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1.
Surg Oncol Clin N Am ; 32(1): 101-117, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36410911

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Partial hepatectomy, one of a few curative therapeutic modalities, is plagued by high recurrence rate of up to 70% at 5 years. Throughout the past 3 decades, many clinical trials have attempted to improve HCC recurrence rate following partial hepatectomy using adjuvant and neoadjuvant treatment modalities such as antiviral therapy, brachytherapy, systemic chemotherapy, immunotherapy, transarterial chemoembolization and radioembolization, and radiotherapy. The goal of this review is to discuss the clinical trials pertaining to resectable HCC including surgical technique considerations, adjuvant, and neoadjuvant treatment modalities.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Hepatectomia , Terapia Neoadjuvante
2.
Gene ; 851: 146964, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36261080

RESUMO

The RAD51 gene plays an important role in DNA repair by homologous recombination, and is involved in the development and progression of multiple cancers. Single nucleotide polymorphisms in RAD51 have been previously described to impact the prognosis of patients with cancers, however, it is still unclear whether this is also true for hepatocellular carcinoma (HCC). This study therefore aimed to identify genetic variants in RAD51 and determine the effect on the survival of patients with HCC. In this study, we performed genotyping assays for RAD51 polymorphisms in a cohort of 368 patients with HCC who had underwent hepatectomy. Using multivariate cox proportional hazards model and Kaplan-Meier analyses with log-rank tests, we compared the survival of patients with HCC according to RAD51 SNP genotypes. We identified one potential functional variant, rs12593359, located in a microRNA (miRNA) binding site in the RAD51 3' untranslated region, to be an independent predictor of overall survival of patients with HCC in the dominant model. Patients carrying GT/TT genotypes had a significantly increased risk of death when compared with those carrying GG genotype (adjusted hazard ratio = 1.34, 95 % confidence interval = 1.02-1.76, P = 0.035). Kaplan-Meier curve analysis showed a markedly shorter survival time for patients with HCC carrying GT/TT genotypes of SNP rs12593359 (19.0 months vs 36.0 months; Plog-rank = 0.012). Notably, this effect was particularly pronounced in several subgroups of patients (e.g., males, Hepatitis B virus-positive patients, patients with a single tumor nodule, patients with alpha-fetoprotein (AFP) < 400 ng/ml, or patients who were cancer embolus-free). Additional expression analysis of quantitative trait loci showed that SNP rs12593359 was significantly associated with RAD51 mRNA expression levels in 483 cell-cultured fibroblasts (P = 1.1 × 10-4). These findings provide evidence that RAD51 rs12593359 is associated with HCC survival and may serve as a promising predictor of survival in patients with HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Regiões 3' não Traduzidas , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Hepatectomia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Rad51 Recombinase/genética
3.
Phytomedicine ; 108: 154478, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36265255

RESUMO

Activation of mitogen-activated protein kinase (MAPK) and PI3K signaling confers resistance against sorafenib, a mainstay treatment for advanced hepatocellular carcinoma (HCC). Antrocin and ovatodiolide constitute as the most potent secondary metabolites isolated from Antrodia camphorata and Anisomeles indica, respectively. Both natural compounds have recently gained a lot of attention due to their putative inhibition of MAPK and PI3K signaling in various solid cancers. However, whether their combination is effective in HCC remains unknown. Here, we investigated their effect, alone or in various combinations, on MAPK and PI3K signaling pathways in HCC cells. An array of in vitro study were used to investigate anticancer and stemness effects to treat HCC, such as cytotoxicity, drug combination index, migration, invasion, colony formation, and tumor sphere formation. Drug effect in vivo was evaluated using mouse xenograft models. In this study, antrocin and ovatodiolide synergistically inhibited the SNU387, Hep3B, Mahlavu, and Huh7 cell lines. Sequential combination treatment of Huh7 and Mahlavu with ovatodiolide followed by antrocin resulted stronger cytotoxic effect than did treatment with antrocin followed by ovatodiolide, their simultaneous administration, antrocin alone, or ovatodiolide alone. In the Huh7 and Mahlavu cell lines, ovatodiolide→antrocin significantly suppressed colony formation and proliferation as well as markedly downregulated ERK1/2, Akt, and mTOR expression. Inhibition of ERK1/2 and Akt/mTOR signaling by ovatodiolide→antrocin suppressed ribosomal biogenesis, autophagy, and cancer stem cell-like phenotypes and promoted apoptosis in Huh7 and Mahlavu cells. The sorafenib-resistant clone of Huh7 was effectively inhibited by synergistic combination of both compound in vitro. Eventually, the ovatodiolide→antrocin combination synergistically suppressed the growth of HCC xenografts. Taken together, our findings suggested that ovatodiolide→antrocin combination may represent potential therapeutic approach for patients with advanced HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Humanos , Carcinoma Hepatocelular/patologia , Sorafenibe , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Apoptose , Ribossomos/metabolismo , Ribossomos/patologia , Proliferação de Células
4.
Clin Liver Dis ; 27(1): 85-102, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36400469

RESUMO

This is a review of current practices and upcoming developments regarding hepatocellular carcinoma (HCC). This includes a contemporary review of the diagnosis, staging, and treatment of HCC. Furthermore, the authors provide a review of certain ongoing trials and future directions of various treatment modalities for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia
5.
Cancer Lett ; 552: 215977, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36279983

RESUMO

IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ+ and IFNγ- Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ- Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ- Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ- Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ- Tc17 and its implications in HCC progression.


Assuntos
Carcinoma Hepatocelular , Tolerância Imunológica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linfócitos T CD8-Positivos , Interferon gama , Interleucina-17/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Proteômica
6.
Radiographics ; 43(1): e220043, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36306219

RESUMO

A differential diagnosis based on a patient's age, clinical presentation, and serum α-fetoprotein level will help guide the initial imaging workup in children with a liver lesion. Children vary significantly in size, the ability to stay still, and the ability to breath hold for imaging examinations. Choosing and tailoring imaging techniques and protocols for each indication and age group is important for optimal care with minimal invasiveness. The need for sedation or anesthesia can be obviated by using techniques like feed and bundle, distraction, contrast-enhanced US, and motion-insensitive sequences for MRI. US is often the first imaging modality used in children with a suspected abdominal mass. Once a hepatic lesion is confirmed, multiphasic contrast-enhanced MRI is recommended for most lesions as the next imaging modality allowing full characterization of the lesion and assessment of the liver parenchyma. Contrast-enhanced CT can also be performed for assessment of pediatric focal liver lesions, especially in patients who have a contraindication to MRI. Contrast-enhanced US has shown promise to decrease the need for MRI or CT in some lesions such as hemangioma and focal nodular hyperplasia. Children with a history of malignancy can develop multiple types of hepatic lesions at various stages, including infections during an immunocompromised state, manifesting as focal liver lesions. Based on available limited data in the literature and the collective experiences of the Liver Imaging and Reporting Data System Pediatric Working Group, the authors provide guidelines for the imaging workup of pediatric focal liver lesions with an indication- and age-based approach and discuss the selection and performance of various imaging techniques and modalities. ©RSNA, 2022 See the invited commentary by Chojniak and Boaventura in this issue.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Criança , Carcinoma Hepatocelular/patologia , Meios de Contraste , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Fígado/patologia , Imageamento por Ressonância Magnética
7.
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
8.
Cell Death Dis ; 13(11): 926, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335087

RESUMO

As the most important RNA epigenetic regulation in eukaryotic cells, N6-metheyladenosine (m6A) modification has been demonstrated to play significant roles in cancer progression. However, this modification in long intergenic non-coding RNAs (lincRNAs) and the corresponding functions remain elusive. Here, we showed a lincRNA LINC02551 was downregulated by AlkB Homolog 5 (ALKBH5) overexpression in a m6A-dependent manner in hepatocellular carcinoma (HCC). Functionally, LINC02551 was required for the growth and metastasis of HCC. Mechanistically, LINC02551, a bona fide m6A target of ALKBH5, acted as a molecular adaptor that blocked the combination between DDX24 and a E3 ligase TRIM27 to decrease the ubiquitination and subsequent degradation of DDX24, ultimately facilitating HCC growth and metastasis. Thus, ALKBH5-mediated LINC02551 m6A methylation was required for HCC growth and metastasis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Epigênese Genética , RNA Helicases DEAD-box/metabolismo
9.
Int J Oncol ; 61(6)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36321789

RESUMO

Tumor­associated (TA) autoantibodies are considered to be promising biomarkers for the early detection of cancer, prior to the development of clinical symptoms. In the present study, a novel TA autoantibody was detected, which may prove to be useful as a diagnostic marker of human HCC using an HBx­transgenic (HBx­tg) hepatocellular carcinoma (HCC) mouse model. Its target antigen was identified as the bromodomain­containing protein 2 (BRD2), a transcriptional regulator that plays a pivotal role in the transcriptional control of diverse genes. BRD2 was upregulated in HCC tissues of the H­ras12V­tg mouse and human subjects, as demonstrated using western blotting or immunohistochemical analysis, with the BRD2 autoantibody. In addition, the truncated BRD2 reactive to the BRD2 autoantibody was detected in tumor cell­derived exosomes, which possibly activated TA immune responses and the generation of autoantibodies. For the detection of the serum BRD2 autoantibody, epitope mimicries of autoantigenic BRD2 were screened from a random cyclic peptide CX7C library with the BRD2 autoantibody. A mimotope with the sequence of CTSVFLPHC, which was cyclized by one pair of cysteine residues, exhibited high affinity to the BRD2 autoantibody and competitively inhibited the binding of the autoantibody to the cellular BRD2 antigen. The use of this cyclic peptide as a capture antigen in human serum enzyme­linked immunosorbent assay allowed the distinction of patients with HCC from healthy subjects with 64.41% sensitivity and 82.42% specificity (area under the ROC curve, 0.7761), which is superior to serum alpha­fetoprotein (AFP; 35.83% sensitivity; 100% specificity; area under the ROC curve, 0.5337) for the diagnosis of HCC. In addition, the detection of the BRD2 autoantibody combined with other autoantibody biomarkers or AFP has increased the accuracy of HCC diagnosis, suggesting that the combinational detection of cancer biomarkers, including the BRD2 autoantibody, is a promising assay for HCC diagnosis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , alfa-Fetoproteínas , Autoanticorpos , Biomarcadores Tumorais , Peptídeos , Camundongos Transgênicos , Curva ROC , Peptídeos Cíclicos , Fatores de Transcrição
10.
Exp Biol Med (Maywood) ; 247(19): 1741-1751, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36330895

RESUMO

Intra-tumor heterogeneity poses a serious challenge in the treatment of cancer, including hepatocellular carcinoma (HCC). Recent developments in single-cell RNA sequencing (scRNA-seq) make it possible to examine the heterogeneity of tumor cells. The Gene Expression Omnibus (GEO) database was retrieved to obtain scRNA-seq data of 13 HCC and 8 para cancer samples, and the cells were clustered using FindNeighbors and FindClusters functions. Cell subsets were defined using the "Enricher" function of the clusterProfiler package. Monocle was used to predict cell developmental trajectory. The LIMMA package included in the R program was utilized to detect differentially expressed genes (DEGs) between HCC and paracancerous tissues. Univariate Cox analysis and Least Absolute and Selection Operator (Lasso) Cox regression analysis were conducted to establish a risk assessment model. Thirteen cell subpopulations were identified from the sequencing data of 64,634 single cells. Four cell subgroups (dendritic cells, hepatocytes, liver bud hepatic cells, and liver progenitor cells) in tumor tissues were highly enriched. Between HCC and para cancer tissues, 3024 DEGs were identified, and 641 were specific markers of four cell subgroups. To develop a prognostic risk model, 9 genes among the 641 genes were selected. In the training and validation sets, the model demonstrated a higher 5-year AUC and independently served as a prognostic marker as confirmed by multivariate and univariate Cox analyses. This study revealed the characteristics of different cell subpopulations of immune cells and tumor cells from the HCC microenvironment. We established a novel nine-gene prognostic model to determine the death risk of HCC patients. The discoveries in this research improved the current knowledge of HCC heterogeneity and may inspire future research.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Análise de Célula Única , Prognóstico , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Microambiente Tumoral/genética
11.
Cancer Biol Ther ; 23(1): 1-12, 2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36404439

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Ephrin A4 (EFNA4) acts as an oncogene in multiple cancers but is little known in HCC. It is revealed that EFNA4 is highly expressed in patients with HCC and influences the proliferation of HCC cells; however, detailed regulatory mechanism of EFNA4 in HCC needs to be unveiled. Here, we discovered that EFNA4 was highly expressed in HCC cell lines. EFNA4 knockdown greatly suppressed cell proliferation, migration and invasion, as well as inhibiting angiogenesis in Huh7 cells. EFNA4 was demonstrated to interact with pygopus-2 (PYGO2) and positively regulate PYGO2 expression. Gene gain- and loss-of-function experiments revealed that the anti-tumor effect of EFNA4 knockdown was partly abolished by PYGO2 overexpression. Furthermore, EFNA4 knockdown blocked wnt/ß-catenin signaling in Huh7 cells, which was then abolished by PYGO2. In conclusion, this study further ensured the oncogenic role of EFNA4 in HCC, and disclosed that EFNA4 knockdown suppressed cell proliferation, invasion, angiogenesis, and wnt/ß-catenin signaling in HCC by downregulating PYGO2.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Efrina-A4/metabolismo , beta Catenina/metabolismo , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Neovascularização Patológica/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
12.
Sci Transl Med ; 14(672): eabp8704, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36417488

RESUMO

Cell-free DNA (cfDNA)-based liquid biopsy is a promising approach for the early detection of cancer. A major hurdle is the limited yield of cfDNA from one blood draw, limiting the use of most samples to one test of either mutation or methylation. Here, we develop a technology, Mutation Capsule Plus (MCP), which enables multiplex profiling of one cfDNA sample, including simultaneous detection of genetic and epigenetic alterations and genome-wide discovery of methylation markers. With this technology, we performed de novo screening of methylation markers on cfDNA samples from 30 hepatocellular carcinoma (HCC) cases and 30 non-HCC controls. The methylation markers enriched in HCC cfDNA were further profiled in parallel with a panel of mutations on a training cohort of 60 HCC and 60 non-HCC cases, resulting in an HCC detection model. We validated the model in an independent retrospective cohort with 58 HCC and 198 non-HCC cases and got 90% sensitivity with 94% specificity. Furthermore, we applied the model to a prospective cohort of 311 asymptomatic hepatitis B virus carriers with normal liver ultrasonography and serum AFP concentration. The model detected four of the five HCC cases in the cohort, showing 80% sensitivity and 94% specificity. These findings demonstrate that the MCP technology has potential for the discovery and validation of multiomics biomarkers for the noninvasive detection of cancer. This study also provides a comprehensive database of genetic and epigenetic alterations in the cfDNA of a large cohort of HCC cases and high-risk non-HCC individuals.


Assuntos
Carcinoma Hepatocelular , Ácidos Nucleicos Livres , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Estudos Prospectivos , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Mutação/genética , Metilação de DNA/genética
13.
BMJ Open ; 12(11): e064526, 2022 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-36410831

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) remains a major clinical problem as more than half of these cases recur after radical resection. Natural killer (NK) cells are at the forefront of the innate immune system and attack microcarcinomas and circulating tumour cells. The objective of this study was to evaluate the feasibility and toxicity of peripheral blood CD34+ stem cell-derived NK cell infusion after radical hepatectomy for HCC. METHODS AND ANALYSIS: This is an open-label, single-arm, single-centre phase I study. Patients who have undergone initial hepatectomy for HCC with three or more risk factors for recurrence (≥10 ng/mL of Alpha fetoprotein (AFP), ≥360 mAU/mL of PIVKA-II, multiple tumours and ≥3 peripheral blood circulating tumour cells) will be enrolled and be treated with three peripheral blood CD34+ stem cell-derived NK cell infusions every 3 months. The primary endpoint will be safety assessment including the type and severity of adverse events, frequency of occurrence and duration of occurrence. The secondary endpoints will include survival, effect of immune response and clinical laboratory test results. ETHICS AND DISSEMINATION: Ethical approval of the trial was obtained from the Certified Committee for Regenerative Medicine Hiroshima University in Japan. The trial results will be shared with the scientific community at international conferences and by publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTb060200020.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Neoplásicas Circulantes , Humanos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Hepatectomia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/cirurgia , Células Matadoras Naturais , Moléculas de Adesão Celular , Células-Tronco , Ensaios Clínicos Fase I como Assunto
14.
BMC Cancer ; 22(1): 1193, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36402986

RESUMO

The incidence of primary liver tumors, hepatocellular carcinoma (HCC), intrahepatic cholangiocellular carcinoma (ICC), and combined HCC/ICC (cHCC/CC) is increasing. For ICC, targeted therapy exists only for a small subpopulation of patients, while for HCC, Sorafenib and Lenvatinib are in use. Diagnosis of cHCC/CC is a great challenge and its incidence is underestimated, bearing the risk of unintended non-treatment of ICC. Here, we investigated effects of targeted inhibitors on human ICC cell lines (HUH28, RBE, SSP25), in comparison to extrahepatic (E)CC lines (EGI1, CCC5, TFK1), and HCC/hepatoblastoma cell lines (HEP3B, HUH7, HEPG2). Cells were challenged with: AKT inhibitor MK-2206; multikinase inhibitors Sorafenib, Lenvatinib and Dasatinib; PI3-kinase inhibitors BKM-120, Wortmannin, LY294002, and CAL-101; and mTOR inhibitor Rapamycin. Dosage of the substances was based on the large number of published data of recent years. Proliferation was analyzed daily for four days. All cell lines were highly responsive to MK-2206. Thereby, MK-2206 reduced expression of phospho(p)-AKT in all ICC, ECC, and HCC lines, which mostly corresponded to reduction of p-mTOR, whereas p-ERK1/2 was upregulated in many cases. Lenvatinib showed inhibitory effects on the two HCC cell lines, but not on HEPG2, ICCs and ECCs. Sorafenib inhibited proliferation of all cells, except the ECC line CCC5. However, at reduced dosage, we observed increased cell numbers in some ICC experiments. Dasatinib was highly effective especially in ICC cell lines. Inhibitory effects were observed with all four PI3-kinase inhibitors. However, cell type-specific differences were also evident here. Rapamycin was most effective in the two HCC cell lines. Our studies show that the nine inhibitors differentially target ICC, ECC, and HCC/hepatoblastoma lines. Caution should be taken with Lenvatinib and Sorafenib administration in patients with cHCC/CC as the drugs may have no effects on, or might even stimulate, ICC.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Hepatoblastoma , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/patologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Dasatinibe/uso terapêutico , Colangiocarcinoma/patologia , Fosfatidilinositol 3-Quinases , Sirolimo/farmacologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia
15.
J Nanobiotechnology ; 20(1): 488, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36402994

RESUMO

The liver is an important organ in the human body and performs many functions, such as digestion, detoxification, metabolism, immune responses, and vitamin and mineral storage. Therefore, disorders of liver functions triggered by various hepatic diseases, including hepatitis B virus infection, nonalcoholic steatohepatitis, hepatic fibrosis, hepatocellular carcinoma, and transplant rejection, significantly threaten human health worldwide. Polymer-based nanomedicines, which can be easily engineered with ideal physicochemical characteristics and functions, have considerable merits, including contributions to improved therapeutic outcomes and reduced adverse effects of drugs, in the treatment of hepatic diseases compared to traditional therapeutic agents. This review describes liver anatomy and function, and liver targeting strategies, hepatic disease treatment applications and intrahepatic fates of polymeric nanomedicines. The challenges and outlooks of hepatic disease treatment with polymeric nanomedicines are also discussed.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Nanomedicina , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Polímeros
16.
J Exp Clin Cancer Res ; 41(1): 329, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411480

RESUMO

BACKGROUND: Aerobic glycolysis has been recognized as one of the growth-promoting metabolic alterations of cancer cells. Emerging evidence indicates that nuclear factor κB (NF-κB) plays significant roles in metabolic adaptation in normal cells and cancer cells. However, whether and how NF-κB regulates metabolic reprogramming in hepatocellular carcinoma (HCC), specifically hepatitis B virus X protein (HBx)-initiated HCC, has not been determined. METHODS: A dataset of the HCC cohort from the TCGA database was used to analyse the expression of NF-κB family members. Expression of NF-κBp65 and phosphorylation of NF-κBp65 (p-p65) were detected in liver tissues from HBV-related HCC patients and normal controls. A newly established HBx+/+/NF-κBp65f/f and HBx+/+/NF-κBp65Δhepa spontaneous HCC mouse model was used to investigate the effects of NF-κBp65 on HBx-initiated hepatocarcinogenesis. Whether and how NF-κBp65 is involved in aerobic glycolysis induced by HBx in hepatocellular carcinogenesis were analysed in vitro and in vivo. RESULTS: NF-κBp65 was upregulated in HBV-related HCC, and HBx induced NF-κBp65 upregulation and phosphorylation in vivo and in vitro. Hepatocyte-specific NF-κBp65 deficiency remarkably decreased HBx-initiated spontaneous HCC incidence in HBx-TG mice. Mechanistically, HBx induced aerobic glycolysis by activating NF-κBp65/hexokinase 2 (HK2) signalling in spontaneous hepatocarcinogenesis, and overproduced lactate significantly promoted HCC cell pernicious proliferation via the PI3K (phosphatidylinositide 3-kinase)/Akt pathway in hepatocarcinogenesis. CONCLUSION: The data elucidate that NF-κBp65 plays a pivotal role in HBx-initiated spontaneous HCC, which depends on hyperactive NF-κBp65/HK2-mediated aerobic glycolysis to activate PI3K/Akt signalling. Thus, phosphorylation of NF-κBp65 will be a potential therapeutic target for HBV-related HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Hexoquinase/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinogênese/genética , Glicólise
17.
Biomed Pharmacother ; 156: 113976, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411668

RESUMO

Hepatocellular carcinoma (HCC) is a malignant tumor with limited treatment options. Given this fact, it may be important to develop new molecular targeted therapies from natural products, especially those which are primary sources of effective anticancer drugs with distinct mechanisms. Moreover, the complementary use of traditional herbs or fruit may increase the possibility of finding curative options for cancer. Here we explore the anticancer effects and possible molecular mechanism of Barhi date extract using an HCC rat model. Thirty two male albino rats were arbitrarily allocated into four groups: a negative control group (NCG); a positive control group (PCG), which received CCl4 (1 ml/kg b.wt./ i.p.) twice a week for three months; a Barhi date extract (400 mg/kg b.wt./day/orally) treatment group (DTG) during the third month of CCl4 administration; and a cisplatin (1.5 mg/kg b.wt./ i.p.) treatment group ( CTG) during the third month of CCl4 administration. After treatment we performed biochemical analyses of all groups to assess relative eukaryotic initiation factor 2 alpha (eIF2α), extracellular signal-regulated kinases (ERKs), protein kinase RNA-like endoplasmic reticulum kinase (PERK), poly (ADP-ribose) polymerase (PARP), and CASPASE 3 protein content, and examined expression of the genes phosphatase and tensin homolog (PTEN) and protein kinase B (AKT). We also performed an immunohistochemistry assay for alpha-fetoprotein (AFP). Our data showed higher PARP and CASPASE3 levels and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) in the PCG compared to the DTG and the cisplatin treatment group CTG. However, we also found a significant decrease in PTEN in the PCG relative to both the DTG and the CTG. We conclude that the anti-tumor activity of Barhi date extract may be mediated by the inhibition of cell proliferation and apoptosis via the ERK /PARP/caspase3 pathway and the AKT/ PTEN signaling pathways.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Phoeniceae , Animais , Carcinoma Hepatocelular/patologia , Phoeniceae/química , Proteínas Proto-Oncogênicas c-akt , Neoplasias Hepáticas/patologia , Cisplatino/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(10): 1303-1314, 2022 Oct 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36411681

RESUMO

OBJECTIVES: Our previous study has verified that high level of SET and MYND domain-containing protein 2 (SMYD2) plays an important role in acquiring aggressive ability for liver cancer cells in hepatocellular carcinoma. MiR-200b as a tumor suppressor gene involves in a variety of cancers. This study aims to investigate the correlation between miR-200b and SMYD2 in hepatocellular carcinoma and the underlying mechanism. METHODS: Firstly, the levels of SMYD2 and miR-200b in hepatocellular carcinoma tissues and matched adjacent non-tumor liver tissues were tested with real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Secondly, we evaluated the interaction between miR-200b and SMYD2 using dual-luciferase reporter assay. Thirdly, we elucidated the effect of miR-200b on SMYD2 and its downstream targets p53/CyclinE1. Finally, we silenced SMYD2 in hepatocellular carcinoma cell lines to investigate its effect on tumor proliferation and cell cycle progression, and further confirmed the correlation among SMYD2 and p53/CyclinE1. RESULTS: Compared with the matched adjacent non-tumor liver tissues, miR-200b was obviously decreased, and SMYD2 was significantly increased in hepatocellular carcinoma (both P<0.05). Spearman's rank correlation revealed that miR-200b expression was negatively correlated with SMYD2 (P<0.01). Computer algorithm and dual-luciferase reporter assay revealed that miR-200b directly targeted and suppressed SMYD2 in HEK 293T cells. The down-regulated miR-200b expression promoted hepatoma cell proliferation (P<0.05) and increased SMYD2 expression(P<0.01), while the up-regulated expression of miR-200b had an opposite effect. The knockdown of SMYD2 suppressed the proliferation of MHCC-97L cells (P<0.01), down-regulated CyclinE1, and up-regulated p53 expression (both P<0.05). CONCLUSIONS: MiR-200b is involved in hepatocellular carcinoma progression via targeting SMYD2 and regulating SMYD2/p53/CyclinE1 signaling pathway and may be used as a potential target for hepatocellular carcinoma treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Carcinoma Hepatocelular/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Neoplasias Hepáticas/patologia , Proliferação de Células/genética , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo
19.
Biomed Res Int ; 2022: 6441179, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36411770

RESUMO

Objectives. Preparation of a multifunctional drug-loaded phase-change nanoparticle (NP), pirfenidone perfluoropentane liposome NPs (PPL NPs), and combined with low-intensity focused ultrasound (LIFU) to influence epithelial mesenchymal transition (EMT) for hepatocellular carcinoma (HCC) by inhibiting the activity of activated Hepatic Stellate Cells (a-HSCs). Methods. PPL NPs were prepared by the thin film dispersion method. The appearance, particle size, zeta potential, encapsulation efficiency, drug loading rate, drug release in vitro, and stability of PPL NPs were tested. The role of a-HSCs in HCC metastasis was studied by CCK-8, colony formation assay, apoptosis, cellular uptake assay, wound healing assay, and Transwell assay. Western blot was used to detect the related protein expression levels. In vitro and vivo, the acoustic droplet vaporization (ADV) of PPL NPs was tested at different times and LIFU intensities. Biosafety of the PPL NPs was assessed by measuring nude mouse body weight and hematoxylin and eosin (H&E) staining. Results. The results showed that the PPL NPs had good biosafety, with an average particle size of 346.6 ± 62.21 nm and an average zeta potential of -15.23 mV. When the LIFU power is 2.4 W/cm2, it can improve the permeability of cells, further promote the uptake of drugs by cells, and improve the toxicity of drugs. In vitro experiments showed that PPL NPs could inhibit the proliferation of a-HSCs cells, thereby affecting the metastasis of HCC, and were related to the TGFß-Smad2/3-Snail signaling pathway. Both in vivo and in vitro PPL NPs enhanced ultrasound imaging by LIFU-triggered ADV. Conclusion. The PPL NPs designed and prepared in this study combined with LIFU irradiation could significantly alter the EMT of HCC by inhibiting LX2. Clinically, PPL NPs will also be considered a promising contrast agent due to their ultrasound imaging capabilities.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Camundongos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal , Células Estreladas do Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Lipossomos , Camundongos Nus
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