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1.
J Clin Transl Hepatol ; 9(6): 898-908, 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34966653

RESUMO

Background and Aims: The overall survival (OS) of hepatocellular carcinoma (HCC) remains dismal. Bioinformatic analysis of transcriptome data could identify patients with poor OS and may facilitate clinical decision. This study aimed to develop a prognostic gene model for HCC. Methods: GSE14520 was retrieved as a training set to identify differential expressed genes (DEGs) between tumor and adjacent liver tissues in HCC patients with different OS. A DEG-based prognostic model was then constructed and the TCGA-LIHC and ICGC-LIRI datasets were used to validate the model. The area under the receiver operating characteristic curve (AUC) and hazard ratio (HR) of the model for OS were calculated. A model-based nomogram was established and verified. Results: In the training set, differential expression analysis identified 80 genes dysregulated in oxidation-reduction and metabolism regulation. After univariate Cox and LASSO regression, eight genes (LPCAT1, DHRS1, SORBS2, ALDH5A1, SULT1C2, SPP1, HEY1 and GOLM1) were selected to build the prognostic model. The AUC for 1-, 3- and 5-year OS were 0.779, 0.736, 0.754 in training set and 0.693, 0.689, 0.693 in the TCGA-LIHC validation set, respectively. The AUC for 1- and 3-year OS were 0.767 and 0.705 in the ICGC-LIRI validation set. Multivariate analysis confirmed the model was an independent prognostic factor (training set: HR=4.422, p<0.001; TCGA-LIHC validation set: HR=2.561, p<0.001; ICGC-LIRI validation set: HR=3.931, p<0.001). Furthermore, a nomogram combining the model and AJCC stage was established and validated, showing increased OS predictive efficacy compared with the prognostic model (p=0.035) or AJCC stage (p<0.001). Conclusions: Our eight-gene prognostic model and the related nomogram represent as reliable prognostic tools for OS prediction in HCC patients.

2.
J Cancer ; 12(23): 6937-6947, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34729096

RESUMO

Background: Current treatment options for intrahepatic cholangiocarcinoma (ICC) are limited by the lack of understanding of the disease pathogenesis. It has been known that mucin 1 (MUC1) is a cell surface mucin that highly expressed in various cancer tissues. However, its role in ICC has not been well studied. The purpose of this study was to investigate the clinical significance and biological function of MUC1 in ICC. Methods: qRT-PCR and western blot assays were performed to examine MUC1 expression. RNA-Seq (RNA Sequencing) s conducted to explore the RNA expression. A tissue microarray study including 214 ICC cases was also conducted to evaluate the clinical relevance and prognostic significance of MUC1. The role and underlying mechanisms of MUC1 in regulating cell growth and invasion were further explored both in vitro and in vivo models. Results: The mRNA and protein levels of MUC1 were significantly up-regulated in ICC compared to paired non-tumor tissues. Depletion of MUC1 in HCCC9810 cells significantly inhibited cell proliferation, migration and invasion in vitro and overexpression of MUC1 in RBE cells resulted in increased cell proliferation, migration and invasion. Both univariate and multivariate analysis revealed that the protein expression of MUC1 was associated with overall survival and relapse-free survival after tumor resection. Clinically, high MUC1 expression was more commonly observed in aggressive tumors. Further studies indicated that MUC1 exerted its function through activating Wnt/ ß-catenin pathway. Conclusions: Our data suggests that MUC1 promoted ICC progression via activating Wnt / ß-catenin pathway. This study not only deciphered the role of MUC in ICC pathogenesis, but also shed light upon identifying novel potential therapeutic targets.

3.
J Cancer ; 12(23): 7190-7200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34729120

RESUMO

Background: This study aimed to evaluate the role of plasma microRNA panel (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-801) for prediction and surveillance of early tumor recurrence in hepatocellular carcinoma (HCC) patients who had undergone liver transplantation (LT). Methods: The expression of plasma microRNA panel was assayed in 193 HCC patients (training cohort, n =151; validation cohort, n = 42). Sensitivity and specificity for detecting post-transplant HCC recurrence, and the relationship of microRNA panel expression with clinical characteristics were analyzed accordingly. The prognostic value of microRNA panel was compared with that of AFP (alpha-fetoprotein) and DCP (Des-gamma-carboxyprothrombin). Cox regression analyses were used to evaluate independent prognostic factors. Results: In the training cohort, the rate of positive plasma microRNA panel status at 7-14 days after LT (late phase; 44.2%) decreased than that before (76.2%, P < 0.001) and 1-6 days after LT (early phase; 78.5%, P < 0.001). At late phase, positive microRNA panel status correlated with higher early tumor recurrence rate (one year after LT) than negative status (45.9% vs 10.7%; P < 0.001). Patients with persistent positive microRNA panel status both before and after LT had the highest early tumor recurrence rate in this cohort (54.9%, P < 0.001). The results were consistent in the validation cohort. Cox regression analysis found that positive plasma microRNA panel status at late phase was the only independent risk factor for early recurrence (HR: 4.903, 95% CI = 2.195 - 10.951; P < 0.001). Dynamic monitoring demonstrated plasma microRNA panel status changed from negative to positive earlier than AFP and DCP upon recurrence, and the median time between positivity of plasma microRNA and imaging evidence of recurrence was 2.4 (0.5-10.0) months. Conclusions: Plasma microRNA panel could be a noninvasive biomarker for prediction and surveillance of early tumor recurrence in HCC patients who have undergone LT.

4.
Front Oncol ; 11: 704042, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327143

RESUMO

Background: Intrahepatic cholangiocarcinoma (ICC) remains one of the most intractable malignancies. The development of effective drug treatments for ICC is seriously hampered by the lack of reliable tumor models. At present, patient derived xenograft (PDX) models prove to accurately reflect the genetic and biological diversity required to decipher tumor biology and therapeutic vulnerabilities. This study was designed to investigate the establishment and potential application of PDX models for guiding personalized medicine and identifying potential biomarker for lenvatinib resistance. Methods: We generated PDX models from 89 patients with ICC and compared the morphological and molecular similarities of parental tumors and passaged PDXs. The clinicopathologic features affecting PDX engraftment and the prognostic significance of PDX engraftment were analyzed. Drug treatment responses were analyzed in IMF-138, IMF-114 PDX models and corresponding patients. Finally, lenvatinib treatment response was examined in PDX models and potential drug resistance mechanism was revealed. Results: Forty-nine PDX models were established (take rate: 55.1%). Successful PDX engraftment was associated with negative HbsAg (P = 0.031), presence of mVI (P = 0.001), poorer tumor differentiation (P = 0.023), multiple tumor number (P = 0.003), presence of lymph node metastasis (P = 0.001), and later TNM stage (P = 0.039). Moreover, patients with tumor engraftment had significantly shorter time to recurrence (TTR) (P < 0.001) and worse overall survival (OS) (P < 0.001). Multivariate analysis indicated that PDX engraftment was an independent risk factor for shortened TTR (HR = 1.84; 95% CI, 1.05-3.23; P = 0.034) and OS (HR = 2.13; 95% CI, 1.11-4.11; P = 0.024). PDXs were histologically and genetically similar to their parental tumors. We also applied IMF-138 and IMF-114 PDX drug testing results to guide clinical treatment for patients with ICC and found similar treatment responses. PDX models also facilitated personalized medicine for patients with ICC based on drug screening results using whole exome sequencing data. Additionally, PDX models reflected the heterogeneous sensitivity to lenvatinib treatment and CDH1 might be vital to lenvatinib-resistance. Conclusion: PDX models provide a powerful platform for preclinical drug discovery, and potentially facilitate the implementation of personalized medicine and improvement of survival of ICC cancer patient.

5.
Ann Transl Med ; 9(9): 774, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34268387

RESUMO

Background: Hepatectomy for huge hepatocellular carcinoma (HCC) (diameter ≥10 cm) is characterized by high mortality. This study aimed to establish a preoperative model to evaluate the risk of postoperative 90-day mortality for huge HCC patients. Methods: We retrospectively enrolled 1,127 consecutive patients and prospectively enrolled 93 patients with huge HCC who underwent hepatectomy (training cohort, n=798; validation cohort, n=329; prospective cohort, n=93) in our institute. Based on independent preoperative predictors of 90-day mortality, we established a logistic regression model and visualized the model by nomogram. Results: The 90-day mortality rates were 9.6%, 9.2%, and 10.9% in the training, validation, and prospective cohort. The α-fetoprotein (AFP) level, the prealbumin levels, and the presence of portal vein tumor thrombosis (PVTT) were preoperative independent predictors of 90-day mortality. A logistic regression model, AFP-prealbumin-PVTT score (APP score), was subsequently established and showed good performance in predicting 90-day mortality (training cohort, AUC =0.87; validation cohort, AUC =0.91; prospective cohort, AUC =0.93). Using a cut-off of -1.96, the model could stratify patients into low risk (≤-1.96) and high risk (>-1.96) with different 90-day mortality rates (~30% vs. ~2%). Furthermore, the predictive performance for 90-day mortality and overall survival was significantly superior to the Child-Pugh score, the model of end-stage liver disease (MELD) score, and the albumin-bilirubin (ALBI) score. Conclusions: The APP score can precisely predict postoperative 90-day mortality as well as long-term survival for patients with huge HCC, assisting physician selection of suitable candidates for liver resection and improving the safety and efficacy of surgical treatment.

6.
Nat Commun ; 12(1): 4091, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215748

RESUMO

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Heterogeneidade Genética , Evasão da Resposta Imune , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Células Neoplásicas Circulantes/imunologia , Idoso , Animais , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Quimiocina CCL5/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Metástase Neoplásica , Células Neoplásicas Circulantes/metabolismo , Prognóstico , RNA-Seq , Transcriptoma , Microambiente Tumoral
7.
Am J Cancer Res ; 11(4): 1557-1571, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33948373

RESUMO

Various epidemiology studies showed the correlation between Alzheimer's disease (AD) and low incidence of cancer. However, the etiology underlying etiology of AD-related carcinogenesis remains largely elusive. Our study focused on characterizing the role of TM2D1 (TM2 domain containing 1) in hepatocellular carcinoma. TM2D1 is also known as ß-amyloid peptide binding protein and is critical to the pathogenesis of AD. We found that TM2D1 is increasingly expressed in HCC tumors relative to the peritumoral tissues of the matched tumors and high TM2D1 expression predicts unfavorable clinical outcomes. TM2D1 overexpression induced HCC cell proliferation, migration and invasion, which was related to the epithelial-mesenchymal transition (EMT) observed in these cells. Conversely, TM2D1 depletion led to opposite phenotype in HCC. Mechanistically, we found that TM2D1 promoted Akt and ß-catenin hyper-activation, which corresponded with molecular marker change in EMT signaling pathway. Taken together, our results indicated that TM2D1 played an important role in the EMT process in HCC cells by activating AKT and ß-catenin signaling and may become a promising therapeutic target in HCC.

8.
Clin Transl Med ; 11(2): e335, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33634982

RESUMO

OBJECTIVE: Differentiation-inducing therapy for tumors is a strategy that aims to induce the differentiation and maturation of cancer stem cells (CSCs). The differentiation-inducing capacity of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC) and the underlying mechanism were previously unknown. METHODS: In the present study, we explored the ATO-induced differentiation of CSCs in HCC by detecting the expression of CSC-related markers and tumorigenicity variation in vivo and in vitro. We developed a combined chemotherapeutic approach to HCC by characterizing the effects of combinatorial treatment with 5-fluorouracil (5-FU)/cisplatin and ATO in vitro and in patient-derived xenograft models. Changes in gene expression patterns were investigated by gene microarray analysis. RESULTS: ATO effectively induced differentiation of CSCs by downregulation of CSC-related genes and suppression of tumorigenicity capability. Combinatorial treatment with ATO and 5-FU/cisplatin significantly enhanced therapeutic effects in HCC cells compared with the treatment with 5-FU/cisplatin alone. Synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways by ATO and 5-FU/cisplatin is a potential molecular mechanism underlying the differentiation effect. CONCLUSIONS: ATO induced the differentiation of HCC CSCs and potentiated the cytotoxic effects of 5-FU/cisplatin through synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways. These results offer new insights for the clinical treatment of HCC.

9.
Liver Int ; 41(3): 562-573, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33205544

RESUMO

BACKGROUND & AIMS: Liver transplantation (LTx) is one of the most effective treatments for hepatocellular carcinoma (HCC); however, tumour recurrence after LTx often leads to poor outcomes. This study investigated the value of circulating tumour cells (CTCs) as a predictor of recurrence following LTx in patients with HCC. METHODS: This analysis included 193 patients with HCC who underwent LTx at our institute and accepted pre- and post-operative CTC detection; 38 were selected for serial CTC monitoring. The predictive value of CTCs for tumour recurrence in patients with HCC following LTx was evaluated. Single-cell whole genome sequencing was used to characterize CTCs. RESULTS: Overall, the CTC burden decreased after LTx (P < .05). Post-operative CTC count ≥ 1 per 5 mL peripheral blood was identified as a potential biomarker for predicting tumour recurrence after LTx, especially in patients with no detectable CTCs prior to LTx and negative tumour serological biomarkers. The predictive value of post-operative CTC count ≥ 1 per 5 mL blood was retained in patients who did not meet the Milan criteria, University of California San Francisco (UCSF) criteria, or Fudan criteria (all P < .05). Furthermore, post-operative serial CTC detection may be useful in post-surgical surveillance for HCC recurrence. CONCLUSIONS: CTCs may be a useful biomarker to evaluate recurrence risk following LTx in patients with HCC. Evaluation based on CTC detection may enhance the post-transplant management of HCC, and improve the therapeutic efficacy of LTx.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Células Neoplásicas Circulantes , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , São Francisco
10.
Mol Oncol ; 15(9): 2345-2362, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33301640

RESUMO

Circulating tumor cell (CTC) analysis holds great potential to be a noninvasive solution for clinical cancer management. A complete workflow that combined CTC detection and single-cell molecular analysis is required. We developed the ChimeraX® -i120 platform to facilitate negative enrichment, immunofluorescent labeling, and machine learning-based identification of CTCs. Analytical performances were evaluated, and a total of 477 participants were enrolled to validate the clinical feasibility of ChimeraX® -i120 CTC detection. We analyzed copy number alteration profiles of isolated single cells. The ChimeraX® -i120 platform had high sensitivity, accuracy, and reproducibility for CTC detection. In clinical samples, an average value of > 60% CTC-positive rate was found for five cancer types (i.e., liver, biliary duct, breast, colorectal, and lung), while CTCs were rarely identified in blood from healthy donors. In hepatocellular carcinoma patients treated with curative resection, CTC status was significantly associated with tumor characteristics, prognosis, and treatment response (all P < 0.05). Single-cell sequencing analysis revealed that heterogeneous genomic alteration patterns resided in different cells, patients, and cancers. Our results suggest that the use of this ChimeraX® -i120 platform and the integrated workflow has validity as a tool for CTC detection and downstream genomic profiling in the clinical setting.

11.
Clin Transl Med ; 10(8): e233, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33377659

RESUMO

RATIONALE: CD13 is a new marker for liver cancer stem cells (CSCs) that contributes to sorafenib resistance in hepatocellular carcinoma (HCC). However, the underlying mechanism of CD13 in HCC sorafenib resistance remains enigmatic. METHODS: The expression of CD13 in HCC cell lines and tissues was assayed by RT-PCR, western-blot, and immunohistochemistry staining. Athymic BALB/c nu/nu mice model was used to study the in vivo functions of CD13. Clinical significance of CD13 was evaluated by Kaplan-Meier methods. Cellular proliferation rate was evaluated by cell counting kit-8 cell proliferation assay and colony formation assay. Tunel assay was used to detect cell death ratio. Transwell assay was used to evaluate the motility of cells. Immunoprecipitation (IP), liquid chromatography-mass spectrometry (LC-MS)/MS, and co-IP were applied to investigate potential protein interactions of CD13. RESULTS: In this research, we found that CD13 expression was higher in metastatic HCC samples, and its overexpression was predicted worse prognosis for patients after surgical resection. Functionally, CD13 promoted HCC proliferation, invasion, cell cycle progression as well as sorafenib resistance. Mechanistically, CD13 interacted with histone deacetylase5 (HDAC5) to promote its protein stability, thus resulting in HDAC5-mediated lysine-specific demethylase 1 (LSD1) deacetylation and protein stabilization. Consequently, LSD1 decreased the NF-κB catalytic unit p65 methylation that led to p65 protein stability. A CD13 inhibitor ubenimex in combination with sorafenib, suppressed the tumor growth and attenuated the resistance of HCC cells toward sorafenib in patient-derived xenograft models. CONCLUSIONS: CD13 promotes HCC progression and induces sorafenib resistance, mainly via interacting with HDAC5 to prevent the degradation of p65 and activate NF-kB signaling pathway. CD13 is a prognostic indicator for HCC patients underwent curative resection as well as a predictor of response to treatment with sorafenib. Our study establishes the new therapeutic potential of targeting CD13-HDAC5-LSD1-NF-κB in HCC.

12.
EBioMedicine ; 62: 103107, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33181461

RESUMO

BACKGROUND: High rates of recurrence after resection severely worsen hepatocellular carcinoma (HCC) prognosis. This study aims to explore whether circulating tumor cell (CTC) is helpful in determine the appropriate liver resection margins for HCC patients. METHODS: HCC patients who underwent liver resection were enrolled into training (n=117) or validation (n=192) cohorts, then classified as CTC-positive (CTC≥1) or CTC-negative (CTC=0). A standardized pathologic sampling method was used in the training cohort to quantify microvascular invasion (mVI) and the farthest mVI from the tumor (FMT). FINDINGS: CTC number positively correlated with mVI counts (r=0.655, P<0.001) and FMT (r=0.495, P<0.001). The CTC-positive group had higher mVI counts (P=0.032) and greater FMT P=0.008) than the CTC-negative group. In the CTC-positive group, surgical margins of >1 cm independently protected against early recurrence (training cohort, P=0.004; validation cohort, P=0.001) with lower early recurrence rates (training cohort, 20.0% vs. 65.1%, P=0.005; validation cohort, 36.4% vs. 65.1%, P=0.003) compared to surgical margins of ≤1 cm. No differences in postoperative liver function were observed between patients with margins >1 cm vs. ≤1 cm. Surgical margin size minimally impacted early postoperative HCC recurrence in CTC-negative patients when using 0.5 cm or 1 cm as the threshold. INTERPRETATIONS: Preoperative CTC status predicts mVI severity in HCC patients and is a potential factor for determining optimal surgical margin size to ensure disease eradication and conserve liver function. A surgical margin of >1 cm should be achieved for patients with positive CTC. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgement section.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Margens de Excisão , Células Neoplásicas Circulantes/patologia , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Testes de Função Hepática , Masculino , Microvasos/patologia , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia , Período Pré-Operatório , Prognóstico , Resultado do Tratamento
13.
Ann Transl Med ; 8(20): 1301, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209881

RESUMO

Background: Survival after resection of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) still remains poor. Apatinib, a vascular endothelial cell growth factor receptor 2 inhibitor, has been shown to be safe and effective in patients with advanced HCC, so in the present study its efficacy and safety in the adjuvant setting was explored. Methods: In this single-center, open-label phase II trial, the patients received apatinib (500 mg/day) until they experienced disease recurrence or intolerable toxicity. The primary endpoint was recurrence-free survival (RFS); the secondary endpoints included overall survival (OS) and safety. Results: From a total of 49 patients who were screened between August 2017 and December 2018, 30 study participants received apatinib. According to the Liver Cancer Study Group of Japan classification of PVTT, there were 7, 11, and 12 participants with Vp1, Vp2, and Vp3, respectively. The median duration of treatment was 4.8 months [interquartile range (IQR): 2.0-8.8], and the median dose of apatinib was 339.7 mg/day (IQR: 267.7-500 mg/day). The median follow-up was 14.3 months (IQR: 12.3-19.3). The median RFS was 7.6 months [95% confidence interval (CI): 5.7-9.5 months]. The 1-year RFS rate and the 1-year OS rate were 36.1% and 93.3%, respectively. A total of 29 (96.7%) patients experienced adverse events, and 14 (46.7%) had grade 3 or 4 adverse events. No treatment-related deaths occurred. Conclusions: Apatinib was well tolerated in patients after resection of HCC with PVTT. The median RFS in this group was improved compared with that previously reported. Trial registration: No.: NCT03261791 (ClinicalTrials.gov).

14.
Cell Death Dis ; 11(10): 895, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093445

RESUMO

Accumulating evidence indicates that hepatocellular carcinoma (HCC) tumorigenesis, recurrence, metastasis, and therapeutic resistance are strongly associated with liver cancer stem cells (CSCs), a rare subpopulation of highly tumorigenic cells with self-renewal capacity and differentiation potential. Previous studies identified B cell leukemia/lymphoma-11b (BCL11B) as a novel tumor suppressor with impressive capacity to restrain CSC traits. However, the implications of BCL11B in HCC remain unclear. In this study, we found that low BCL11B expression was an independent indicator for shorter overall survival (OS) and time to recurrence (TTR) for HCC patients with surgical resection. In vitro and in vivo experiments confirmed BCL11B as a tumor suppressor in HCC with inhibitory effects on proliferation, cell cycle progression, apoptosis, and mobility. Furthermore, BCL11B could suppress CSC traits, as evidenced by dramatically decreased tumor spheroid formation, self-renewal potential and drug resistance. A Cignal Finder Array and dual-luciferase activity reporter assays revealed that BCL11B could activate the transcription of P73 via an E2F1-dependent manner. Thus, we concluded that BCL11B is a strong suppressor of retaining CSC traits in HCC. Ectopic expression of BCL11B might be a promising strategy for anti-HCC treatment with the potential to cure HBV-related HCC regardless of P53 mutation status.


Assuntos
Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Repressoras/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Repressoras/farmacologia , Transdução de Sinais , Proteína Tumoral p73/fisiologia , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Clin Chim Acta ; 511: 67-74, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32979338

RESUMO

AIMS: The present study aimed to determine the prognostic significance of soluble Programmed Death-ligand 1 (sPD-L1) in hepatocellular carcinoma (HCC) patients undergoing transcatheter arterial chemoembolization (TACE). METHODS: We treated 114 HCC patients with TACE from 2012 to 2013 and determined their sPD-L1 levels by enzyme-linked immunosorbent assay. We evaluated prognosis according to mRESIST criteria and analyzed prognostic values by Cox regression and Kaplan-Meier analysis. We further evaluated correlations between sPD-L1 level and inflammatory status, as well as immunosuppressive environment. RESULTS: sPD-L1 levels were significantly increased in patients who developed HCC progression (P = 0.002) and death (P < 0.001). Patients with higher pre-treatment sPD-L1 levels had a significantly shorter time to progression (10.50 vs. 18.25 months, P = 0.001) and decreased overall survival (16.50 vs. 28.50 months, P = 0.003). Importantly, sPD-L1 levels positively correlated with SII (r = 0.284, P = 0.002), sIL-2R (r = 0.239, P = 0.010), IL-10 (r = 0.283, P = 0.002), HBV-DNA loads (r = 0.229, P = 0.014), and CRP (r = 0.237, P = 0.011). Moreover, high sPD-L1 levels had increased numbers of Treg cells (FOXP3+; P = 0.026), Macrophage cells (CD68+; P = 0.014), and M2-Macrophage cells (CD163+; P = 0.026) CONCLUSIONS: sPD-L1 level is a prognostic indicator of poor outcomes after TACE. High sPD-L1 might reflect increased immune activation in an immunosuppressive environment that hindered anti-tumor response activity.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Antígeno B7-H1 , Biomarcadores Tumorais , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/terapia , Prognóstico
16.
Signal Transduct Target Ther ; 5(1): 146, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782275

RESUMO

The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia
17.
Cell Death Dis ; 11(7): 573, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709873

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from bile duct epithelium. Its characteristics include an insidious onset and frequent recurrence or metastasis after surgery. Current chemotherapies and molecular target therapies provide only modest survival benefits to patients with ICC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that has good antitumor effects in a variety of solid tumors. However, there are few studies of anlotinib-associated mechanisms and use as a treatment in ICC. In this study using in vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration and invasion restraint, and cell-cycle arrestment. Anlotinib treatment affected induction of apoptosis and the mesenchymal-epithelial transition. Patient-derived xenograft models generated directly from patients with ICC revealed that anlotinib treatment dramatically hindered in vivo tumor growth. We also examined anlotinib's mechanism of action using transcriptional profiling. We found that anlotinib treatment might mainly inhibit tumor cell proliferation and invasion and promote apoptosis via cell-cycle arrestment by inactivating the VEGF/PI3K/AKT signaling pathway, as evidenced by significantly decreased phosphorylation levels of these kinases. The activation of vascular endothelial growth factor receptor 2 (VEGFR2) can subsequently activate PI3K/AKT signaling. We identified VEGRF2 as the main target of anlotinib. High VEGFR2 expression might serve as a promising indicator when used to predict a favorable therapeutic response. Taken together, these results indicated that anlotinib had excellent antitumor activity in ICC, mainly via inhibiting the phosphorylation level of VEGFR2 and subsequent inactivation of PIK3/AKT signaling. This work provides evidence and a rationale for using anlotinib to treat patients with ICC in the future.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Progressão da Doença , Indóis/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/efeitos adversos , Indóis/farmacologia , Camundongos Nus , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Clin Transl Med ; 10(3): e137, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32702202

RESUMO

BACKGROUND: High rates of postoperative tumor recurrence contribute to poor outcome in hepatocellular carcinoma (HCC). Here, we investigated whether circulating tumor cells (CTCs) status can predict the benefit of adjuvant transcatheter arterial chemoembolization (TACE) in patients with HCC. METHODS: The retrospective study enrolled 344 HCC patients with preoperative CTCs analysis. Clinical outcomes including recurrence and survival were compared between those who received and who did not receive adjuvant TACE. Similar comparisons were made for patients stratified according to CTC status (CTC-negative [CTC = 0], n = 123; CTC-positive [CTC ≥ 1], n = 221). Propensity score matching (PSM) strategy was adopted to offset differences between two groups. RESULTS: In the study cohort as a whole or in CTC-negative cohort, there were no observable differences in overall survival (OS) or time to recurrence (TTR) between TACE and control group (P > .05). In CTC-positive patients, PSM generated 64 patient pairs, and patients with adjuvant TACE had significantly better clinical outcomes (OS: not reached vs 36.4 months, P < .001; TTR: 45.8 vs 9.8 months, P < .001). Adjuvant TACE significantly reduced early recurrence (≤2 years) (64.1% vs 31.7%, P < .001) in CTC-positive patients. Notably, adjuvant TACE influenced TTR and OS even in subgroups of CTC-positive patients with low risk of recurrence according to traditional evaluation. CONCLUSIONS: Preoperative CTC status could serve as an indicator for the administration of adjuvant TACE in HCC patients. Adjuvant TACE benefits CTC-positive HCC patients mainly by reducing early recurrence.

19.
Cancer Cytopathol ; 128(10): 733-745, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32501632

RESUMO

BACKGROUND: Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery. METHODS: A total of 197 patients with HCC who were undergoing curative surgical resection were assigned to a retrospective training cohort (144 patients) or a prospective validation cohort (53 patients). The CELLSEARCH system was used for the detection of CTCs prior to surgical resection and 1 month thereafter. The cutoff value of CTCs was estimated using receiver operating characteristic analysis. Bonferroni correction was applied for multiple testing in a Cox proportional hazards regression model. RESULTS: In the training cohort, EHM was found to be associated with a higher postoperative CTC burden compared with no EHM (mean: 4.33 vs 0.52; P < .001). Receiver operating characteristic analysis demonstrated a postoperative CTC count ≥3 as the optimal cutoff value for the prediction of EHM. Patients with a postoperative CTC count ≥3 experienced a higher EHM risk (56.3% vs 5.5%) and a shorter median overall survival (31.25 months vs not reached) (all P < .001). The prognostic significance of a postoperative CTC count ≥3 also applied to patient subgroups with a low EHM risk, such as those with an α-fetoprotein level ≤400 ng/mL, absence of vascular invasion, well differentiation, and early tumor stage, and its predictive value was retained in patients with a continuous normal α-fetoprotein level during postoperative follow-up (all P < .05). The results were confirmed in the validation cohort. CONCLUSIONS: A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of EHM after curative surgical resection of HCC. More careful surveillance should be recommended to patients with a high CTC load to ensure the greater possibility of early interventions for postoperative EHM.


Assuntos
Neoplasias Abdominais/secundário , Neoplasias Ósseas/secundário , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Neoplasias Pulmonares/secundário , Células Neoplásicas Circulantes/patologia , Complicações Pós-Operatórias/patologia , Neoplasias Abdominais/sangue , Neoplasias Ósseas/sangue , Carcinoma Hepatocelular/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
20.
J Gastrointest Oncol ; 11(1): 112-120, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32175113

RESUMO

Utilization of next-generation sequencing (NGS) to identify potential therapeutic targets and then prescribe matched agents provides new hope for patients with advanced cancer, such as hepatocellular carcinoma (HCC). However, intratumoral heterogeneity (ITH) challenges precise genomic profiling and may lead to target treatment failure. This study aims to evaluate whether and to what extent would genetic profiling be biased by ITH in HCC. We datamined publications focusing on the ITH of HCC and extracted the sequencing and clinicopathological information to make data reanalysis. Potential therapeutic targets and driver genes in HCC were specially pooled as reference to analyze the bias effect of ITH on genetic profiling. Five studies which analyzed ITH using NGS of multi-site samples were enrolled, with a total of 207 tumor samples from 36 HCC patients. The ITH ranged from 5.21% to 88.27% and no correlations between ITH extent and sample numbers, sequencing depth, or clinicopathological parameters were observed. In total, 72 therapeutic and 15 candidate driver genes were pooled as reference. Totally, 38.8% HCCs were found to be drugable in single-site sample, of which only 19.4% might be biased by ITH. Of the driver genes, 86% could be detected in single-site sample. HCC is a highly heterogeneous disease. While ITH indeed hinders comprehensive and precise HCC genome profiling, it has limited influences on identification of actionable and driver mutations. Single-site sampling/biopsy assayed with targeted deep sequencing might be efficient in the clinical management of HCC.

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