95% CI = 0.532-0.747) and Child-Pugh score (0.612, 95% CI = 0.506-0.719). Moreover, the patients with CSPH had worse overall survival (OS) rates than the patients without CSPH in the whole cohort (p = 0.011) and PSM cohort (p = 0.017). After PSM, multivariable Cox analyses identified that CSPH was an independent risk factor for OS (hazard ratio = 1.585, 95% CI = 1.107-2.269; p = 0.012). CONCLUSION: CSPH is a significant risk factor for PHLF and OS in ICC patients with cirrhosis after surgery. Selecting the proper patients before operation can effectively avoid PHLF and improve the prognosis of ICC.

3.
J Cell Mol Med ; 25(12): 5615-5627, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33942483

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with aggressive biological behaviour. Its rapid proliferation and tumour growth require reprogramming of glucose metabolism or the Warburg effect. However, the association between glycolysis-related genes with clinical features and prognosis of PDAC is still unknown. Here, we used the meta-analysis to correlate the hazard ratios (HR) of 106 glycolysis genes from MSigDB by the cox proportional hazards regression analysis in 6 clinical data sets of PDAC patients to form a training cohort, and a single group of PDAC patients from the TCGA, ICGC, Arrayexpress and GEO databases to form the validation cohort. Then, a glycolysis-related prognosis (GRP) score based on 29 glycolysis prognostic genes was established in 757 PDAC patients from the training composite cohort and validated in 267 ICGC-CA validation cohort (all P < .05). In addition, including PADC, the prognostic value was also confirmed in other 7 out of 30 pan-cancer cohorts. The GRP score was significantly related to specific metabolism pathways, immune genes and immune cells in the patients with PADC (all P < .05). Finally, by combining with immune cells, the GRP score also well-predicted the chemosensitivity of patients with PADC in the TCGA cohort (AUC = 0.709). In conclusion, this study developed a GRP score for patients with PDAC in predicting prognosis and chemosensitivity for PDAC.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Regulação Neoplásica da Expressão Gênica , Glicólise , Neoplasias Pancreáticas/patologia , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Perfilação da Expressão Gênica , Humanos , Metanálise como Assunto , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , Taxa de Sobrevida
4.
Cell Death Dis ; 11(10): 894, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093444

RESUMO

Long non-coding RNAs (lncRNAs) have extremely complex roles in the progression of intrahepatic cholangiocarcinoma (ICC) and remain to be elucidated. By cytological and animal model experiments, this study demonstrated that the expression of lncRNA MNX1-AS1 was remarkably elevated in ICC cell lines and tissues, and was highly and positively correlated with motor neuron and pancreas homeobox protein 1 (MNX1) expression. MNX1-AS1 significantly facilitated the proliferation, migration, invasion, and angiogenesis in ICC cells in vitro, and remarkably promoted tumor growth and metastasis in vivo. Further study revealed that MNX1-AS1 promoted the expression of MNX1 via recruiting transcription factors c-Myc and myc-associated zinc finger protein (MAZ). Furthermore, MNX1 upregulated the expression of Ajuba protein via binding to its promoter region, and subsequently, Ajuba protein suppressed the Hippo signaling pathway. Taken together, our results uncovered that MNX1-AS1 can facilitate ICC progression via MNX1-AS1/c-Myc and MAZ/MNX1/Ajuba/Hippo pathway, suggesting that MNX1-AS1 may be able to serve as a potential target for ICC treatment.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Proteínas de Homeodomínio/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , RNA Longo não Codificante/fisiologia , Fatores de Transcrição/fisiologia , Adulto , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Front Oncol ; 10: 1210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903581

RESUMO

Hepatocellular carcinoma (HCC) samples were clustered into three energy metabolism-related molecular subtypes (C1, C2, and C3) with different prognosis using the gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). HCC energy metabolism-related molecular subtype analysis was conducted based on the 594 energy metabolism genes. Differential expression analysis yielded 576 differentially expressed genes (DEGs) among the three subtypes, which were closely related to HCC progression. Six genes were finally selected from the 576 DEGs through LASSO-Cox regression and used in constructing a six-gene signature-associated prognostic risk model, which was validated using the TCGA internal and three GEO external validation cohorts. The risk model showed that high ANLN, ENTPD2, TRIP13, PLAC8, and G6PD expression levels were associated with bad prognosis, and high expression of ADH1C was associated with a good prognosis. The validation results showed that our risk model had a high distinguishing ability of prognosis in HCC patients. The four enriched pathways of the risk model were obtained by gene set enrichment analysis (GSEA) and found to be associated with the tumorigenesis and development of HCC, including the cell cycle, Wnt signaling pathway, drug metabolism cytochrome P450, and primary bile acid biosynthesis. The risk score calculated from the established risk model in 204 samples and other clinical characteristics were used in building a nomogram with a good prognostic prediction ability (C-index = 0.746, 95% CI = 0.714-0.777). The area under the curves (AUCs) of the nomogram model in 1-, 2-, and 3-years were 0.82, 0.77, and 0.79, respectively. Then, qRT-PCR and immunohistochemistry were used to validate the mRNA expression levels of the six genes, and significant differences in mRNA and gene expression were observed among the tumor and adjacent tissues. Overall, our study divided HCC patients into three energy metabolism-related molecular subtypes with different prognosis. Then, a risk model with a good performance in prognostic prediction was built using the TCGA dataset. This model can be used as an independent prognostic evaluation index for HCC patients.

6.
J Cancer ; 11(19): 5623-5634, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32913457

RESUMO

Background: This study aimed to establish a model predicting the prognosis of intrahepatic cholangiocarcinoma (ICC) patients with cirrhosis before liver resection (LR). Methods: An Eastern Hepatobiliary Surgery Hospital (EHBH) model using the preoperative factors was established in a training cohort (305 patients from 2006 to 2011) and validated in an internal validation cohort (113 patients from 2012 to 2014). Predictive performance and discrimination were evaluated and compared with other staging systems. Results: The EHBH model containing preoperative factors of carbohydrate antigen 19-9 (CA19-9), radiological tumor diameter, tumor number, and satellite nodules outperformed other staging systems in predicting the prognosis of ICC. A contour plot of 3-year survival probability and a nomogram to form two differentiated groups of patients (high-risk group and low-risk group) were constructed based on the EHBH model to help surgeons predicting the overall survival (OS) before LR. Patients from the high-risk group (>86.56 points) in the training cohort had worse OS rates compared with those from the low-risk group (≤86.56 points). The one-, three-, and five-year OS rates were 50.4%, 29.0%, and 21.0% for the high-risk group and 68.2%, 45.5%, and 39.7% for the low-risk group, respectively (P<0.001). The same results were obtained in the internal validation patients. Conclusion: The contour plot is an easy-to-use tool to individually show the 3-year prognosis of ICC patients with different preoperative CA19-9 values and radiological characteristics before surgery. The EHBH model was suitable for selecting cirrhotic patients for LR to acquire a better survival.

7.
J Cancer ; 11(17): 4947-4956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742442

RESUMO

Background: This study developed a novel inflammation score system to predict survival outcomes using preoperational inflammatory markers in hepatocellular carcinoma (HCC) after surgery. Materials and Methods: An inflammation score system was developed using five preoperative inflammatory markers based on the clinical data of 455 HCC patients (training cohort) receiving radical resection in the Eastern Hepatobiliary Surgery Hospital. The system was validated using a cohort from a different hospital (external validation). Kaplan-Meier curves and log-rank test were used to compare the survival of patients with different inflammation scores. A nomogram including inflammation scores for survival prediction was created to exhibit the risk factors of overall survival (OS). Results: The patients in the low-score group showed better OS and recurrence-free survival (RFS) in the training and external validation cohorts than those from the high-score group. Subgroup analysis showed that compared with patients in the training cohort from the high-score group, stage I (eighth TNM stage) patients in the low-score group exhibited better prognosis results, whereas the findings for Stage II and III patients were different. Multivariate Cox analysis revealed that high inflammation score is an independent risk factor of OS and RFS. The nomogram established using the inflammation score with the C-index value of 0.661 (95% confidence interval=0.624-0.698) revealed a good three- and five-year calibration curves. Conclusions: The inflammation score system based on five preoperative inflammatory markers well predicted the survival of HCC patients after surgery, especially in those at the early stage (Stage I).

8.
J Cancer ; 9(22): 4223-4233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30519323

RESUMO

Background: Prognosis remains poor for hepatocellular carcinoma (HCC) patients with extrahepatic metastases (EHMs). This study aimed to develop a nomogram to predict EHMs in HCC patients who underwent adjuvant transarterial chemoembolization (TACE) following hepatectomy. Methods: Data of 578 HCC patients who underwent TACE after hepatectomy at the Eastern Hepatobiliary Surgery Hospital was retrospectively reviewed. Cox regression analyses was used to select variables to construct the nomogram. Predictive accuracy and discriminative ability of the model were performed using concordance index (C-index), calibration curve and the area under time-dependent receiver operating characteristic (ROC) curve. Results: Postoperative EHMs were detected in 89 and 31 patients in the training cohort (n = 453) and validation cohort (n = 125), respectively. Multivariate analysis showed that tumor size (HR, 1.099; 95% CI, 1.049-1.152), coarse beam type of tumor histopathological structure (HR, 2.382; 95% CI, 1.030-5.512), presence of satellite nodules (HR, 1.936; 95% CI, 1.156-3.244) and alpha-fetoprotein (AFP) (HR, 1.399; 95% CI, 1.098-1.783) were independent risk factors for EHMs (all p < 0.05). The nomogram incorporated these factors achieved good agreement between prediction and actual observation with a concordance index (C-index) of 0.73 (95% CI, 0.68 to 0.78) and 0.71 (95% CI, 0.63 to 0.79) in the training cohort and validation cohort, respectively. In addition, patients who had a nomogram score > 17 were considered to have higher risk for EHMs compared with those scored ≤ 12. Furthermore, the time-dependent area under the ROC curve indicated comparative stability and adequate discriminative ability of the model. Conclusions: This novel nomogram can identify those with high risk of EHMs after adjuvant TACE following hepatectomy. The validation cohort showed a good performance, suggesting it could benefit surgeons on decision-making.

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