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1.
Clin Cancer Res ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526363

RESUMO

PURPOSE: Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma(ICC). However, little is known about the intertumor heterogeneity(ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. EXPERIMENTAL DESIGN: We obtained 66 tumor samples from sixteen multifocal ICC patients and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA-sequencing, methylation-microarray and multiplex immunostaining. Patients were divided into high or low ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed. RESULTS: Multifocal ICC presented considerable intertumor genomic, transcriptional and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor-immune cell interactions and upregulated IFN-signature expression in high immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA-methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression. CONCLUSIONS: There is comprehensive heterogeneity in the genome, transcriptome and epigenome of multifocal ICC. Based on the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34453221

RESUMO

PURPOSE: The aim of this retrospective study was to compare the clinical outcomes of pembrolizumab-lenvatinib-transarterial chemoembolization (TACE) versus lenvatinib-TACE sequential therapy in selected populations of Chinese patients with initially unresectable hepatocellular carcinoma (uHCC) harbouring programmed cell death ligand-1 (PD-L1) expression. METHODS: Consecutive patients with initial PD-L1-positive uHCC who received pembrolizumab-lenvatinib-TACE or lenvatinib-TACE sequential therapy were retrospectively identified from three medical institutions during 2016-2020. The primary endpoints included the rate of conversion therapy, defined as converting initially uHCC to hepatectomy, overall survival (OS), and progression-free survival (PFS); secondary endpoint was the frequency of key adverse events (AEs). RESULTS: In total, 220 consecutively recruited patients were retrospectively reviewed, 78 of whom were ineligible according to the current criteria, leaving 142 patients [pembrolizumab-lenvatinib-TACE: n = 70, median age 58 years (range 36-69) and lenvatinib-TACE: n = 72, 57 years (35-68)] who were eligible for the study. The median duration of follow-up was 27 months [95% confidence interval (CI), 26.3-28.7 months]. At the last follow-up, the rate of conversion therapy was 25.7% in the pembrolizumab-lenvatinib-TACE group and 11.1% in the lenvatinib-TACE group (p = 0.025). The median OS was 18.1 months (95% CI 16.5-20.7) in the pembrolizumab-lenvatinib-TACE group versus 14.1 months (95% CI 12.2-16.9) in the lenvatinib-TACE group [hazard ratio (HR) 0.56, 95% CI 0.38-0.83; p = 0.004]. A distinct difference in the median PFS interval between the groups was detected [9.2 months (95% CI 7.1-10.4) in the pembrolizumab-lenvatinib-TACE group vs. 5.5 months (95% CI 3.9-6.6) in the lenvatinib-TACE group (HR 0.60; 95% CI 0.39-0.91; p = 0.006)]. The rates of the key AEs assessed, which were hypertension, nausea, and rash, were higher in the pembrolizumab-lenvatinib-TACE group than in the lenvatinib-TACE group (all p < 0.05). CONCLUSION: Among the selected populations of patients with initial PD-L1-positive uHCC, pembrolizumab-lenvatinib-TACE sequential therapy may have promising antitumour activity, with an acceptable conversion rate and a well-characterized safety profile.

3.
Mol Cell ; 81(16): 3339-3355.e8, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352206

RESUMO

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.


Assuntos
Colangiocarcinoma/genética , Proteínas de Ligação ao GTP/genética , Metiltransferases/genética , Biossíntese de Proteínas , Animais , Carcinogênese/genética , Colangiocarcinoma/patologia , Progressão da Doença , Receptores ErbB/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Camundongos , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
4.
Asian J Surg ; 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34120821

RESUMO

OBJECTIVE: To compare the safety and short-term outcomes between robotic-assisted and laparoscopic left hemi-hepatectomies in a single academic medical center. METHODS: A cohort of 52 patients, who underwent robotic-assisted or laparoscopic left hemi-hepatectomies between April 2015 and January 2020 in Department of Pancreatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University was recruited into the study. Their clinicopathological features and short-term outcomes were analyzed retrospectively. RESULTS: There were 25 robotic-assisted and 27 laparoscopic cases, with a median age of 55 years (34-77 years). There was one conversion to open in laparoscopic group. There were no significant differences in clinicopathological features between two groups, except robotic group had higher body mass index (23.9 vs. 22.0 kg/m2, p = 0.047). Robotic-assisted and laparoscopic groups had similar operative time (300 vs. 310 min, p = 0.515), length of hospital stay (8 vs. 8 days, p = 0.981) and complication rates (4.0% vs. 14.8%, p = 0.395), but the former had less blood loss (100 vs. 200 ml, p < 0.001) and lower incidence of blood transfusion (0% vs. 22.2%, p = 0.023) in comparison with laparoscopic group. R0 resection was achieved for all patients with malignancies. There was no perioperative mortality in both groups. The cost of robotic group was higher than laparoscopic group (105,870 vs. 64,191 RMB yuan, p = 0.02). CONCLUSION: The robotic-assisted and laparoscopic approaches had similar safety and short-term outcomes in left hemi-hepatectomy, and the former can reduce operative blood loss and blood transfusion. However, the costs were higher in robotic group.

5.
J Gastroenterol Hepatol ; 36(9): 2531-2539, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33948991

RESUMO

BACKGROUND AND AIM: The evidences for use of postoperative antibiotics (POA) in hepatocellular carcinoma (HCC) patients who underwent hepatectomy are controversial. We aimed to explore the relationship between POA and hepatectomy-related infection in a hepatitis B virus (HBV)-related HCC population. METHODS: We retrospectively collected 934 HCC patients who underwent hepatectomy for curative intent from three tertiary hospitals in China. The incidences of postoperative infection including surgical site infection and remote site infection were recorded and calculated. Univariable and multivariable logistic regression analyses were performed to explore related factors of postoperative infection and POA. And the relationship between infection rates with different durations of POA was investigated. RESULTS: The overall infection rate was 8.2% (77/934), including 6.5% (61/934) of surgical site infection and 2.0% (19/934) of remote site infection. Multivariable analysis revealed that the administration of POA was negatively related with the incidence of postoperative infection significantly (odds ratio = 0.50, 95% confidence interval = 0.30 to 0.83; P = 0.008). Albumin-bilirubin score, Barcelona Clinic Liver Cancer (BCLC) stage and extent of hepatectomy were independently related to the POA. And 3-day regimen seemed to be the shortest duration of POA to gain the lowest incidence of postoperative infection. CONCLUSIONS: Postoperative antibiotic is necessary for HBV-related HCC patients to prevent postoperative infection, especially for those with higher albumin-bilirubin score, at BCLC stage B-C, or who underwent major hepatectomy. For HBV-related HCC patients, postoperative second-generation cephalosporins, or ceftriaxone for 3 days after surgery might be proper.

6.
Ann Surg Oncol ; 27(10): 3740-3753, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32424586

RESUMO

BACKGROUND: Postsurgical recurrence is common in early-stage hepatocellular carcinoma (HCC). Prolonged time to surgery (TTS) may lead to tumor progression. However, the impact of TTS on HCC prognosis is controversial in Western studies and unknown in China. We aim to investigate the impact of TTS on the prognosis of Chinese HCC patients at Barcelona Clinic Liver Cancer (BCLC) stage 0-A who underwent surgery. PATIENTS AND METHODS: We retrospectively enrolled 967 BCLC 0-A HCC patients who underwent surgery at three tertiary centers in China. Primary outcomes were recurrence-free survival (RFS) and overall survival (OS). Restricted cubic spline (RCS) was used to select the cutoff value of TTS. Propensity score matching (PSM) was performed to reduce confounding bias, and a time-dependent Cox model was utilized to investigate factors influencing TTS. RESULTS: The median TTS of BCLC 0-A HCC patients was 13 days (interquartile range: 10-21 days). For patients with TTS ≤ 70 days, the cutoff value of TTS was 13 days according to RCS. After PSM, corresponding 1-, 3-, and 5-year RFS of the TTS > 13 days and TTS ≤ 13 days groups were 75.6%, 55.3%, 46.4% and 71.2%, 52.3%, 38.8%, respectively (P = 0.103). Corresponding 1-, 3-, and 5-year OS of TTS > 13 days and TTS ≤ 13 days groups were 93.7%, 82.8%, 69.6% and 92.4%, 78.5%, 68.4%, respectively (P = 0.580). Time-dependent Cox analysis revealed that age and tumor size were factors influencing TTS. CONCLUSIONS: Our study suggests that, for patients with TTS ≤ 70 days, prolonged TTS had no impact on BCLC 0-A Chinese HCC patients receiving surgery.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , China/etnologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologia
7.
J Gastroenterol Hepatol ; 35(12): 2220-2228, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32246889

RESUMO

BACKGROUND AND AIM: Prognosis of infiltrative hepatocellular carcinoma (iHCC) is poor, and the treatments selection based on efficacy is unclear. We performed this multicenter study to compare the efficacy of hepatic resection and transarterial chemoembolization (TACE) in treating patients with iHCC. METHODS: We retrospectively analyzed the overall survivals (OS) in 319 patients with iHCC who were initially treated by hepatic resection (n = 133) or TACE (n = 186) at four tertiary centers. Fifty-eight patients in the TACE group were assessed as resectable and compared with the hepatic resection group in subgroup analysis. A propensity score matched (PSM) analysis was performed to reduce selection bias. Cox regression was performed to identify significant factors associated with OS. RESULTS: The median OS time was significantly longer in the hepatic resection group than that in the TACE group, before and after PSM (before PSM, 17.5 vs 7.3 months, P < 0.0001; after PSM, 14.0 vs 7.3 months, P < 0.0001). The multivariable analysis indicated TACE as a risk factor of OS (hazard ratio = 2.233, 95% confidence interval = 1.492 to 3.341, P < 0.0001), as well as portal venous tumor thrombosis grades 3-4 and alpha fetal protein (AFP) > 400 ng/mL. In the subgroup analysis, the better efficacy of hepatic resection over TACE persisted regardless of the grade of portal venous tumor thrombosis and the level of AFP. As for resectable patients, hepatic resection still showed significant survival benefit (before PSM, 17.5 vs 11.2 months, P = 0.0013; after PSM, 14.0 vs 10.9 months, P = 0.0304). CONCLUSION: Hepatic resection might be the better choice for patients with iHCC due to its better survival benefit than TACE.

8.
Eur Radiol ; 30(6): 3473-3485, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32048035

RESUMO

OBJECTIVES: We used the status of microvascular invasion (MVI) at primary resection to help treatment selection for hepatitis B virus-positive (HBV+) recurrent hepatocellular carcinoma (rHCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B-C. METHODS: From 2009 to 2017, we enrolled 221 consecutive HBV+ rHCC patients at BCLC stage B-C who underwent re-resection (RR), radiofrequency ablation (RFA), or transarterial chemoembolization (TACE). Post recurrence survival (PRS) and overall survival (OS) were compared between RR/RFA and TACE according to MVI status. A one-to-one propensity score matching analysis was performed. RESULTS: For MVI(-) patients, the median PRS was 62.3 months for the RR/RFA group and 21.1 months for the TACE group (p = 0.039). The corresponding OS was 71.4 months and 26.6 months, respectively (p = 0.010). For MVI(+) patients, the median PRS in the RR/RFA group and TACE group was 14.7 months and 10.1 months (p = 0.115). The corresponding OS was 23.4 months and 16.4 months, respectively (p = 0.067). After matching, the dominance of RR/RFA over TACE remained in MVI(-) patients for both PRS (62.3 months vs 15.3 months, p = 0.019) and OS (98.1 months vs 33.4 months, p = 0.046). No significant difference was found in MVI(+) patients for either PRS (14.7 months vs 11.8 months, p = 0.593) or OS (23.4 months vs 28.1 months, p = 0.662). CONCLUSIONS: MVI status definitely helps select treatment options in HBV+ rHCC patients. For MVI(-) patients, RR/RFA provided better survival than TACE while for MVI(+) patients, TACE shared similar survival outcomes. KEY POINTS: • This study aimed at the determination of the optimal treatment options (ablation /resection vs TACE) in case of recurrent HBV-related HCC. • It showed that MVI status, established at primary resection of HCC, was a powerful marker for selecting the best treatment option in these patients. • In MVI(-) patients, RR/RFA achieved a better survival than TACE. In MVI(+) patients, TACE shared similar survival.


Assuntos
Carcinoma Hepatocelular/terapia , Ablação por Cateter , Quimioembolização Terapêutica , Hepatectomia , Hepatite B Crônica/complicações , Neoplasias Hepáticas/terapia , Microvasos/patologia , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Terapia Combinada , Feminino , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Seleção de Pacientes , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento
9.
Int J Surg ; 57: 111-116, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29777880

RESUMO

BACKGROUND: A number of pancreatic anastomosis methods for pancreaticoduodenectomy including pancreaticogastrostomy(PG), duct-to-mucosa pancreaticojejunostomy(duct-to-mucosa PJ), invagination pancreaticojejunostomy(invagination PJ) and binding pancreaticojejunostomy(BPJ), but the optimal choice remains unclear. We performed a network meta-analysis to synthesize direct and indirect evidence to identify the optimal choice for pancreatic anastomosis after pancreaticoduodenectomy METHODS: We searched the Embase, PubMed and Cochrane library databases for randomized control trials. The relative risk (RR) and its 95% confidence interval (CI) were calculated. The primary outcome is postoperative pancreatic fistula (POPF). RESULT: In total, 16 RCT studies, including a total of 2396 patients, met our criteria. The results showed that PG is not superior to invagination PJ (RR 0.70 95%CI: 0.35-1.39) and duct-to-mucosa PJ (RR 0.58 95%CI: 0.30-1.10) according to the ISGPS definition. Furthermore PG cannot reduce the POPF rates than invagination PJ (RR 0.51 95%CI: 0.2-1.21) and duct-to-mucosa PJ (RR 0.46 95%CI: 0.16-1.14) according to the soft pancreatic texture. BPJ might reduce the incidence of POPF than duct-to-mucosa PJ (RR 0.00 95%CI: 0.00-0.04), invagination PJ (RR 0.00 95%CI: 0.00-0.03), PG (RR 0.00 95%CI: 0.00-0.03), but the results have major limitations with only one RCT reported BPJ and different definition of POPF. CONCLUSION: There are no significant differences among BPJ, duct-to-mucosa PJ, invagination PJ and PG in the prevention of POPF, overall morbidity, mortality and DGE. However, further randomized controlled trials should be undertaken to ascertain these findings, especially for BPJ.


Assuntos
Mucosa Intestinal/cirurgia , Metanálise em Rede , Pâncreas/cirurgia , Fístula Pancreática/epidemiologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticojejunostomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Anastomose Cirúrgica/efeitos adversos , Anastomose Cirúrgica/métodos , Humanos , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/métodos , Pancreaticojejunostomia/métodos , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Int J Oncol ; 53(2): 672-684, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845225

RESUMO

Alterations in Wiskott-Aldrich syndrome protein family verprolin-homologous protein 3 (WAVE3) expression play various roles in certain types of cancer. However, the roles of WAVE3 expression in pancreatic cancer remain unknown. The present retrospective study demonstrated that WAVE3 expression was higher in cancerous pancreatic tissues than in non-neoplastic tissues. Moreover, WAVE3 overexpression was related to lymphatic metastasis, a poor differentiation and high pre-operative CA19-9 levels and was an adverse prognostic factor for patients with pancreatic cancer. In vitro, the knockdown of WAVE3 inhibited the proliferative, migratory and invasive potential of pancreatic cancer cells and promoted cell apoptosis. Western blot analysis demonstrated that WAVE3 influenced the protein kinase B (PBK/AKT) pathway by suppressing the expression of pyruvate dehydrogenase kinase isoform 2 (PDK2) and then negatively inhibiting the phosphorylation of Ser473 on AKT. Furthermore, the expression of AKT pathway downstream proteins [certain epithelial-mesenchymal transition (EMT)-related proteins, p53, Bcl-2 and cyclin D1] was accordingly altered. Taken together, our findings suggest that WAVE3 influences cell proliferation, migration and invasion via the AKT pathway, and targeting WAVE3 and/or the AKT pathway may potentially serve as a treatment strategy for pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Gradação de Tumores , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Prognóstico , Estudos Retrospectivos
11.
PLoS One ; 13(1): e0191095, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29324837

RESUMO

Limited data exists in China on the comparative cost of gadolinium ethoxybenzyl diethylenetriamine magnetic resonance imaging (Gd-EOB-DTPA-MRI) with other imaging techniques. This study compared the total cost of Gd-EOB-DTPA-MRI with multidetector computed tomography (MDCT) and extracellular contrast media-enhanced MRI (ECCM-MRI) as initial imaging procedures in patients with suspected hepatocellular carcinoma (HCC). We developed a decision-tree model on the basis of the Chinese clinical guidelines for HCC, which was validated by clinical experts from China. The model compared the diagnostic accuracy and costs of alternative initial imaging procedures. Compared with MDCT and ECCM-MRI, Gd-EOB-DTPA-MRI imaging was associated with higher rates of diagnostic accuracy, i.e. higher proportions of true positives (TP) and true negatives (TN) with lower false positives (FP). Total diagnosis and treatment cost per patient after the initial Gd-EOB-DTPA-MRI evaluation was similar to MDCT (¥30,360 vs. ¥30,803) and lower than that reported with ECCM-MRI (¥30,360 vs. ¥31,465). Lower treatment cost after initial Gd-EOB-DTPA-MRI was driven by reduced utilization of confirmatory diagnostic procedures and unnecessary treatments. The findings reported that Gd-EOB-DTPA-MRI offered higher diagnostic accuracy compared with MDCT and ECCM-MRI at a comparable cost, which indicates Gd-EOB-DTPA-MRI could be the preferred initial imaging procedure for the diagnosis of HCC in China.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , China , Feminino , Humanos , Masculino
13.
Cancer Discov ; 7(10): 1116-1135, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28667006

RESUMO

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3' untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1116-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.


Assuntos
Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Ilhas de CpG , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Receptor ErbB-2/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteína Supressora de Tumor p53/genética
14.
Cancer Lett ; 380(2): 403-412, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27378242

RESUMO

Eye absent homolog 4 (EYA4) was initially found as key gene in controlling eye development in Drosophila. We recently found that EYA4 was an independent prognostic factor in hepatocellular carcinoma. Its biological functions in malignancies remained unknown. The present study aimed at investigating its biological functions, molecular mechanisms and prognostic values in pancreatic ductal adenocarcinoma (PDAC). Overexpression of EYA4 in PDAC cells inhibited proliferation and invasion in vitro and tumor growth in vivo. Depletion of EYA4 in PDAC cells enhanced proliferation and invasion in vitro and tumor growth in vivo. Mechanistically, armed with the serine/threonine-specific protein phosphatase activity, EYA4 dephosphorylated ß-catenin at Ser675, blocked ß-catenin nuclear translocation and inhibited ID2 transactivation. Consistently, EYA4 expression inversely correlated with the levels of p-Ser675-ß-catenin and ID2 in tissues. EYA4 expression in PDAC tissues was significantly reduced as compared with adjacent non-tumoral tissues. EYA4 expression was an independent prognostic factor in PDAC, with a lower EYA4 level in association with shorter long-term survival and disease-free time. We showed that EYA4 functioned as tumor suppressor gene in PDAC via repressing ß-catenin/ID2 activation, and was an independent prognostic factor in PDAC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Proteína 2 Inibidora de Diferenciação/metabolismo , Neoplasias Pancreáticas/metabolismo , Transativadores/metabolismo , Proteínas Supressoras de Tumor/metabolismo , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 2 Inibidora de Diferenciação/genética , Estimativa de Kaplan-Meier , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Fosforilação , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Transativadores/genética , Transfecção , Carga Tumoral , Proteínas Supressoras de Tumor/genética
15.
Chin J Cancer ; 35(1): 70, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27469137

RESUMO

BACKGROUND: The molecular prognostic markers and carcinogenesis of intrahepatic cholangiocarcinoma (ICC) have not been well documented. The purpose of this study was to investigate the prognostic value of the eyes absent homolog 4 (EYA4) gene in ICC and its biological effects on ICC growth in vitro and in vivo. METHODS: One hundred twelve patients with ICC who underwent hepatectomy were enrolled in the study. EYA4 mRNA and EYA4 protein levels in ICC and adjacent non-tumoral tissues were evaluated using real-time quantitative polymerase chain reaction and immunohistochemical staining, respectively. EYA4 protein levels in ICC cells were determined using western blot analysis. The associations between EYA4 expression and clinicopathologic features of ICC were analyzed. To identify independent prognostic factors, univariate and multivariate analyses were performed. The biological effects of EYA4 on ICC cells were evaluated by establishing stable EYA4-overexpressing transfectants in vitro, and EYA4's effects on tumor growth were evaluated by intra-tumoral injection of EYA4-expressing plasmids in a NOD/SCID murine model of xenograft tumors. RESULTS: ICC tissues had significantly lower EYA4 mRNA and protein levels compared with adjacent non-tumoral tissues (both P < 0.001). Univariate and multivariate analyses showed that EYA4 protein level, tumor number, adjacent organ invasion, lymph node metastasis, and tumor differentiation were independent prognostic factors for disease-free survival and overall survival (all P < 0.05). In vitro, EYA4 overexpression inhibited tumor cell growth, foci formation, and cell invasiveness. In vivo, intra-tumoral injection of EYA4-expressing plasmids significantly inhibited ICC growth in the murine xenograft model compared with the control group (P < 0.05). CONCLUSION: EYA4 gene functioned as a molecular prognostic marker in ICC, and its overexpression inhibited tumor growth in vitro and in vivo.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Colangiocarcinoma/patologia , Transativadores/metabolismo , Adulto , Idoso , Animais , Apoptose , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Biomarcadores Tumorais/genética , Western Blotting , Movimento Celular , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Sci Rep ; 6: 22976, 2016 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-26964667

RESUMO

We determined the mitogen-activated protein kinase (MAPK) gene expression profile of acquired resistance in sorafenib-sensitive hepatocellular carcinoma (HCC) cells and aimed to identify c-Jun as an important molecule mediating the efficacy of sorafenib. Differences in gene expression of the MAPK signaling between untreated and sorafenib-treated HCC cell lines were investigated using real-time polymerase chain reaction array. Western blot and real-time PCR further evaluated the expression of c-Jun. Pathological specimens from 50 patients with advanced HCC were collected to measure p-c-Jun expression. Sorafenib-resistant HCC cells demonstrated greater levels of basal c-Jun mRNA and protein compared with sorafenib-sensitive HCC cells. Sorafenib activated p-c-Jun in a dose- and time-dependent manner in PLC/PRF/5 and MHCC97H cell lines. Decreased expression levels of 6 genes after sorafenib treatment suggested a robust inhibitory impact of sorafenib on MAPK signaling in HCC cells. c-Jun and p-c-Jun expression levels were inversely correlated with the efficacy of sorafenib; a high expression level of p-c-Jun was associated with resistance to sorafenib and poor overall survival in patients with clinical HCC. p-c-Jun may act as a biomarker for predicting responses of sorafenib treatment, thus advocating targeting of JNK/c-Jun signaling as an optimal therapeutic strategy in a subset of HCC.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Adulto , Idoso , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/biossíntese , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Niacinamida/administração & dosagem , RNA Mensageiro/biossíntese , Transdução de Sinais/efeitos dos fármacos , Sorafenibe
17.
Oncotarget ; 7(13): 17220-9, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-26967384

RESUMO

Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Piridinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Dig Dis Sci ; 61(7): 1950-60, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26971088

RESUMO

BACKGROUND: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 3 (WAVE3) plays a critical role in cancer progression and metastasis. However, the specific role of WAVE3 in intrahepatic cholangiocarcinoma (ICC) has not been studied. AIMS: This study aimed to explore the role and mechanism of WAVE3 in the progression and metastasis of ICC. METHODS: The expression of WAVE3 in ICC tissues and adjacent non-cancerous tissues was detected by immunohistochemistry. Western blot analysis was utilized to detect the expression of WAVE3 in ICC cells. A transwell assay was used to assess the potential for migration and invasion. The expression of WAVE3 in CC-LP-1 cells was knocked down by small interfering RNA (siRNA) interference. RESULTS: The expression of WAVE3 in ICC tissues was significantly higher than that in adjacent non-cancerous tissues. The overall survival was lower in the subgroup of ICC patients with higher WAVE3 expression compared to the subgroup with a lower level of WAVE3 expression. WAVE3 expression was an adverse prognostic factor for ICC patients. CC-LP-1 cells expressed higher levels of WAVE3 protein compared to RBE cells and human intrahepatic biliary epithelial cells, which correlated with greater migration and invasion capabilities compared with the RBE cells. After the transfection of CC-LP-1 cells with WAVE3 siRNA, the level of WAVE3 protein was significantly decreased, accompanied by a marked reduction in migration, invasion and proliferation. Moreover, after the knockdown of WAVE3 expression in CC-LP-1 cells, the protein levels of Slug and Vimentin were significantly decreased, while that of E-cadherin was significantly increased. CONCLUSIONS: WAVE3 may represent a new adverse prognostic factor for patients with ICC. This protein enhances migration and invasion capabilities in ICC, most likely through the induction of an epithelial-mesenchymal transition.


Assuntos
Movimento Celular/fisiologia , Colangiocarcinoma/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Invasividade Neoplásica/patologia , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética
19.
Dig Dis Sci ; 60(5): 1273-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25487191

RESUMO

BACKGROUND: Biliary tract cancers encompass gallbladder carcinoma, and intrahepatic, perihilar and distal cholangiocarcinoma. Upregulated serum CYFRA 21-1 has been reported in intrahepatic cholangiocarcinoma. AIMS: The present study aimed to explore the clinical significance of serum CYFRA 21-1 in all biliary tract cancer subtypes. METHODS: Serum CYFRA 21-1, carbohydrate antigen 19-9 and carcinoembryonic antigen were quantitated preoperatively, postoperatively and during follow-up in 134 malignant and 52 benign patients. Receiver operator characteristic curves of biomarkers were analyzed. Level of CYFRA 21-1 was correlated with patients' clinicopathological features and follow-up data. RESULTS: CYFRA 21-1 was significantly upregulated in biliary malignancies, and expressional difference existed between these subtypes. Based on the maximal Youden's index, cutoff values were selected (ng/mL): 2.61 for biliary tract cancers (sensitivity 74.6 % and specificity 84.6 %); 3.27 for intrahepatic cholangiocarcinoma (75.6 and 96.2 %) and gallbladder carcinoma (93.7 and 96.2 %); 2.27 for perihilar cholangiocarcinoma (71.0 and 71.2 %); and 2.61 for distal cholangiocarcinoma (63.3 and 84.6 %). CYFRA 21-1 showed better diagnostic performance than other biomarkers in gallbladder carcinoma and intrahepatic cholangiocarcinoma; its performance was not inferior to that of the combination of these three biomarkers and declined after curative resection and re-elevated when tumor recurred, which was correlated with tumor aggressiveness and TNM stage; it was an independent predictor for 1-year recurrence-free survival and overall survival on multivariate analysis. CONCLUSION: Serum CYFRA 21-1 represents a reliable biomarker for gallbladder carcinoma and intrahepatic cholangiocarcinoma.


Assuntos
Antígenos de Neoplasias/sangue , Neoplasias dos Ductos Biliares/sangue , Biomarcadores Tumorais/sangue , Colangiocarcinoma/sangue , Neoplasias da Vesícula Biliar/sangue , Queratina-19/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/cirurgia , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , Distribuição de Qui-Quadrado , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Intervalo Livre de Doença , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Razão de Chances , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Regulação para Cima
20.
J Biol Chem ; 289(40): 27526-39, 2014 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-25118289

RESUMO

IL-6/Stat3 is associated with the regulation of transcription of key cellular regulatory genes (microRNAs) during different types of liver injury. This study evaluated the role of IL-6/Stat3 in regulating miRNA and miR-21 in alcoholic liver disease. By microarray, we identified that ethanol feeding significantly up-regulated 0.8% of known microRNAs in mouse liver compared with controls, including miR-21. Similarly, the treatment of normal human hepatocytes (N-Heps) and hepatic stellate cells (HSCs) with ethanol and IL-6 significantly increased miR-21 expression. Overexpression of miR-21 decreased ethanol-induced apoptosis in both N-Heps and HSCs. The expression level of miR-21 was significantly increased after Stat3 activation in N-Heps and HSCs, in support of the concept that the 5'-promoter region of miR-21 is regulated by Stat3. Using real time PCR, we confirmed that miR-21 activation is associated with ethanol-linked Stat3 binding of the miR-21 promoter. A combination of bioinformatics, PCR array, dual-luciferase reporter assay, and Western blot analysis revealed that Fas ligand (TNF superfamily, member 6) (FASLG) and death receptor 5 (DR5) are the direct targets of miR-21. Furthermore, inhibition of miR-21 by specific Vivo-Morpholino and knock-out of IL-6 in ethanol-treated mice also increased the expression of DR5 and FASLG in vivo during alcoholic liver injury. The identification of miR-21 as an important regulator of hepatic cell survival, transformation, and remodeling in vitro, as well as its upstream modulators and downstream targets, will provide insight into the involvement of altered miRNA expression in contributing to alcoholic liver disease progression and testing novel therapeutic approaches for human alcoholic liver diseases.


Assuntos
Apoptose , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/fisiopatologia , MicroRNAs/metabolismo , Animais , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/citologia , Fígado/metabolismo , Hepatopatias Alcoólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Regulação para Cima
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