Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
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.
J Cancer ; 12(17): 5260-5267, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335942

RESUMO

Objective: To validate and compare the predictive ability of albumin-bilirubin model (ALBI) with other 5 liver functional reserve models (APRI, FIB4, MELD, PALBI, King's score) for posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) who underwent major hepatectomy. Methods: Data of patients undergoing major hepatectomy for HCC from 4 hospitals between January 01, 2008 and December 31, 2019 were retrospectively analyzed. PHLF was evaluated according to the definition of the 50-50 criteria. Performances of six liver functional reserve models were determined by the area under the receiver operating characteristic curve (AUC), calibration plot and decision curve analysis. Results: A total of 745 patients with 103 (13.8%) experienced PHLF were finally included in this study. Among six liver functional reserve models, ALBI showed the highest AUC (0.64, 95% CI: 0.58-0.69) for PHLF. All models showed good calibration and greater net benefit than treating all patients at a limit range of threshold probabilities, but the ALBI demonstrated net benefit across the largest range of threshold probabilities. Subgroup analysis also showed ALBI had good predictive performance in cirrhotic (AUC=0.63) or non-cirrhotic (AUC=0.62) patients. Conclusion: Among the six models, the ALBI model shows more accurate predictive ability for PHLF in HCC patients undergoing major hepatectomy, regardless of having cirrhosis or not.

3.
BMC Cancer ; 21(1): 840, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284743

RESUMO

BACKGROUND: The objective of this study was to investigate the survival outcomes of surgical margin width in intrahepatic cholangiocarcinoma (ICC). METHODS: Between November 2011 and August 2017, patients who underwent hepatectomy for ICC were collected from 13 major hepatopancreatobiliary centers in China. The survival outcomes for patients who underwent wide margin hepatectomy (WMH) were compared with those who underwent narrow margin hepatectomy (NMH) using the 1:1 propensity score matching (PSM). RESULTS: Among 478 included patients, 195 (40.8%) underwent WMH whereas 283 (59.2%) underwent NMH. PSM yielded 79 matched patients with similar baseline characteristics. Patients underwent WMH had a significant better OS and DFS compared with those underwent NMH (before PSM: median OS 27 vs 17 months, P < 0.05; median DFS 15 vs 8 months, P = 0.001, after PSM: median OS 41 vs 22 months, p < 0.05; median DFS 16 vs 10 months, p < 0.05). However, subgroup analysis based on the AJCC staging system, WMH could only improve the survival outcomes in AJCC I ICC patients (Stage I: OS, DFS, P<0.05). CONCLUSIONS: Surgeons should strive to achieve a wide surgical margin for patients with AJCC I ICC to optimize the long-term outcome.

4.
Drug Dev Res ; 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34189738

RESUMO

To explore the biological activity of transmembrane prostateandrogen induced RNA (PMEPA1) in human pancreatic cancer (hPAC) cells and its drug sensitivity to gemcitabine (GEM) and cisplatin (DDP). Gene Expression Profiling Interactive Analysis (GEPIA) and Cancer Cell Line Encyclopedia (CCLE) were consulted to indicate the expression of PMEPA1 in hPAC tissues and cells. Quantitative real-time PCR (RT-qPCR) and western blot were performed to verify the indication. RT-qPCR and western blot also detected the expressions of PTEN/PI3K/AKT before and after transfection of PMEPA1 siRNA plasmids. Cell counting Kit-8 (CCK-8) and EdU staining were performed to examine cell proliferation before and after transfection of phosphatase and tensin homologue delet2ed on chromosome ten (PTEN) siRNA plasmids. Transwell and wound healing detected the invasion and migration of hPAC cells. The expressions of MMP-2 and MMP-9 were detected by western blot. After GEM or DDP treatment, cell viability was observed by commercial kits and cell apoptosis by flow cytometry. GEPIA and CCLE predicted increased expression of PMEPA1 in hPAC tissues and cells, which was confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot. PMEPA1 was also shown to be associated with disease-free survival. Transfection of PMEPA1 siRNA plasmids affected the expressions of PTEN/PI3K/AKT. PMEPA1 interference inhibited the proliferation, invasion and migration of hPAC cells. Furthermore, PMEPA1 interference also enhanced the sensitivity of hPAC cells to GEM and DDP via PTEN interference. PMEPA1 interference inhibits the proliferation, invasion and migration of pancreatic cancer cells and enhances the sensitivity to GEM and cisplatin by activating PTEN/PI3K/AKT signaling.

5.
J Gastrointest Oncol ; 12(2): 819-830, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34012669

RESUMO

Background: Microvascular invasion (MVI) is an independent risk factor associated with tumor recurrence and poor survival in patients with intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy (PH). The potential impact of adjuvant TACE on the prognosis of patients with ICC involving MVI (ICC-MVI) remains uncertain. Our aim was to investigate the effectiveness of postoperative adjuvant transarterial chemoembolization (TACE) on ICC involving MVI. Methods: Multicentric data consisted of 223 patients who underwent curative-intent PH for ICC-MVI from 2002-2015 were retrospectively analyzed. The impact of adjuvant TACE was evaluated using inverse probability of treatment weighting (IPTW) and propensity-score matched (PSM) analyses. Results: No association between the TACE and the overall survival (OS) and recurrence rates was observed among the overall ICC-MVI patients. However, subgroup analyses revealed that adjuvant TACE favored OS (HR, 0.62; 95% CI, 0.39-0.99; P=0.047) and time to recurrence (TTR) (HR, 0.59; 95% CI, 0.36-0.97; P=0.037) among patients with elevated CA19-9 and those without lymphadenectomy (HR, 0.53; 95% CI, 0.30-0.93; P=0.027 for OS, and HR, 0.49; 95% CI, 0.28-0.87; P=0.015 for TTR, respectively). In the CA19-9 ≥39 U/L subgroup and Nx subgroup, adjuvant TACE was associated with higher 1-, 3-, and 5-year OS rates (P=0.033 and P=0.034, respectively) and lower corresponding recurrence rates (P=0.024 and P=0.023, respectively). Conclusions: Among the ICC-MVI patients undergoing curative-intent PH, only those have elevated CA19-9 or who did not undergo lymphadenectomy might be suitable for adjuvant TACE.

6.
HPB (Oxford) ; 22(12): 1722-1731, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32284280

RESUMO

BACKGROUND: Iatrogenic biliary injury (IBI) following laparoscopic cholecystectomy (LC) is the most serious iatrogenic complications. Little is known whether LC-IBI would lead to surgeon's severe mental distress (SMD). METHODS: A cross-sectional survey in the form of electronic questionnaire was conducted among Chinese general surgeons who have caused LC-IBI. The six collected clinical features relating to mental distress included: 1) feeling burnout, anxiety, or depression, 2) avoiding performing LC, 3) having physical reactions when recalling the incidence, 4) having the urge to quit surgery, 5) taking psychiatric medications, and 6) seeking professional psychological counseling. Univariable and multivariable analyses were performed to identify risk factors of SMD, which was defined as meeting ≥3 of the above-mentioned clinical features. RESULTS: Among 1466 surveyed surgeons, 1236 (84.3%) experienced mental distress following LC-IBI, and nearly half (49.7%, 614/1236) had SMD. Multivariable analyses demonstrated that surgeons from non-university affiliated hospitals (OR:1.873), patients who required multiple repair operations (OR:4.075), patients who required hepaticojejunostomy/partial hepatectomy (OR:1.859), existing lawsuit litigation (OR:10.491), existing violent doctor-patient conflicts (OR:4.995), needing surgeons' personal compensation (OR:2.531), and additional administrative punishment by hospitals (OR:2.324) were independent risk factors of surgeon's SMD. CONCLUSION: Four out of five surgeons experienced mental distress following LC-IBI, and nearly half had SMD. Several independent risk factors of SMD were identified, which could help to make strategies to improve surgeons' mental well-being.

7.
Exp Cell Res ; 390(1): 111955, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32165166

RESUMO

Tumor-initiating cells (T-ICs) are involved in the tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Herein, we find that miR-454 is upregulated in liver T-ICs and has an important function in liver T-ICs. Functional studies have revealed that knockdown of miR-454 inhibits liver T-IC self-renewal and tumorigenesis. Conversely, forced miR-454 expression promotes liver T-IC self-renewal and tumorigenesis. Mechanistically, we found that miR-454 downregulates SOCS6 expression in liver T-ICs. The correlation between miR-454 and SOCS6 is validated in human HCC tissues. Furthermore, HCC cells that overexpress miR-454 are resistant to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrates that miR-454 may predict sorafenib benefits in HCC patients. In conclusion, our findings reveal the crucial role of miR-454 in liver T-IC expansion and sorafenib response.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Células Hep G2 , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , Células-Tronco Neoplásicas/fisiologia , Sorafenibe/uso terapêutico , Proteínas Supressoras da Sinalização de Citocina/metabolismo
8.
JAMA Oncol ; 6(2): 255-263, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774468

RESUMO

Importance: Repeat hepatectomy and percutaneous radiofrequency ablation (PRFA) are most commonly used to treat early-stage recurrent hepatocellular carcinoma (RHCC) after initial resection, but previous studies comparing the effectiveness of the 2 treatments have reported conflicting results. Objective: To compare the long-term survival outcomes after repeat hepatectomy with those after PRFA among patients with early-stage RHCC. Design, Setting, and Participants: This open-label randomized clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital and the National Center for Liver Cancer of China. A total of 240 patients with RHCC (with a solitary nodule diameter of ≤5 cm; 3 or fewer nodules, each ≤3 cm in diameter; and no macroscopic vascular invasion or distant metastasis) were randomized 1:1 to receive repeat hepatectomy or PRFA between June 3, 2010, and January 15, 2013. The median (range) follow-up time was 44.3 (4.3-90.6) months (last follow-up, January 15, 2018). Data analysis was conducted from June 15, 2018, to September 28, 2018. Interventions: Repeat hepatectomy (n = 120) or PRFA (n = 120). Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included repeat recurrence-free survival (rRFS), patterns of repeat recurrence, and therapeutic safety. Results: Among the 240 randomized patients (216 men [90.0%]; median [range] age, 53.0 [24.0-59.0] years), 217 completed the trial. In the intention-to-treat (ITT) population, the 1-year, 3-year, and 5-year OS rates were 92.5% (95% CI, 87.9%-97.3%), 65.8% (95% CI, 57.8%-74.8%), and 43.6% (95% CI, 35.5%-53.5%), respectively, for the repeat hepatectomy group and 87.5% (95% CI, 81.8%-93.6%), 52.5% (95% CI, 44.2%-62.2%), and 38.5% (95% CI, 30.6%-48.4%), respectively, for the PRFA group (P = .17). The corresponding 1-year, 3-year, and 5-year rRFS rates were 85.0% (95% CI, 78.8%-91.6%), 52.4% (95% CI, 44.2%-62.2%), and 36.2% (95% CI, 28.5%-46.0%), respectively, for the repeat hepatectomy group and 74.2% (95% CI, 66.7%-82.4%), 41.7% (95% CI, 33.7%-51.5%), and 30.2% (95% CI, 22.9%-39.8%), respectively, for the PRFA group (P = .09). Percutaneous radiofrequency ablation was associated with a higher incidence of local repeat recurrence (37.8% vs 21.7%, P = .04) and early repeat recurrence than repeat hepatectomy (40.3% vs 23.3%, P = .04). In subgroup analyses, PRFA was associated with worse OS vs repeat hepatectomy among patients with an RHCC nodule diameter greater than 3 cm (hazard ratio, 1.72; 95% CI, 1.05-2.84) or an α fetoprotein level greater than 200 ng/mL (hazard ratio, 1.85; 95% CI, 1.15-2.96). Surgery had a higher complication rate than did ablation (22.4% vs 7.3%, P = .001). Conclusions and Relevance: No statistically significant difference was observed in survival outcomes after repeat hepatectomy vs PRFA for patients with early-stage RHCC. Repeat hepatectomy may be associated with better local disease control and long-term survival in patients with an RHCC diameter greater than 3 cm or an AFP level greater than 200 ng/mL. Trial Registration: ClinicalTrials.gov identifier: NCT00822562.


Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Ablação por Radiofrequência , Reoperação , Adulto , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Adulto Jovem
9.
Cell Cycle ; 18(24): 3550-3561, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724462

RESUMO

Liver cancer stem cells contribute to tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liverCSCs is not fully understood yet. Here we show that miR-219 is upregulated in liver CSCs. Knockdown of miR-219 attenuates the self-renewal and tumorigenicity of liver CSCs. Conversely, miR-219 overexpressing enhances the self-renewal and tumorigenicity of liver CSCs.Mechanistically,miR-219 downregulates E-cadherin via itsmRNA 3'UTR in liver CSCs. The correlation between miR-219 and E-cadherin is validated in human HCC tissues. Furthermore, the miR-219 expression determines the responses of hepatoma cells to sorafenib treatment. Our findings indicate that miR-219 plays a critical role in liver CSCs expansion and sorafenib response, rendering miR-219 as an optimal target for the prevention and intervention of HCC.Abbreviations: HCC: Hepatocellular carcinoma; CSCs: cancer stem cells; DMEM: Dulbecco's modified Eagle's medium; FBS: fetal bovine serum; OS: overall survival.


Assuntos
Caderinas/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Transdução de Sinais/genética
10.
BMC Cancer ; 19(1): 887, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488102

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80-90% of cases. Mutations are commonly found in the signaling regulating the PI3K/Akt pathway, leading to oncogenic cell proliferation and survival. Key transcription factors that are negatively regulated downstream of PI3K/Akt are members of the forkhead box O family (FOXO). FOXOs were initially considered as tumor suppressors by inducing cell cycle arrest and apoptosis. However, there is increasing evidence showing that FOXOs, especially FOXO3, can support tumorigenesis. METHODS: To understand the roles of FOXO3 in liver tumorigenesis and hepatocarcinogenesis, we analyzed HCC patient specimens and also established a doxycycline-regulated transgenic mouse model with hepatocyte-specific FOXO3 expression in a constitutively active form. RESULTS: We found that FOXO3 protein is significantly overexpressed and activated in livers of HCC patients. Hepatic activation of FOXO3 induced extensive hepatic damage and elevated gene expression of several HCC-associated factors. Furthermore, FOXO3 expression enhanced hepatotoxicin-induced tumorigenesis. Mechanistically, FOXO3 activation caused oxidative stress and DNA damage and triggered positive feedback-loop for Akt activation as well as mTORC2 activation. Interestingly, FOXO3 activated not only reactive oxygen species (ROS)-promoting pathways, but also ROS-eliminating systems, which can be associated with the activation of the pentose phosphate pathway. CONCLUSIONS: FOXO3 is a master regulator of ROS in a 'carrot and stick' manner; on one side avoiding cellular crisis while also supporting hepatocellular carcinogenesis. Clinically, we suggest analyzing FOXO3 activation status in patients with liver diseases, in addition to PI3K/Akt signaling. Personalized therapy of FOXO3 inhibition may be a reasonable, depending on the activation status of FOXO3.


Assuntos
Carcinoma Hepatocelular/metabolismo , Transformação Celular Neoplásica/metabolismo , Retroalimentação Fisiológica , Proteína Forkhead Box O3/metabolismo , Neoplasias Hepáticas/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Carcinógenos/metabolismo , Carcinoma Hepatocelular/patologia , Dano ao DNA/genética , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box O3/genética , Regulação Neoplásica da Expressão Gênica , Hepatócitos/metabolismo , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oncogenes , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral
11.
HPB (Oxford) ; 21(12): 1656-1666, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31307889

RESUMO

BACKGROUND: Several studies have noted that the discriminatory ability and stratification performance of the AJCC 8th edition staging system is not entirely satisfactory. We aimed to improve the American Joint Committee on Cancer (AJCC) 8th edition staging system for intrahepatic cholangiocarcinoma (ICC). METHODS: A multicentric database from three Chinese mainland centers (n = 1601 patients) was used to modify the 8th edition staging system. This modified TNM (mTNM) staging system was then validated using the SEER database (n = 761 patients). A new TNM staging system, by incorporating serum tumor markers (TNMIS) into the mTNM staging system was then proposed. RESULTS: The 8th edition staging system did not provide an adequate stratification of prognosis in the Chinese multicentric cohort. The mTNM staging system offered a better discriminatory capacity in the multicentric cohort than the original 8th edition. External validation in the SEER cohort showed that the mTNM staging system also had a good stratification performance. After further incorporating a serum marker stage into the mTNM staging, the TNMIS staging system was able to stratify prognosis even better. CONCLUSION: The proposed mTNM staging system resulted in better stratification performance and the TNMIS staging system provided even more accurate prognostic classification than the conventional TNM system.


Assuntos
Antígenos Glicosídicos Associados a Tumores/sangue , Neoplasias dos Ductos Biliares/patologia , Antígeno Carcinoembrionário/sangue , Colangiocarcinoma/patologia , Estadiamento de Neoplasias/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Biomarcadores Tumorais/sangue , China , Colangiocarcinoma/mortalidade , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Fatores de Risco , Programa de SEER , Adulto Jovem
12.
Cancer Lett ; 460: 10-17, 2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31212000

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Appropriate treatment of this aggressive and heterogeneous cancer requires accurate staging and prognostic stratification, as does patient selection for clinical trials. Over the past two decades, several staging systems and prognostic models for ICC have been developed. Most include independent prognostic factors such as tumor extent, clinical parameters and histopathological features and are inaccurate. Accumulating findings offer new insights into the genetic and molecular basis of ICC progression. Hence, staging systems and prognostic models that incorporate in clinicalpathological factors, molecular and genomic information, and tumor biomarkers, and hence more accurately estimate prognosis, will become a reality. This review summarizes the current staging systems and prognostic models for ICC and highlights the need to establish more precise and personalized systems and models that incorporate tumor biologic factors.


Assuntos
Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Técnicas de Diagnóstico Molecular , Estadiamento de Neoplasias/métodos , Medicina de Precisão/métodos , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Humanos , Nomogramas , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco
13.
Mol Carcinog ; 58(8): 1389-1399, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30997702

RESUMO

Hepatocellular carcinoma (HCC) is a fatal disease with increasing morbidity and poor prognosis due to surgical recurrence and metastasis. Moreover, the molecular mechanism of HCC progression remains unclear. Although the role of p120-catenin (p120ctn) in liver cancer is well studied, the effects of secreted p120ctn transported by exosomes are less understood. Here, we show that p120ctn in exosomes secreted from liver cancer cells suppresses HCC cell proliferation and metastasis and expansion of liver cancer stem cells (CSCs). Mechanically, exosome p120ctn inhibits HCC cell progression via the STAT3 pathway, and the STAT3 inhibitor S3I-201 abolishes the observed effects on growth, metastasis, and self-renewal ability between exosome p120ctn-treated HCC cells and control cells. Taken together, we propose that p120ctn-containing exosomes derived from cancer cells inhibit the progression of liver cancer and may offer a new therapeutic strategy.


Assuntos
Carcinoma Hepatocelular/patologia , Cateninas/metabolismo , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , Fator de Transcrição STAT3/metabolismo , Ácidos Aminossalicílicos/farmacologia , Benzenossulfonatos/farmacologia , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Exossomos/patologia , Humanos , Neoplasias Hepáticas/genética , Metástase Neoplásica/patologia , Fator de Transcrição STAT3/antagonistas & inibidores
14.
Ann Surg Oncol ; 26(6): 1841-1850, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843164

RESUMO

OBJECTIVE: The aim of this study was to examine the impact of anatomical resection (AR) versus non-anatomical resection (NAR) on the survival outcomes in patients with intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: Data on 702 consecutive patients who underwent either AR (n = 319) or NAR (n = 383) for ICC were reviewed. Disease-free survival (DFS) and overall survival (OS) following AR versus NAR was compared using propensity score matching (PSM). Subgroups of patients who benefited from AR versus NAR were examined after being stratified by the 8th TNM staging of ICC. RESULTS: AR and NAR had similar complication rates (26.6% vs. 25.1%, p = 0.634). AR was associated with better 1-, 3-, and 5-year DFS and OS rates compared with NAR after PSM (58.1%, 35.7% and 28.1% vs. 44.1%, 23.9% and 18.0%; 72.9%, 45.7% and 36.0% vs. 62.0%, 30.8% and 25.3%; both p = 0.002). On multivariate analysis, NAR was associated with worse DFS and OS than AR [hazard ratio (HR) 1.461 and 1.488; 95% confidence interval (CI) 1.184-1.804 and 1.189-1.863, respectively]. Stratified analysis demonstrated similar outcomes following AR versus NAR for ICC at stages IA, II with vascular invasion, and III with visceral peritoneum perforation, local extrahepatic invasion and nodal metastasis, while NAR was associated with worse DFS and OS versus AR for stages IB (HR 1.897 and 2.321; 95% CI 1.179-3.052 and 1.376-3.914, respectively) or II ICC without vascular invasion (2.071 and 2.077; 95% CI 1.239-3.462 and 1.205-3.579, respectively). CONCLUSIONS: AR was associated with better survival outcomes compared with NAR in ICC patients with stage IB or II tumors without vascular invasion.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Hepatectomia/mortalidade , Idoso , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Taxa de Sobrevida
15.
Sci Rep ; 9(1): 2320, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787318

RESUMO

Brahma-related gene 1 (Brg1), a catalytic subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, is known to be involved in proliferative cell processes. Liver regeneration is initiated spontaneously after injury and leads to a strong proliferative response. In this study, a hepatocyte-specific Brg1 gene knockout mouse model was used to analyse the role of Brg1 in liver regeneration by performing a 70% partial hepatectomy (PH). After PH, Brg1 was significantly upregulated in wildtype mice. Mice with hepatocyte-specific Brg1 gene knockout showed a significantly lower liver to body weight ratio 48 h post-PH concomitant with a lower hepatocellular proliferation rate compared to wildtype mice. RNA sequencing demonstrated that Brg1 controlled hepatocyte proliferation through the regulation of the p53 pathway and several cell cycle genes. The data of this study reveal a crucial role of Brg1 for liver regeneration by promoting hepatocellular proliferation through modulation of cell cycle genes and, thus, identify Brg1 as potential target for therapeutic approaches.


Assuntos
Ciclo Celular , DNA Helicases/metabolismo , Hepatectomia , Regeneração Hepática , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proliferação de Células , Fígado/crescimento & desenvolvimento , Masculino , Camundongos Knockout , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
16.
HPB (Oxford) ; 21(6): 722-730, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30389432

RESUMO

BACKGROUND: Spontaneous tumor rupture (STR) of hepatocellular carcinoma (HCC) is a life-threatening condition. This study investigates the influences of STR on the observed survival and conditional survival of patients received hepatectomy. METHODS: A retrospective cohort of patients who underwent hepatectomy from 2009 to 2013 was divided into tumor rupture group and non-rupture group. Propensity score matching (PSM) was used for comparison of the observed survival and conditional survival probabilities between these two groups. RESULTS: 89 pairs of patients who had comparable background and tumor characteristics were created using PSM analysis. There was significant association between STR and increased risk of OS no matter when before or after PSM (p < 0.01). STR was significantly associated with increased risks of PFS before, while not after PSM. Multivariate Cox regression analyses demonstrated that STR was an independent risk factor associated with OS. There were significant differences in two groups for conditional probabilities of OS and PFS for an additional 6 months and 1 year before PSM, while not after PSM. CONCLUSIONS: This study identified STR but not PFS as an independent risk factor influencing OS, in patients with HCC following hepatectomy. In selected patients with STRHCC, hepatectomy should be performed with acceptable outcomes.


Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/cirurgia , Estadiamento de Neoplasias , Complicações Pós-Operatórias/mortalidade , Pontuação de Propensão , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , China/epidemiologia , Seguimentos , Hepatectomia/mortalidade , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Complicações Pós-Operatórias/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Ruptura Espontânea , Taxa de Sobrevida/tendências , Resultado do Tratamento
17.
Gene ; 684: 95-103, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30359743

RESUMO

Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of THOR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of THOR expression in OV6 or EpCAM-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference THOR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found ß-catenin as the downstream of THOR in HCC cells. The special ß-catenin inhibitor FH535 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between THOR knockdown HCC cells and control cells, which further confirmed that ß-catenin was required in THOR promoted liver CSCs expansion. Moreover, interference THOR hepatoma cells were more sensitive to sorafenib treatment, indicates that HCC patients with low THOR expression may benefit from sorafenib treatment. Collectively, THOR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting ß-catenin signaling.


Assuntos
Neoplasias Hepáticas/genética , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Fígado/metabolismo , Masculino , Recidiva Local de Neoplasia/genética , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Proteína Smad3/metabolismo , beta Catenina/metabolismo
18.
Surgery ; 165(4): 721-730, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30554724

RESUMO

BACKGROUND: The impact of the resection margin on survival outcomes in patients with hepatocellular carcinoma remains to be determined. This study aimed to examine the association between the width of resection margin and the presence of microvascular invasion in hepatitis B virus-related hepatocellular carcinoma. METHODS: We reviewed data on 2,508 consecutive patients who underwent liver resection for a solitary, hepatitis B virus-related hepatocellular carcinoma for operative morbidity, tumor recurrence, and overall survival. RESULTS: Microvascular invasion was identified histologically in 929 patients (37.0%). A wide margin of resection (≥1 cm, n = 384) resulted in better 5-year recurrence and overall survival versus a narrow margin of resection (<1 cm, n = 545) among patients with microvascular invasion (71.1% versus 85.9%; 44.9% versus 25.0%; both P < .001), but not in patients without microvascular invasion (P = .131, .182). Similar results were identified after propensity-score matching. A wide margin resection also had a lesser incidence of early recurrence developed within the first postoperative 24 months (58.1% versus 72.7%; P < .001). Compared with a wide resection margin, a narrow margin was associated with worse recurrence and overall survival in patients with microvascular invasion (hazard ratio: 1.50 and 1.75). In addition, a wide or a narrow resection margin had differences in the rate of grade I-III, but not grade IV complications (31.0% versus 21.7%; P = .017; 3.5% versus 1.6%; P = .147) among cirrhotic patients with microvascular invasion. CONCLUSION: The presence of microvascular invasion was associated with a worse prognosis after resection. A wide resection margin resulted in better long-term prognoses versus a narrow resection margin among patients with hepatitis B virus-related hepatocellular carcinoma with microvascular invasion.


Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Hepatite B Crônica/complicações , Neoplasias Hepáticas/cirurgia , Margens de Excisão , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia
19.
Gene ; 678: 129-136, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30098425

RESUMO

Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the development and progression of multiple cancers by previous studies. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in hepatocellular carcinoma (HCC) is still unclear. In this study, we found that THOR was relatively highly expressed in human HCC tissues and cell lines. Notably, high THOR expression was associated with worse prognosis. THOR depletion resulted in significant inhibition of the growth and metastasis of HCC cells. Mechanistically, THOR drives HCC cell progression via the PTEN/AKT pathway. Moreover, the specific PI3-K inhibitor LY294002 abolished the discrepancy in the growth and metastatic capacity between THOR-silenced HCC cells and control cells, which further confirmed that AKT was required in THOR-driven HCC cell growth and metastasis. Taken together, our results suggest that THOR could promote HCC cell growth and metastasis by amplifying PTEN/AKT signaling and may be a new therapeutic target and predictive factor for HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , Regulação para Cima , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , PTEN Fosfo-Hidrolase/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais
20.
Sci Rep ; 8(1): 11894, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089804

RESUMO

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a nuclear receptor demonstrated to play an important role in various biological processes. The aim of this study was to determine the effect of PPARγ on liver regeneration upon partial hepatectomy (PH) in mice. Mice were subjected to two-thirds PH. Before surgery, mice were either treated with the PPARγ agonist rosiglitazone, the PPARγ antagonist GW9662 alone, or with the c-met inhibitor SGX523. Liver-to-body-weight ratio, lab values, and proliferation markers were assessed. Components of the PPARγ-specific signaling pathway were identified by western blot and qRT-PCR. Our results show that liver regeneration is being inhibited by rosiglitazone and accelerated by GW9662. Inhibition of c-Met by SGX523 treatment abrogates GW9662-induced liver regeneration and hepatocyte proliferation. Hepatocyte growth factor (HGF) protein levels were significantly downregulated after rosiglitazone treatment. Activation of HGF/c-Met pathways by phosphorylation of c-Met and ERK1/2 were inhibited in rosiglitazone-treated mice. In turn, blocking phosphorylation of c-Met significantly abrogated the augmented effect of GW9662 on liver regeneration. Our data support the concept that PPARγ abrogates liver growth and hepatocellular proliferation by inhibition of the HGF/c-Met/ERK1/2 pathways. These pathways may represent potential targets in response to liver disease and could impact on the development of molecular therapies.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Regeneração Hepática/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/fisiologia , Anilidas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Hepatectomia/métodos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/fisiologia , Regeneração Hepática/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Piridazinas/farmacologia , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triazóis/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...