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1.
BMC Cancer ; 22(1): 335, 2022 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-35346114

RESUMO

OBJECTIVE: The purpose of this study was to explore the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib and camrelizumab (TACE + AC) for unresectable hepatocellular carcinoma (HCC), and the impact of the timing of the combination on it. METHODS: In this single-arm retrospective study, consecutive data of patients with unresectable HCC treated to our hospital from March 2017 to September 2021 were collected. These patients were treated with TACE and started on camrelizumab and apatinib within one week of TACE. Camrelizumab 200 mg intravenously once every three weeks and apatinib 250 mg orally once daily. Repeat TACE treatment was available on an on-demand basis. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. The univariate and multivariate Cox regression analyses were used to assess the effect of early and late combination on OS and PFS. RESULTS: A total of 80 patients were enrolled in this study. The median OS was 22.1 months (95% confidence interval [CI]: 13.8-30.5 months) and the median PFS was 15.7 months (95% CI: 14.7-16.6 months). The ORR was 58.8% (95% CI: 47.2-69.6) and DCR reached 81.2% (95% CI: 71.0-89.1). Multivariable Cox proportional hazard regression analyses showed that TACE late combined with apatinib and camrelizumab provided better OS than early combination (HR = 0.175, 95% CI:0.060-0.509, P = 0.001), as did PFS (HR = 0.422, 95% CI:0.184-0.967, P = 0.041). All treatment-related adverse events were tolerable, and no serious adverse events were observed. CONCLUSION: TACE combined with apatinib plus camrelizumab for patients with unresectable HCC has promising antitumor activity and a manageable safety profile. For unresectable HCC with large tumor burden, late combination provides better OS and PFS compared to early combination.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Anticorpos Monoclonais Humanizados , Carcinoma Hepatocelular/tratamento farmacológico , Quimioembolização Terapêutica/efeitos adversos , Terapia Combinada , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Piridinas , Estudos Retrospectivos
2.
Anticancer Res ; 42(4): 1905-1910, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35347009

RESUMO

AIM: The present study evaluated the efficacy and safety of ramucirumab (RAM) in clinical practice as post-treatment, following atezolizumab plus bevacizumab (Atz/Bev) for advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) levels of ≥400 ng/ml. PATIENTS AND METHODS: Of the 77 patients treated with Atz/Bev at our institution, 13 patients for whom RAM was introduced as post-treatment following Atz/Bev were enrolled in this retrospective study. There were 9 patients (69.2%) with Child-Pugh A and 11 patients (84.6%) for whom RAM was initiated as 3rd- or later-line therapy. The median AFP level was 2259 ng/ml. RESULTS: The objective response rate by Response Evaluation Criteria in Solid Tumours at 6 weeks was 15.4%, and the disease control rate was 69.2%. The median time to progression was 3.0 months; AFP level decreased at 2 weeks in 11 patients (84.6%) and at 6 weeks in seven patients (53.8%). The most common adverse events (AEs) within 6 weeks were ascites, peripheral oedema, and proteinuria, while grade 3 AEs occurred in six patients (46.2%). Albumin-bilirubin scores at both 4 and 6 weeks were significantly worse than those at baseline. CONCLUSION: In HCC patients with AFP levels of ≥400 ng/mL, RAM after Atz/Bev is expected to be an effective treatment option. Careful attention should be paid to the development of AEs and deterioration of liver function, especially when RAM is used as 3rd- or later-line therapy. Additional studies are needed to confirm the efficacy and safety of RAM as 2nd-line treatment after Atz/Bev in Child-Pugh A patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticorpos Monoclonais Humanizados , Bevacizumab/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Estudos Retrospectivos
3.
Biol Pharm Bull ; 45(3): 309-315, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34937830

RESUMO

Anti-angiogenic gene therapy is a promising strategy in treating cancer. Endostatin and angiostatin are widely used in tumor anti-angiogenesis therapy. Our previous studies have shown that the BDS-hEA, a baculovirus long-term expressing the fusion protein of human endostatin and angiostatin, has a favorable effect in inhibiting the growth and angiogenesis of hepatocellular carcinoma. The purpose of this study was to further investigate its synergistic antitumor efficiency in combination with low-dose chemotherapeutic gemcitabine (GEM) on the subcutaneous hepatocellular carcinoma xenograft model in nude mice. The results showed that the combined group significantly inhibited (p < 0.05 or p < 0.01 or p < 0.001) the growth of tumor weight and volume, reduced the expression of ki67 (cell proliferation marker), CD31 (angiogenic marker) and Matrix metalloproteinase 9 (MMP-9, tumor invasion and metastasis marker) and increased the apoptosis of tumor cells compared with the monotherapy and control groups, respectively. Synergistic index results showed that BDS-hEA combined with GEM had a synergistic effect in inhibiting tumor volume, proliferation, microvessel density, metastasis and promoting tumor apoptosis. Furthermore, there were no metastatic nodules and obvious pathological changes in liver tissue of the combined group, and the serum liver function indicators aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-BIL), alkaline phosphatase (ALP) and glutamyl transpeptidase (GGT) were significantly reduced (p < 0.05 or p < 0.01 or p < 0.001) in the BDS-hEA or GEM groups compared with the control group. Notably, the combined therapy showed lower levels of liver function indicators than the GEM group. These data support the view that the combination of BDS-hEA and GEM has a synergistic anti-tumor properties and can reduce the damage of liver to certain extent.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Inibidores da Angiogênese/uso terapêutico , Angiostatinas/genética , Angiostatinas/uso terapêutico , Animais , Baculoviridae , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Desoxicitidina/análogos & derivados , Endostatinas/genética , Endostatinas/uso terapêutico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus
4.
Eur Rev Med Pharmacol Sci ; 26(14): 5014-5032, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35916798

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death, with high morbidity and low survival. Research on the relationship between cancer cells and oxidative stress has rapidly increased in recent years. Therefore, finding new therapeutic and prognostic targets for hepatocellular carcinoma based on oxidative stress-related genes (OSRGs) has far-reaching significance. MATERIALS AND METHODS: We first obtained OSRGs on GeneCards and then, based on the TCGA database, compared tumor tissues with normal tissues. Using the LASSO Cox regression method, we obtained six differentially expressed genes associated with prognosis. We also divided all HCC patients in the TCGA cohort into a low-risk group and a high-risk group based on these six genes and accordingly performed a correlation analysis of differentially expressed oxidative-stress-related genes (DEOSRGs). These analyses included GSEA, PPI, survival analysis, immune correlation analysis, tumor microenvironment correlation analysis, m6A analysis, gene mutation analysis, drug-sensitivity analysis, and molecular docking validation. The reliability of the model genes was further verified using a multi-platform database, qRT-PCR and MTT assay. RESULTS: These six genes may play an important role in the prognosis of hepatocellular carcinoma patients by affecting the kinase, carboxylic acid synthesis and metabolism, ROS production, lipid oxidation and immune response. Validation experiment results further confirm that these model genes are good indicators for the diagnosis and prognosis of hepatocellular carcinoma. CONCLUSIONS: This study analyzed the prognosis and function of HCC prognosis-related differential genes, predicted that the prognosis-related differential genes played an essential role in HCC immunity, and proposed therapeutic targets and biomarkers for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica/métodos , Humanos , Imunoterapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Simulação de Acoplamento Molecular , Estresse Oxidativo , Prognóstico , Reprodutibilidade dos Testes , Microambiente Tumoral/genética
5.
BMC Cancer ; 22(1): 857, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931993

RESUMO

BACKGROUND: Liver cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC). However, some HCC cases can also originate from non-cirrhotic livers. The aim of this study was to identify key circular RNAs (circRNAs) associated with the tumorigenesis of non-cirrhotic liver disease. METHODS: The differently expressed circRNAs between non-cirrhotic and cirrhotic HCCs were assessed with use of high-throughput circRNAs sequencing and validated with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Potential biological functions of these dysregulated circRNAs were predicted with use of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA-miRNA-mRNA regulation network was constructed as achieved with use of miRanda software and visualized using Cytoscape software. Biological functions of the four most prominent dysregulated circRNAs identified were confirmed by in vitro experiments. Moreover, possible translations of these dysregulated circRNAs were also predicted. RESULTS: A total of 393 dysregulated circRNAs were identified between non-cirrhotic and cirrhotic HCC, including 213 that were significantly up-regulated and 180 significantly down-regulated circRNAs. Expression levels of the six most prominent dysregulated circRNAs were further validated using qRT-PCR. Many tumor related miRNAs were involved in the circRNA-miRNA-mRNA networks, including miR-182-5p, miR-561-3p, miR-125a-5p, miR-145, miR-23b-3p and miR-30e-3p, and downstream mRNAs of dysregulated circRNAs were significantly related with biological processes involved in the progression of tumors, including proliferation, migration, differentiation, and focal adhesion. Results from the in vitro experiments demonstrated that the most prominent dysregulated circRNAs exerted notable effects upon the proliferation and migration of HCC cells. Finally, we also identified 19 dysregulated circRNAs having potential for the coding of functional peptides. CONCLUSION: The results of this present study indicate that circRNAs may play important roles in tumorigenesis of non-cirrhotic HCC. Such findings provide some novel insights and pave the way for the development of future studies directed at investigating the initiation and treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Carcinogênese , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/genética , RNA/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA
6.
World J Surg Oncol ; 20(1): 252, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35932027

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) as a common tumor has a poor prognosis. Recently, a combination of atezolizumab and bevacizumab has been recommended as the preferred regimen for advanced HCC. However, the overall response rate of this therapy is low. There is an urgent need to identify sensitive individuals for this precise therapy among HCC patients. METHODS: The Wilcox test was used to screen the differentially expressed immune-related genes by combining the TCGA cohort and the Immunology Database. Univariate and multivariate Cox regression analysis were used to screen the immune gene pairs concerning prognosis. A predictive model was constructed using LASSO Cox regression analysis, and correlation analysis was conducted between the signature and clinical characteristics. ICGC cohort and GSE14520 were applied for external validations of the predictive risk model. The relationship between immune cell infiltration, TMB, MSI, therapeutic sensitivity of immune checkpoint inhibitors, targeted drugs, and the risk model were assessed by bioinformatics analysis in HCC patients. RESULTS: A risk predictive model consisting of 3 immune-related gene pairs was constructed and the risk score was proved as an independent prognostic factor for HCC patients combining the TCGA cohort. This predictive model exhibited a positive correlation with tumor size (p < 0.01) and tumor stage (TNM) (p < 0.001) in the chi-square test. The predictive power was verified by external validations (ICGC and GSE14520). The risk score clearly correlated with immune cell infiltration, MSI, immune checkpoints, and markers of angiogenesis. CONCLUSIONS: Our research established a risk predictive model based on 3 immune-related gene pairs and explored its relationship with immune characteristics, which might help to assess the prognosis and treatment sensitivity to immune and targeted therapy of HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Biologia Computacional , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico
7.
Nat Commun ; 13(1): 4594, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933472

RESUMO

Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generate a single-cell atlas of the multicellular ecosystem of HCC from four tissue sites. We show the enrichment of central memory T cells (TCM) in the early tertiary lymphoid structures (E-TLSs) in HCC and assess the relationships between chronic HBV/HCV infection and T cell infiltration and exhaustion. We find the MMP9+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and PPARγ to be the pivotal transcription factor driving their differentiation. We also characterize the heterogeneous subpopulations of malignant hepatocytes and their multifaceted functions in shaping the immune microenvironment of HCC. Finally, we identify seven microenvironment-based subtypes that can predict prognosis of HCC patients. Collectively, this large-scale atlas deepens our understanding of the HCC microenvironment, which might facilitate the development of new immune therapy strategies for this malignancy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Estruturas Linfoides Terciárias , Carcinoma Hepatocelular/patologia , Ecossistema , Humanos , Neoplasias Hepáticas/patologia , Microambiente Tumoral
8.
Anal Chim Acta ; 1221: 340102, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35934348

RESUMO

Golgi protein 73 (GP73) is a new type of marker that can specifically detect hepatocellular carcinoma (HCC). Herein, a dual-signal sandwich-type electrochemical aptasensor for GP73 determination was constructed on the basis of hemin-reduced graphene oxide-manganese oxide (H-rGO-Mn3O4) nanozymes. Gold@poly(o-phenylenediamine) (Au@POPD) nanohybrids with a large specific surface area and conductance were co-electro-deposited onto a screen-printed electrode (SPE) surface to immobilize GP73 capture aptamer 2 (Apt2). H-rGO-Mn3O4 nanozymes were used not only to immobilize amino functionalised GP73 aptamer 1 (Apt1) as the detection probe, but also to serve as an in-situ redox signal indicator because of the redox reaction of Hemin (Fe(Ш)/Hemin(Fe(II)). In addition, given their excellent peroxidase-like activity, H-rGO-Mn3O4 nanozymes can catalyse the decomposition of H2O2 and oxidation of substrate (3,3',5,5'-tetramethylbenzidine, TMB) to oxTMB, which is used as another redox signal. In the presence of the target GP73, the two aptamers specifically bind to the target, thereby affecting two electrochemical signals. Under optimal conditions, the dual-signal sandwich-type electrochemical aptasensor had a salient analytical performance. The two electrochemical redox signals linearly increase with the logarithm of the GP73 concentration in the range of 0.01-100.0 ng/mL with the limit of detection (LOD) of 0.0071 ng/mL and sensitivity of 2.441 µA/µM/cm2. Moreover, the recovery of human serum samples ranged from 98.66% to 121.11%. Furthermore, the two redox signals can simultaneously corroborate each other, thereby preventing missed diagnosis and misdiagnosis. All the results can provide new insights into the clinically effective determination of HCC.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Carcinoma Hepatocelular , Grafite , Neoplasias Hepáticas , Nanopartículas Metálicas , Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , Carcinoma Hepatocelular/diagnóstico , Técnicas Eletroquímicas/métodos , Ouro/química , Grafite/química , Hemina/química , Humanos , Peróxido de Hidrogênio/química , Limite de Detecção , Neoplasias Hepáticas/diagnóstico , Nanopartículas Metálicas/química
9.
Biomater Adv ; 136: 212761, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35929305

RESUMO

Programmed cell death receptor ligand 1 (PD-L1)/PD-1 signaling has been exploited to design inhibitors that deliver promising clinical outcome albeit with limited efficacy. Herein, we prepare graphene oxide (GO)-PEI-PEG with low cytotoxicity and long stability and GO-PEI-PEG delivers PD-L1 siRNAs to hepatocellular carcinoma (HCC) cells by the endocytosis-lysosome pathway. The functional GO-PEI-PEG/PD-L1 siRNAs decrease PD-L1 and PD-1 abundance, increase pro-inflammation cytokine IFN-γ and TNF-α release, and improve the proliferation activity of Jurkat T cells. Since GO-PEI-PEG targets the mouse liver effectively, the intrahepatic tumors in C57BL/6 mice are treated with GO-PEI-PEG/Pd-l1 siRNAs via the tail vein, resulting in shrinkage of the HCC tumors and boosting the anti-tumor efficacy in combination with oral sorafenib. A single treatment improves the total CD3+ and cytotoxic CD8+ T cell infiltration in the HCC tumor tissues and even spleen and upregulates the expression of Perforin, Gzmb, Ifng, Il-1b and Tnfa in the tumors after the combined treatment. Both the single and combined treatments enhance reactive oxygen species (ROS) accumulation, and improved HCC ferroptosis. The results suggest that GO-PEI-PEG delivered PD-L1 siRNAs combined with oral sorafenib can activate the adaptive immunity and tumor ferroptosis and reveal an effective therapy to treat advanced HCC patients.


Assuntos
Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Animais , Antígeno B7-H1/genética , Carcinoma Hepatocelular/tratamento farmacológico , Grafite , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1 , RNA Interferente Pequeno/genética , Sorafenibe/farmacologia
10.
Int J Oncol ; 61(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35929515

RESUMO

Bile acids (BAs) are the major components of bile and products of cholesterol metabolism. Cholesterol is catalyzed by a variety of enzymes in the liver to form primary BAs, which are excreted into the intestine with bile, and secondary BAs are formed under the modification of the gut microbiota. Most of the BAs return to the liver via the portal vein, completing the process of enterohepatic circulation. BAs have an important role in the development of hepatocellular carcinoma (HCC), which may participate in the progression of HCC by recognizing receptors such as farnesoid X receptor (FXR) and mediating multiple downstream pathways. Certain BAs, such as ursodeoxycholic acid and obeticholic acid, were indicated to be able to delay liver injury and HCC progression. In the present review, the structure and function of BAs were introduced and the metabolism of BAs and the process of enterohepatic circulation were outlined. Furthermore, the mechanisms by which BAs participate in the development of HCC were summarized and possible strategies for targeting BAs and key sites of their metabolic processes to treat HCC were suggested.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ácidos e Sais Biliares/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Colesterol/metabolismo , Circulação Êntero-Hepática/fisiologia , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo
12.
Dis Markers ; 2022: 2959846, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909886

RESUMO

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Dysregulation of messenger RNAs (mRNA) has been recognized to be associated with HCC carcinogenesis and development. Polypeptide GalNAc Transferase 6 (GALNT6), an O-type glycosyltransferase, has been confirmed as tumor promoter in different cancers. However, the function of GALNT6 in HCC remains to be studied. Methods: RT-qPCR and western blot experiments were, respectively, performed for evaluating RNA expressions and protein levels. Supported by bioinformatics analysis, mechanism assays were conducted for validating the potential relation between different genes. Functional assays were implemented to analyze HCC cell migration and invasion after different transfections. Results: GALNT6 was aberrantly upregulated in HCC cells. Knockdown of GALNT6 could repress HCC cell migration and invasion. RUNX3 was verified to bind to GALNT6 promoter and activate GALNT6 transcription. GALNT6 depletion led to inhibited O-glycosylation and aggravated degradation of MUC1. MUC1 overexpression could rescue the impeded HCC cell migration and invasion induced by GALNT6 knockdown. Conclusion: To sum up, GALNT6 transcriptionally activated by RUNX3 mediated the O-glycosylation of MUC1, thus exerting promoting influence on HCC cell migration and invasion.


Assuntos
Carcinoma Hepatocelular , Subunidade alfa 3 de Fator de Ligação ao Core , Neoplasias Hepáticas , Mucina-1 , N-Acetilgalactosaminiltransferases , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicosilação , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Mucina-1/metabolismo , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo
13.
World J Surg Oncol ; 20(1): 248, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918753

RESUMO

BACKGROUND: Posthepatectomy liver failure (PHLF) is a life-threatening complication following hepatic resection. The aspartate aminotransferase-to-platelet ratio index (APRI) is a non-invasive model for assessing the liver functional reserve in patients with hepatocellular carcinoma (HCC). This study aimed to establish a scoring model to stratify patients with HCC at risk for PHLF. METHODS: This single-center retrospective study included 451 patients who underwent hepatic resection for HCC between 2004 and 2017. Preoperative factors, including non-invasive liver fibrosis markers and intraoperative factors, were evaluated. The predictive impact for PHLF was evaluated using receiver operating characteristic (ROC) curves of these factors. RESULTS: Of 451 patients, 30 (6.7%) developed severe PHLF (grade B/C). Multivariate logistic analysis indicated that APRI, model for end-stage liver disease (MELD) score, operating time, and intraoperative blood loss were significantly associated with severe PHLF. A scoring model (over 0-4 points) was calculated using these optimal cutoff values. The area under the ROC curve of the established score for severe PHLF was 0.88, which greatly improved the predictive accuracy compared with these factors alone (p < 0.05 for all). CONCLUSIONS: The scoring model-based APRI, MELD score, operating time, and intraoperative blood loss can predict severe PHLF in patients with HCC.


Assuntos
Carcinoma Hepatocelular , Doença Hepática Terminal , Neoplasias Hepáticas , Aspartato Aminotransferases , Perda Sanguínea Cirúrgica , Carcinoma Hepatocelular/patologia , Doença Hepática Terminal/etiologia , Hepatectomia/efeitos adversos , Humanos , Neoplasias Hepáticas/patologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença
14.
Front Immunol ; 13: 923031, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35924241

RESUMO

Background: We aimed to characterize serine protease inhibitor Kazal type 1 (SPINK1) as a gene signature for the early diagnosis, molecular targeting, and prediction of immune checkpoint blockade (ICB) treatment response of hepatocellular carcinoma (HCC). Methods: The transcriptomics, proteomics, and phenotypic analyses were performed separately or in combination. Results: We obtained the following findings on SPINK1. Firstly, in the transcriptomic training dataset, which included 279 stage I and II tumor samples (out of 1,884 stage I-IV HCC specimens) and 259 normal samples, significantly higher area under curve (AUC) values and increased integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were demonstrated for HCC discrimination in SPINK1-associated models compared with those of alpha-fetoprotein (AFP). The calibration of both SPINK1-related curves fitted significantly better than that of AFP. In the two independent transcriptomic validation datasets, which included 201, 103 stage I-II tumor and 192, 169 paired non-tumor specimens, respectively, the obtained results were consistent with the above-described findings. In the proteomic training dataset, which included 98 stage I and II tumor and 165 normal tissue samples, the analyses also revealed better AUCs and increased IDI and NRI in the aforementioned SPINK1-associated settings. A moderate calibration was shown for both SPINK1-associated models relative to the poor results of AFP. Secondly, in the in vitro and/or in vivo murine models, the wet-lab experiments demonstrated that SPINK1 promoted the proliferation, clonal formation, migration, chemoresistance, anti-apoptosis, tumorigenesis, and metastasis of HCC cells, while the anti-SPINK1 antibody inhibited the growth of the cells, suggesting that SPINK1 has "tumor marker" and "targetable" characteristics in the management of HCC. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that SPINK1 was engaged in immunity-related pathways, including T-cell activation. Thirdly, in the transcriptomic analyses of the 368 HCC specimens from The Cancer Genome Atlas (TCGA) cohort, the high abundance of SPINK1 was positively correlated with the high levels of activated tumor-infiltrating CD4+ and CD8+ T lymphocytes and dendritic and natural killer cells, while there were also positive correlations between SPINK1 and immune checkpoints, including PD-1, LAG-3, TIM-3, TIGIT, HAVCR2, and CTLA-4. The ESTIMATE algorithm calculated positive correlations between SPINK1 and the immune and ESTIMATE scores, suggesting a close correlation between SPINK1 and the immunogenic microenvironment within HCC tissues, which may possibly help in predicting the response of patients to ICB therapy. Conclusions: SPINK1 could be a potential biomarker for the early detection, targeted therapy, and prediction of ICB treatment response in the management of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Detecção Precoce de Câncer , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Proteômica , Inibidor da Tripsina Pancreática de Kazal/genética , Inibidor da Tripsina Pancreática de Kazal/metabolismo , Microambiente Tumoral , alfa-Fetoproteínas
15.
Anal Chim Acta ; 1221: 340106, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35934396

RESUMO

Due to high recurrence and metastasis rates leading to high mortality of hepatocellular carcinoma (HCC), detection of HCC circulating tumor cells (HCC-CTCs), which are regarded as an HCC blood marker, holds great significance in HCC early diagnosis, metastasis evolution, and prognosis. However, current existing circulating tumor cell (CTC) detection methods require multiple steps, and have low accuracy due to extremely rare CTCs in peripheral blood (PB). Thus, a simple and sensitive HCC-CTCs detection method is urgently needed. Here, a glutathione (GSH) activatable bioprobe (LacCC) targeting HCC cells was first developed through coordinating copper ions (Cu2+) to lactose modified coumarin derivative (LacC). Owing to the carbohydrate-protein interaction between lactose group and asialoglycoprotein receptors (ASGPRs) overexpressed on the membrane of HCC cells, LacCC displays selectivity towards HCC cells. The fluorescence of LacCC recovers rapidly within 2 min upon demetallation by high concentration of GSH in HCC cells. In simulated PB samples, as low as 10 HepG2 cells were detected via CLSM after removing red blood cells (RBCs) and culturing with LacCC. By coupling with flow cytometry, LacCC can achieve quantitative detection of HCC cells with low detection limit (LOD) of 3 cells per sample. Thus, this bioprobe possessing ASGPRs targetability and fast GSH responsiveness shows ultrasensitive detectability towards HCC cells in PB, which may have the potential for simple yet highly sensitive HCC-CTCs detection.


Assuntos
Técnicas Biossensoriais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Neoplásicas Circulantes , Receptor de Asialoglicoproteína/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Glutationa , Humanos , Lactose , Neoplasias Hepáticas/metabolismo , Células Neoplásicas Circulantes/patologia
16.
FASEB J ; 36(9): e22482, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35947136

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Transformação Celular Neoplásica/patologia , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos
17.
Proc Natl Acad Sci U S A ; 119(32): e2119514119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914158

RESUMO

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
18.
Cell Mol Life Sci ; 79(9): 472, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933495

RESUMO

Cholesterol biosynthesis plays a critical role in rapidly proliferating tumor cells. X-box binding protein 1 (XBP1), which was first characterized as a basic leucine zipper-type transcription factor, exists in an unspliced (XBP1-u) and spliced (XBP1-s) form. Recent studies showed that unspliced XBP1 (XBP1-u) has unique biological functions independent from XBP1-s and could promote tumorigenesis; however, whether it is involved in tumor metabolic reprogramming remains unknown. Herein, we found that XBP1-u promotes tumor growth by enhancing cholesterol biosynthesis in hepatocellular carcinoma (HCC) cells. Specifically, XBP1-u colocalizes with sterol regulatory element-binding protein 2 (SREBP2) and inhibits its ubiquitination/proteasomal degradation. The ensuing stabilization of SREBP2 activates the transcription of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. We subsequently show that the XBP1-u/SREBP2/HMGCR axis is crucial for enhancing cholesterol biosynthesis and lipid accumulation as well as tumorigenesis in HCC cells. Taken together, these findings reveal a novel function of XBP1-u in promoting tumorigenesis through increased cholesterol biosynthesis in hepatocarcinoma cells. Hence, XBP1-u might be a potential target for anti-tumor therapeutic strategies that focus on cholesterol metabolism in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Proteína 1 de Ligação a X-Box , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Transformação Celular Neoplásica , Colesterol/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína 1 de Ligação a X-Box/genética
19.
PLoS One ; 17(8): e0269941, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35939428

RESUMO

In dogs with non-resectable hepatic neoplasia, treatment options are limited. The objectives of this study were to describe the use of a novel drug-eluting embolic microsphere containing paclitaxel for use during transarterial chemoembolization (TACE), to compare results of liver-specific owner questionnaires and tumor volume pre- and post-TACE, and to measure systemic paclitaxel concentration post-TACE. Client-owned dogs with non-resectable hepatic neoplasia were prospectively enrolled. All owners completed questionnaires validated for the assessment of subjective outcomes in dogs with cancer before the TACE procedure and approximately 4 weeks after the TACE procedure. A CT scan was performed before TACE and 1 month after TACE; results were compared. Blood samples were obtained at specified time points post-TACE to determine systemic paclitaxel concentrations. Seven dogs (median weight: 8.9 kg; range, 4.3-31 kg) were enrolled. TACE was successfully performed in all dogs, and no intra-procedural complications were encountered. Questionnaire scores improved significantly post-TACE. Among the 6 dogs for which full data were available, median pre-TACE tumor volume was 390 cc (range 152-1,484; interquartile range 231-1,139) and median post-TACE tumor volume was 203 cc (range 98-889; interquartile range 151-369), which was significantly (P = .028) lower. All 6 dogs had a reduction in volume at the post-TACE measurement. Mean percent change in tumor volume was -45.6% (95%CI -58.6 to -32.6%). The mean plasma paclitaxel concentration in canine blood peaked at 4 days post-TACE procedure and was 25.7 ng/mL (range = 3.09-110 ng/mL) Median survival time was 629 days (95%CI 18 to upper limit not reached). The use of a novel paclitaxel-eluting microsphere in this cohort of dogs successfully decreased tumor volume significantly after TACE and improved clinical signs. Future investigation into the use of TACE and other similar therapies is warranted due to the promising outcomes noted in this cohort.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Implantes Absorvíveis , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/veterinária , Quimioembolização Terapêutica/métodos , Cães , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/veterinária , Microesferas , Paclitaxel/uso terapêutico , Polímeros/uso terapêutico , Resultado do Tratamento
20.
BMC Gastroenterol ; 22(1): 378, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941537

RESUMO

BACKGROUND: The stromal antigen 3 (STAG3) gene encodes an adhesion complex subunit that can regulate sister chromatid cohesion during cell division. Chromosome instability caused by STAG3 gene mutation may potentially promote tumor progression, but the effect of STAG3 on hepatocellular carcinoma (HCC) and the related molecular mechanism are not reported in the literature. The mechanism of the occurrence and development of HCC is not adequately understood. Therefore, the biological role of STAG3 in HCC remains to be studied, and whether STAG3 might be a sensitive therapeutic target in HCC remains to be determined. METHODS: The expression and clinical significance of STAG3 in HCC tissues and cell lines were determined by RT-qPCR and immunohistochemistry analyses. The biological functions of STAG3 in HCC were determined through in vitro and in vivo cell function tests. The molecular mechanism of STAG3 in HCC cells was then investigated by western blot assay. RESULTS: The mRNA expression of STAG3 was lower in most HCC cells than in normal cells. Subsequently, an immunohistochemical analysis of STAG3 was performed with 126 samples, and lower STAG3 expression was associated with worse overall survival in HCC patients. Moreover, cytofunctional tests revealed that the lentivirus-mediated overexpression of STAG3 in HCC cells inhibited cell proliferation, migration, and invasion; promoted apoptosis; induced G1/S phase arrest in vitro; and inhibited tumor growth in vivo. Furthermore, studies of the molecular mechanism suggested that the overexpression of STAG3 increased Smad3 expression and decreased CDK4, CDK6, cyclin D1, CXCR4 and RhoA expression. CONCLUSION: STAG3 exhibits anticancer effects against HCC, and these effects involve the Smad3-CDK4/CDK6-cyclin D1 and CXCR4/RhoA pathways. STAG3 is a tumor-suppressor gene that may serve as a potential target for molecular therapy, which provides a new idea for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Receptores CXCR4 , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad3/farmacologia , Regulação para Cima , Proteína rhoA de Ligação ao GTP/genética
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