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1.
Future Oncol ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729887

RESUMO

Aim: To elucidate the integrative combinational gene regulatory network landscape of hepatocellular carcinoma (HCC) molecular carcinogenesis from diverse background. Materials & methods: Modified gene regulatory network analysis was used to prioritize differentially regulated genes and links. Integrative comparisons using bioinformatics methods were applied to identify potential critical molecules and pathways in HCC with different backgrounds. Results: E2F1 with its surrounding regulatory links were identified to play different key roles in the HCC risk factor dysregulation mechanisms. Hsa-mir-19a was identified as showed different effects in the three HCC differential regulation networks, and showed vital regulatory role in HBV-related HCC. Conclusion: We describe in detail the regulatory networks involved in HCC with different backgrounds. E2F1 may serve as a universal target for HCC treatment.

2.
Cancer Med ; 8(16): 6933-6944, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31566899

RESUMO

BACKGROUND: Portal vein tumor thrombus (PVTT) is a common complication in hepatocellular carcinoma (HCC), signaling dismal outcomes. This study was conducted to evaluate the survival benefit of postoperative portal vein perfusion chemotherapy (PVC) in patients with HCC and PVTT. METHODS: A retrospective review was conducted in 401 consecutive patients with HCC and PVTT who underwent hepatic resection between January 2009 and December 2015 and 67 patients received adjuvant postoperative PVC. A propensity score matching (PSM) was used to match patients with and without PVC at a ratio of 1:1. RESULTS: After PSM, the median time to recurrence (TTR) and overall survival (OS) were significantly longer in PVC group compared with control group (12.3 vs 5.8 months, P = .001; 19.0 vs 13.4 months, P = .037; respectively). At 1, 2, 3, and 5 years, the cumulative recurrence rates in PVC group were 48.1%, 86.5%, 92.3% ,96.2%, respectively, with OS rates of 63.8%, 37.9%, 24.4%, 18.3%, respectively; whereas cumulative recurrence rates of 76.6%, 91.5%, 94.3%, and 97.2%, respectively and OS rates of 55.4%, 23.0%, 12.4%, and 12.4%, respectively were recorded for the control group. In multivariate analysis, postoperative PVC emerged as a significant predictor for TTR (hazard ratio [HR], 0.523; P = .001) and OS (HR, 0.591; P = .010). PVC could reduce early recurrence (≤1 year) rate after surgical resection (40.3% vs 64.2%, P = .006) and clinical outcomes were further enhanced by adding sorafenib to postoperative PVC. CONCLUSIONS: Compared with surgical resection alone, postoperative adjuvant PVC treatment boosts survival and reduces early tumor recurrences in patients surgically treated for HCC and PVTT.

3.
Int J Cancer ; 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310010

RESUMO

Using a method optimized in hepatocellular carcinoma (HCC), we established patient-derived xenograft (PDX) models with an increased take rate (42.2%) and demonstrated that FBS +10% dimethyl sulfoxide exhibited the highest tumor take rate efficacy. Among 254 HCC patients, 103 stably transplantable xenograft lines that could be serially passaged, cryopreserved and revived were established. These lines maintained the diversity of HCC and the essential features of the original specimens at the histological, transcriptome, proteomic and genomic levels. Tumor engraftment was associated with lack of encapsulation, poor tumor differentiation, large size and overexpression of cancer stem cell biomarkers, and was an independent predictor for overall survival and tumor recurrence after resection. To confirm the preclinical value of the PDX model in HCC treatment, several antitumor agents were tested in 16 selected PDX models. The results revealed a high degree of pharmacologic heterogeneity in the cohort, as well as heterogeneity to different agents in the same individual. The sorafenib responses observed between HCC patients and the corresponding PDXs were also consistent. After molecular characterization of the PDX models, we explored the predictive markers for sorafenib response and found that mitogen-activated protein kinase kinase kinase 1 (MAP3K1) might play an important role in sorafenib resistance and sorafenib response is impaired in patients with MAP3K1 downexpression. Our results indicated that PDX models could accurately reproduce patient tumors biology and could aid in the discovery of new treatments to advance in precision medicine.

4.
BMC Med ; 17(1): 106, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31164128

RESUMO

BACKGROUND: Intratumoral immune infiltrates have manifested a robust prognostic signature in patients with hepatocellular carcinoma (HCC). We hypothesized that a novel tissue-related immune signature (TRIS) could improve the prediction of postoperative survival for patients diagnosed with early/intermediate HCC. METHODS: Twenty-eight immune features were immunohistochemically examined on 352 HCC specimens. The LASSO Cox regression model was used to construct a five-feature-based TRIS. The univariate and multivariate Cox analyses were performed. Based on independent predictors, the immune-clinical prognostic index (ICPI) was established. Performance assessment was measured with C-index and compared with seven traditional staging systems. The independent validation cohort (n = 393) was included to validate the model. RESULTS: By using the LASSO method, the TRIS were constructed on the basis of five immune features, CD3intratumoral (T), CD27T, CD68peritumoral (P), CD103T, and PD1T. Multivariate Cox analysis showed that the TRIS was an independent prognostic predictor. In the training cohort, γ-glutamyl transferase, tumor diameter, tumor differentiation, and TRIS were incorporated into the ICPI. The ICPI presented satisfactory discrimination ability, with C-index values of 0.691 and 0.686 in the training and validation cohorts, respectively. Compared with seven conventional staging systems (C-index, training cohort, 0.548-0.597; validation cohort, 0.519-0.610), the ICPI exhibited better performance for early/intermediate-stage HCCs. Further, the patients were categorized into three subgroups with X-tile software, and the stratified ICPI presented a superior corrected Akaike information criterion and homogeneity in both cohorts. CONCLUSIONS: Our ICPI was a useful and reliable prognostic tool which may offer good individualized prediction capability for HCC patients with early/intermediate stage.

5.
Theranostics ; 9(9): 2424-2438, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131045

RESUMO

EBV infection is a recognized epigenetic driver of carcinogenesis. We previously showed that EBV could protect cancer cells from TNF-induced necroptosis. This study aims to explore the epigenetic mechanisms allowing cancer cells with EBV infection to escape from RIP3-dependent necroptosis. Methods: Data from the TCGA database were used to evaluate the prognostic value of RIP3 promoter methylation and its expression. Western blotting, real-time PCR, and immunochemistry were conducted to investigate the relationship between LMP1 and RIP3 in cell lines and NPC tissues. BSP, MSP and hMeDIP assays were used to examine the methylation level. Induction of necroptosis was detected by cell viability assay, p-MLKL, and Sytox Green staining. Results: RIP3 promoter hypermethylation is an independent prognostic factor of poorer disease-free and overall survival in HNSCC patients, respectively. RIP3 is down-regulated in NPC (a subtype of HNSCC). EBV(LMP1) suppresses RIP3 expression by hypermethylation of the RIP3 promoter. RIP3 protein expression was inversely correlated with LMP1 expression in NPC tissues. Restoring RIP3 expression in EBV(LMP1)-positive cells inhibits xenograft tumor growth. The accumulation of fumarate and reduction of α-KG in EBV(LMP1)-positive cells led to RIP3 silencing due to the inactivation of TETs. Decreased FH activity caused fumarate accumulation, which might be associated with its acetylation. Incubating cells with fumarate protected NPC cells from TNF-induced necroptosis. Conclusion: These results demonstrate a pathway by which EBV(LMP1)-associated metabolite changes inhibited necroptosis signaling by DNA methylation, and shed light on the mechanism underlying EBV-related carcinogenesis, which may provide new options for cancer diagnosis and therapy.

6.
Int J Clin Oncol ; 24(7): 825-835, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31020447

RESUMO

BACKGROUND: Various inflammation-based prognostic scores have been associated with poor survival in patients with hepatocellular carcinoma (HCC). METHODS: Data were collected retrospectively from 674 HCC patients who underwent curative resection. The correlation between INS (inflammation-nutrition score), BCLC (Barcelona Clinic Liver Cancer) stage and inflammatory indices and overall survival (OS) and disease free survival (DFS) was examined. RESULTS: An elevated INS was associated with both tumor and host clinical characteristics. The combination of INS and BCLC stage stratifies OS and DFS from 80% and 65% (INS = 0, stage A) to 0% (INS = 2, stage C). Univariate and multivariate analyses revealed that the INS was an independent predictor for OS and DFS, and was superior to inflammation-based scores. In addition, INS was demonstrated to be a prognostic factor for patients with early stage and had a higher AUC value in comparison with inflammation scores. CONCLUSION: This study demonstrates that the INS is an independent marker of poor prognosis in patients with resectable HCC, especially for those with early stage, and it provides complimentary prognostic information to BCLC stage, and may aid in treatment strategy.


Assuntos
Carcinoma Hepatocelular/patologia , Inflamação/patologia , Neoplasias Hepáticas/patologia , Estado Nutricional , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
7.
J Hematol Oncol ; 12(1): 37, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971294

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD73-expressing tumor cell is implicated in development of several types of cancer. However, the role of CD73 in HCC cell has not been systematically investigated and its underlying mechanism remains elusive. METHODS: CD73 expression in HCC cell was determined by RT-PCR, Western blot, and immunohistochemistry staining. Clinical significance of CD73 was evaluated by Cox regression analysis. Cell counting kit-8 and colony formation assays were used for proliferation evaluation. Transwell assays were used for motility evaluations. Co-immunoprecipitation, cytosolic and plasma membrane fractionation separation, and ELISA were applied for evaluating membrane localization of P110ß and its catalytic activity. NOD/SCID/γc(null) (NOG) mice model was used to investigate the in vivo functions of CD73. RESULTS: In the present study, we demonstrate that CD73 was crucial for epithelial-mesenchymal transition (EMT), progression and metastasis in HCC. CD73 expression is increased in HCC cells and correlated with aggressive clinicopathological characteristics. Clinically, CD73 is identified as an independent poor prognostic indicator for both time to recurrence and overall survival. CD73 knockdown dramatically inhibits HCC cells proliferation, migration, invasion, and EMT in vitro and hinders tumor growth and metastasis in vivo. Opposite results could be observed when CD73 is overexpressed. Mechanistically, adenosine produced by CD73 binds to adenosine A2A receptor (A2AR) and activates Rap1, which recruits P110ß to the plasma membrane and triggers PIP3 production, thereby promoting AKT phosphorylation in HCC cells. Notably, a combination of anti-CD73 and anti-A2AR achieves synergistic depression effects on HCC growth and metastasis than single agent alone. CONCLUSIONS: CD73 promotes progression and metastasis through activating PI3K/AKT signaling, indicating a novel prognostic biomarker for HCC. Our data demonstrate the importance of CD73 in HCC in addition to its immunosuppressive functions and revealed that co-targeting CD73 and A2AR strategy may be a promising novel therapeutic strategy for future HCC management.

8.
Oncologist ; 24(7): 997-1007, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30910867

RESUMO

BACKGROUND: Patients with intrahepatic cholangiocarcinoma (ICC) rarely present fever as the initial symptom. We aimed to identify clinical characteristics and prognostic factors for these feverish patients. SUBJECTS, MATERIALS, AND METHODS: This study retrospectively reviewed 31 patients with ICC with fever (≥38.0°C) treated at our hospital between January 2002 and December 2014. A propensity score was used to match patients with and without fever at a ratio of 1:2. RESULTS: Patients with ICC with fever had higher serum γ-glutamyl transferase and carcinoembryonic antigen levels, larger tumors, poorer tumor differentiation, and worse prognosis (all p < .05) than those without fever. This was supported by propensity score matching (PSM) analysis. Univariate and multivariate analyses indicated that microvascular invasion, hilar lymph node metastasis, and temperature ≥ 38.6°C were related to prognosis. Patients with ICC with fever had higher levels of leucocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in peripheral blood before and after PSM analysis. Body temperature positively correlated with leucocytes (r = 0.599, p < .001), neutrophils (r = 0.644, p < .001), NLR (r = 0.681, p < .001), and PLR (r = 0.457, p = .010). CONCLUSION: Patients with ICC with fever ≥38.0°C and ≥38.6°C had poor and extremely poor prognosis, respectively. Radical surgical treatment may improve the prognosis of patients with ICC with fever <38.6°C. However, systemic therapy (e.g., anti-inflammatory and immune therapy) may be preferable to surgery for these patients with fever ≥38.6°C. IMPLICATIONS FOR PRACTICE: Patients with intrahepatic cholangiocarcinoma (ICC) with fever (≥38.0°C) as the initial symptom are extremely rare. Because their symptoms are similar to those of liver abscess, diagnosis is challenging, and most of these patients are already at an advanced stage at the time of diagnosis. Patients with ICC with fever had different clinical characteristics and worse prognosis than those without fever. The prognosis of those with temperature <38.6°C would be improved by timely surgical intervention. Those with fever ≥38.6°C had an extremely dismal outcome, although they all received radical surgical treatment. New therapeutic strategies are needed to improve survival for patients with ICC with temperature ≥38.6°C.

9.
J Immunother Cancer ; 7(1): 77, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885276

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options. Immunotherapies targeting PD-1/PD-L1 pathway represent a promising treatment for ICC. However, PD-L1 expression and microsatellite instability are not common in ICC. This study aimed to investigate whether HHLA2, a newly identified B7 family immune checkpoint for T cells, could be a therapeutic target next to PD-L1 in ICC. METHODS: Expression levels of PD-L1 and HHLA2 as well as infiltrations of CD3+, CD8+, CD4 + Foxp3+, CD68+, CD163+ and CD20+ cells were evaluated by immunohistochemistry in 153 resected ICC samples. Comprehensive comparisons were made between PD-L1 and HHLA2 in terms of the expression rates, clinicopathological features and infiltrations of different immune cells. The expression level and prognostic significance of HHLA2 were further validated in an independent cohort. RESULTS: Expression of HHLA2 is more frequent than PD-L1 in ICC (49.0% vs 28.1%). Co-expression of both immune checkpoints was infrequent (13.1%) and 50% PD-L1 negative cases were with elevated HHLA2. HHLA2 overexpression was associated with sparser CD3+ tumor infiltrating lymphocytes (TILs), CD8+ TILs and a higher CD4 + Foxp3+/CD8+ TIL ratio, whereas PD-L1 expression was associated with prominent T cells and CD163+ tumor associated macrophages infiltrations. PD-L1 failed to stratify overall survival (OS) but HHLA2 was identified as an independent prognostic indicator for OS in two independent cohorts. CONCLUSIONS: Compared with PD-L1, HHLA2 is more prevalent and possesses more explicit prognostic significance, which confer the rationale for HHLA2 as a potential immunotherapeutic target next to PD-L1 for ICC patients.

10.
Mol Carcinog ; 58(1): 19-30, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30182496

RESUMO

S100A11 is reported to associate with progression and poor prognosis in several tumors. We previously reported that S100A11 was highly expressed in intrahepatic cholangiocarcinoma (ICC) cells and promoted TGF-ß1-induced EMT through SMAD2/3 signaling pathway. Here, we explored the prognostic role of S100A11 on ICC patients and preliminary molecular mechanisms how S100A11 regulated ICC cell proliferation. Our results showed that S100A11 was obviously increased in ICC tumor tissues. High expression of S100A11 was closely correlated with lymph node metastasis (LNM) and TNM stage and was an independent risk factor for patients' overall survival (OS) and recurrence-free survival (RFS). The nomograms comprising LNM and S100A11 achieved better predictive accuracy compared with TNM staging system for OS and RFS prediction. Silencing S100A11 significantly suppressed RBE cells and HCCC9810 cells proliferation, colony formation, and activation of P38/mitogen-activated protein kinase (MAPK) signaling pathway in vitro and inhibited tumor growth in vivo. In contrast, the overexpression of S100A11 in RBE cells and HCCC9810 cells achieved the opposite results. S100A11-induced proliferation was abolished after treatment with P38 inhibitor. Our findings suggest S100A11/P38/MAPK signaling pathway may be a potential therapeutic target for ICC patients.


Assuntos
Neoplasias dos Ductos Biliares/secundário , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Colangiocarcinoma/patologia , Recidiva Local de Neoplasia/patologia , Proteínas S100/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Proteínas S100/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/genética
11.
Cancer Manag Res ; 10: 5383-5394, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464634

RESUMO

Background: Radical resection is the treatment of choice for hepatocellular carcinoma (HCC). However, even with this treatment, HCC prognosis and the efficacy of current predictive models for such patients remain unsatisfactory. Here, we describe an accurate and easy-to-use prognostic index for patients with HCC who have undergone curative resection. Methods: The study population comprised of 1,041 patients with HCC who underwent curative resection at Zhongshan Hospital. This population was reduced to 768 patients who were treated in 2012 analyzed as the training cohort and 273 patients treated in 2007 who were used as a validation cohort. Results: The lactic dehydrogenase to albumin ratio (LAR) was identified as a significant prognostic index for both overall survival and recurrence-free survival in two independent cohorts. The optimal cutoff value for LAR was determined to be 5.5. The C-index of LAR was superior to other inflammatory scores and serum parameters. This biomarker was also shown to be a stable predictive index in the validation cohort. The new nomogram combining LAR with the Barcelona Clinic Liver Cancer staging system had an improved ability to discriminate overall survival and recurrence-free survival. Nomogram predictions were consistent with observations based on calibration and decisive curve analysis in both independent cohorts. Conclusion: LAR is a novel, convenient, reliable, and accurate prognostic predictor in patients with HCC undergoing curative resection. Our results suggest the recommendation of LAR to be used in routine clinical practice.

12.
Cell Death Dis ; 9(10): 1036, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305612

RESUMO

Current therapeutic options for intrahepatic cholangiocarcinoma (ICC) are very limited, which is largely attributed to poor understanding of molecular pathogenesis of ICC. Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) has been reported to be a broad-spectrum tumor suppressor in many tumor types, yet its role in ICC remains unknown. The aim of this study was to investigate the clinical implications and biological function of BAP1 in ICC. Our results showed that the messenger RNA and protein levels of BAP1 were significantly downregulated in ICC versus paired non-tumor tissues. Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo. Conversely, knockdown of BAP1 yielded opposing effects. Mechanistically, BAP1 functioned as a tumor suppressor in ICC by inhibiting the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase/c-Jun pathways, and this function was abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated with aggressive tumor characteristics, such as larger tumor size, presence of lymphatic metastasis, and advanced tumor node metastasis stage. Survival analysis revealed that low BAP1 expression was significantly and independently associated with poor overall survival and relapse-free survival after curative surgery. In conclusion, BAP1 is a putative tumor suppressor of ICC, and may serve as a valuable prognostic biomarker as well as potential therapeutic target for ICC.

13.
Oncologist ; 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30257891

RESUMO

BACKGROUND: Fibrotic tumor stroma (FTS) has been implicated in cancer promotion in several neoplasms. The histological features of FTS are convenient and easily accessible in clinical routine in intrahepatic cholangiocarcinoma (ICC) specimens. The goal of this study was to explore prognostic impacts of the quantity and maturity of FTS on surgical ICC patients. Moreover, we aimed to propose an efficient prognostic nomogram for postoperative ICC patients. MATERIALS AND METHODS: The clinical profiles of 154 consecutive postoperative ICC patients were retrospectively analyzed. Tumor-stroma ratio and morphological maturity of FTS were evaluated on hematoxylin and eosin-stained tumor sections. CD3, CD8, and α-smooth muscle actin (α-SMA) staining were performed on corresponding tissue microarrays. The nomogram was established on variables selected by multivariate analyses and was validated in 10-fold cross-validation. RESULTS: Rich tumor stroma and strong α-SMA expression were associated with poor overall survival (OS). However, in multivariate analyses, these two biomarkers failed to stratify both OS and recurrence-free survival (RFS). Immature FTS was correlated with tumor multiplicity, advanced clinical stage, and sparser CD3 and CD8 positive tumor-infiltrating lymphocytes (TILs) and was identified as an independent prognostic indicator for both OS and RFS. The nomogram comprising FTS maturity, tumor number, microvascular invasion, and lymph node metastasis possessed higher predictive power relative to conventional staging systems. CONCLUSION: Immature FTS was an independent risk factor for survival and was associated with sparser CD3 and CD8 positive TILs in ICC. The prognostic nomogram integrating the maturity of FTS offers a more accurate risk stratification for postoperative ICC patients. IMPLICATIONS FOR PRACTICE: Accumulating evidence has suggested that fibrotic components in tumor microenvironment (TME) play a complicated and vital role in TME reprogramming and cancer progression. However, in clinical practice, the evaluation of fibrotic tumor stroma (FTS) is still neglected to some extent. This study's findings indicated that, in intrahepatic cholangiocarcinoma (ICC), the histological maturity of FTS is a robust prognostic indicator for patients who underwent curative resection. Moreover, prognostic nomogram constructed on the maturity of FTS possessed higher predictive power relative to the conventional tumor-node-metastasis staging systems. Taken together, the evaluation of FTS should be emphasized in clinical routine for more accurate prognostic prediction in postoperative ICC patients.

14.
Theranostics ; 8(15): 4050-4061, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30128035

RESUMO

Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer. Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models. Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.

15.
BMC Cancer ; 18(1): 550, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743053

RESUMO

BACKGROUND: Liver cancer is the second leading cause of cancer-related deaths and characterized by heterogeneity and drug resistance. Patient-derived xenograft (PDX) models have been widely used in cancer research because they reproduce the characteristics of original tumors. However, the current studies of liver cancer PDX mice are scattered and the number of available PDX models are too small to represent the heterogeneity of liver cancer patients. To improve this situation and to complement available PDX models related resources, here we constructed a comprehensive database, PDXliver, to integrate and analyze liver cancer PDX models. DESCRIPTION: Currently, PDXliver contains 116 PDX models from Chinese liver cancer patients, 51 of them were established by the in-house PDX platform and others were curated from the public literatures. These models are annotated with complete information, including clinical characteristics of patients, genome-wide expression profiles, germline variations, somatic mutations and copy number alterations. Analysis of expression subtypes and mutated genes show that PDXliver represents the diversity of human patients. Another feature of PDXliver is storing drug response data of PDX mice, which makes it possible to explore the association between molecular profiles and drug sensitivity. All data can be accessed via the Browse and Search pages. Additionally, two tools are provided to interactively visualize the omics data of selected PDXs or to compare two groups of PDXs. CONCLUSION: As far as we known, PDXliver is the first public database of liver cancer PDX models. We hope that this comprehensive resource will accelerate the utility of PDX models and facilitate liver cancer research. The PDXliver database is freely available online at: http://www.picb.ac.cn/PDXliver/.

17.
J Cancer ; 9(6): 1025-1032, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29581782

RESUMO

Backgrounds: Regarding the difficulty of CHC diagnosis and potential adverse outcomes or misuse of clinical therapies, an increasing number of patients have undergone liver transplantation, transcatheter arterial chemoembolization (TACE) or other treatments. Objective: To construct a convenient and reliable risk prediction model for identifying high-risk individuals with combined hepatocellular-cholangiocarcinoma (CHC). Methods: 3369 patients who underwent surgical resection for liver cancer at Zhongshan Hospital were enrolled in this study. The epidemiological and clinical characteristics of the patients were collected at the time of tumor diagnosis. Variables (P <0.25 in the univariate analyses) were evaluated using backward stepwise method. A receiver operating characteristic (ROC) curve was used to assess model discrimination. Calibration was performed using the Hosmer-Lemeshow test and a calibration curve. Internal validation was performed using a bootstrapping approach. Results: Among the entire study population, 250 patients (7.42%) were pathologically defined with CHC. Age, HBcAb, red blood cells (RBC), blood urea nitrogen (BUN), AFP, CEA and portal vein tumor thrombus (PVTT) were included in the final risk prediction model (area under the curve, 0.69; 95% confidence interval, 0.51-0.77). Bootstrapping validation presented negligible optimism. When the risk threshold of the prediction model was set at 20%, 2.73% of the patients diagnosed with liver cancer would be diagnosed definitely, which could identify CHC patients with 12.40% sensitivity, 98.04% specificity, and a positive predictive value of 33.70%. Conclusions: Herein, the study established a risk prediction model which incorporates the clinical risk predictors and CT/MRI-presented PVTT status that could be adopted to facilitate the diagnosis of CHC patients preoperatively.

18.
J Cancer ; 9(6): 1106-1112, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29581790

RESUMO

Aims: To compare the long-term prognosis of younger and elderly patients with combined hepatocellular-cholangiocarcinoma (CHC) who underwent curative resection between 1993 and 2014 at our center. Methods: Two hundred and thirteen patients who underwent liver resection for CHC were enrolled in our study. The overall survival (OS) and disease-free survival (DFS) of elderly patients (age≥60, n=52) and younger patients (age<60, n=161) were compared by multivariate analysis and propensity score matching (PSM) analysis. Results: Among the 213 CHC patients, the elderly patients had a higher rate of worse Child-Pugh grade (P=0.027), abnormal serum albumin (P<0.001) and lymphoid metastases (P=0.024). The proportion of HBV-positive CHC patients (74.6%, 159/213) was much higher than that observed in healthy cohorts. Younger patients had a higher rate of hepatitis B virus (HBV) infection compared to older patients (83.9% vs 46.2%, P<0.001). OS and DFS of the elderly and younger patients before and after propensity score matching were comparable. Conclusion: Elderly and younger patients who underwent liver resection for CHC have comparable long-term OS and DFS.

19.
Cancer Sci ; 109(4): 1195-1206, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29446854

RESUMO

Interleukin-35 (IL-35) is implicated in tumorigenesis, but its exact impact on intrahepatic cholangiocarcinoma (ICC) is not clear. The aim of the present study was to explore the specific effect of IL-35 on patient prognosis. Additionally, we formulated an effective prognostic nomogram for ICC patients after curative resection. Immunohistochemistry was applied to explore IL-35 expression as well as IL-35 receptor (IL-35R) in 102 ICC patients. Results showed that IL-35 was highly expressed in ICC tumor tissues and was positively associated with lymph node metastasis (LNM), TNM stage and vascular invasion and was an independent prognostic factor for patients' overall survival (OS) and recurrence-free survival (RFS). High expression of IL-35R (gp130 and IL-12Rß2) was also observed in ICC cancer tissues, but only gp130 was an independent prognostic factor for OS and RFS and was indispensable in IL-35-mediated ICC clinical prognosis. The nomogram comprising carcinoembryonic antigen, LNM, IL-35 and gp130 expression achieved better predictive accuracy compared with TNM stage for OS. Our data support that high IL-35 expression correlates with ICC aggressiveness and emerges as a valuable biomarker for evaluating ICC progression and prognosis in clinical work.


Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Colangiocarcinoma/metabolismo , Interleucinas/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Receptor gp130 de Citocina/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-1/metabolismo , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Receptores de Interleucina-12/metabolismo , Estudos Retrospectivos
20.
Clin Cancer Res ; 24(9): 2203-2213, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29374055

RESUMO

Background: In the present study, we assessed the clinical value of circulating tumor cells (CTC) with stem-like phenotypes for diagnosis, prognosis, and surveillance in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by an optimized qPCR-based detection platform.Methods: Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter patient study with independent validation (total n = 1,006), including healthy individuals and patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL), and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of the CTC panel in treatment response surveillance and its prognostic significance were further investigated.Results: The AUC of the CTC panel was 0.88 in the training set [sensitivity = 72.5%, specificity = 95.0%, positive predictive value (PPV) = 92.4, negative predictive value (NPV) = 77.8] and 0.93 in the validation set (sensitivity = 82.1%, specificity = 94.2%, PPV = 89.9, NPV = 89.3). This panel performed equally well in detecting early-stage and α-fetoprotein-negative HCC, as well as differentiating HCC from CHB, LC, and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of the CTC panel in predicting tumor recurrence was further confirmed [training: HR = 2.692; 95% confidence interval (CI), 1.617-4.483; P < 0.001; and validation: HR = 3.127; 95% CI, 1.360-7.190; P = 0.007].Conclusions: Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies. Clin Cancer Res; 24(9); 2203-13. ©2018 AACR.

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