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1.
Adv Exp Med Biol ; 1164: 63-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576540

RESUMO

Gankyrin (also called PSMD10, p28, or p28GANK) is a crucial oncoprotein that is upregulated in various cancers and assumed to play pivotal roles in the initiation and progression of tumors. Although the in vitro function of gankyrin is relatively well characterized, its role in vivo remains to be elucidated. We have investigated the function of gankyrin in vivo by producing mice with liver parenchymal cell-specific gankyrin ablation (Alb-Cre;gankyrinf/f) and gankyrin deletion both in liver parenchymal and in non-parenchymal cells (Mx1-Cre;gankyrinf/f). Gankyrin deficiency both in non-parenchymal cells and parenchymal cells, but not in parenchymal cells alone, reduced STAT3 activity, interleukin-6 production, and cancer stem cell marker expression, leading to attenuated tumorigenic potential in the diethylnitrosamine hepatocarcinogenesis model. Essentially similar results were obtained by analyzing mice with intestinal epithelial cell-specific gankyrin ablation (Villin-Cre;Gankyrinf/f) and gankyrin deletion both in myeloid and epithelial cells (Mx1-Cre;Gankyrinf/f) in the colitis-associated cancer model. Clinically, gankyrin expression in the tumor microenvironment was negatively correlated with progression-free survival in patients undergoing treatment with Sorafenib for hepatocellular carcinomas. These findings indicate important roles played by gankyrin in non-parenchymal cells as well as parenchymal cells in the pathogenesis of liver cancers and colorectal cancers, and suggest that by acting both on cancer cells and on the tumor microenvironment, anti-gankyrin agents would be promising as therapeutic and preventive strategies against various cancers, and that an in vitro cell culture models that incorporate the effects of non-parenchymal cells and gankyrin would be useful for the study of human cell transformation.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Complexo de Endopeptidases do Proteassoma , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/fisiopatologia , Carcinoma Hepatocelular/terapia , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Deleção de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/terapia , Camundongos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral
2.
Anticancer Res ; 39(10): 5393-5401, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570434

RESUMO

BACKGROUND/AIM: Local recurrence of hepatocellular carcinoma (HCC) after thermal coagulation therapy may be associated with an aggressive phenotypic change. This study focused on the thermal effects on HCC cells and evaluated the heat shock response and phenotypic changes after heat treatment. MATERIALS AND METHODS: HepG2 and HuH7 cells were used. After heat treatment at 37-50°C for 5-30 min, we assessed their survival rate, induction of heat shock protein (HSP)70 promoter, proliferation rate, induction of the epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related markers. RESULTS: Induction of HSP70 promoter per surviving cell was maximized after 10 min of heat treatment at 48°C. Induction of EMT and CSC-related markers was also observed. CONCLUSION: Sub-lethal heat treatment causes large heat shock response to surviving HCC cells and induce EMT-like and CSC-like phenotypic changes that might contribute to increased aggressiveness.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Resposta ao Choque Térmico/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Transição Epitelial-Mesenquimal/genética , Proteínas de Choque Térmico HSP70/genética , Células Hep G2 , Temperatura Alta , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Taxa de Sobrevida
3.
Anticancer Res ; 39(8): 4423-4430, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366540

RESUMO

BACKGROUND/AIM: To evaluate the impact of DEPDC1 expression on patient prognosis after hepatic resection for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We reviewed data from 75 patients who underwent hepatic resection for HCC between 2004 and 2013. Recurrence at 2 years following resection, which mainly included metastatic recurrence, was defined as late recurrence. RESULTS: DEPDC1 was up-regulated in HCC tissue and in non-tumor tissue of patients with HCC compared to normal liver (p<0.01 and p<0.01, respectively). High expression of DEPDC1 was associated with poor overall, disease-specific, and disease-free survival (p=0.02, p<0.01, and p<0.01, respectively). High DEPDC1 expression was an independent predictor of death and recurrence (p=0.03 and p<0.01, respectively). High expression of DEPDC1 in non-tumor liver was an independent risk factor for late recurrence (p=0.04). CONCLUSION: High expression of DEPDC1 in tumor tissue appears to be associated with tumor progression and poor prognosis.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas Ativadoras de GTPase/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Prognóstico , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade
4.
Anticancer Res ; 39(8): 4065-4071, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366489

RESUMO

BACKGROUND: Surgical orthotopic implantation of human colon cancer tissue to the ceca of mice has been used to mimic behavior of cancer in human patients for the development of precision cancer medicine. However, with the current method of serosal surface implantation (SSI) of pieces of human colon cancer tissue, cancer cells are exposed to the peritoneum, which can artificially increase the rate of peritoneal carcinomatosis (PC) during the disease course. The objective of the present study was to introduce a tumor-sealing method (TSM) and compare it with SSI for the ability to produce clinically-relevant metastases without artificial PC. MATERIALS AND METHODS: HCT116 colon cancer cells transfected with green fluorescence protein (GFP) were cultured and then injected into the subcutaneous layer of athymic nude mice. Subcutaneous tumors were allowed to grow sufficiently to supply adequate tumor for orthotopic implantation. For SSI, a 1 mm3-sized tumor fragment was sutured to partially torn serosa of the cecum. For TSM, the blind end of the cecum was folded over the tumor fragment and sealed with sutures. At 20 days after implantation, all mice were opened to visualize PC by intravital fluorescence imaging. At necropsy, distant metastasis was investigated using frozen section of whole blocks of organs. RESULTS: At 20 days after implantation, PC rates in the SSI group and the TSM group were 80% (12/15) and 20% (3/15), respectively (p<0.001). The liver metastasis rate was 41.7% (5/12) in the SSI group and 50% (5/10) in the TSM group (p=0.696). The lung metastasis rate was 0% (0/12) in the SSI group and 10% (1/10) in the TSM group (p=0.201). The mean survival of mice without PC on the 20th day was significantly longer than that of mice with PC on the 20th day (69.1±14.7 vs. 44.5±12.4 days, p=0.001). CONCLUSION: These results suggest that TSM might be a more patient-like and useful method as a model of metastatic colon cancer than SSI.


Assuntos
Carcinogênese/genética , Neoplasias do Colo/patologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/patologia , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/cirurgia , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/química , Células HCT116 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos , Metástase Neoplásica , Transplante de Neoplasias/métodos , Imagem Óptica , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 39(8): 4315-4324, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366523

RESUMO

BACKGROUND/AIM: This study aimed to obtain accurate differential diagnosis (DDx) of multicentric carcinogenesis (MC) and intrahepatic metastasis (IM) in recurrent lesions of hepatocellular carcinoma. MATERIALS AND METHODS: A total of 79 patients who underwent re-hepatectomy (2000-2013) were examined. PCR was used to analyze 13 chromosomal microsatellite loci by PCR. On the basis of this genetic analysis, the recurrent lesions were diagnosed as IM, MC or not determined (ND). Subsequently, DDx was compared with types of resection and outcome. RESULTS: The recurrent lesions were diagnosed as IM in 33 patients, MC in 44, and ND in 2. The anatomical resection group included 14 IM lesions (28%) and 36 MC lesions (72%), while the non-anatomical resection group included 19 IM lesions (70%) and 8 MC lesions (30%) (p<0.001). CONCLUSION: Anatomical resection at initial hepatectomy may reduce the likelihood of IM recurrence, leading to a better outcome for patients with HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Metástase Neoplásica/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Diagnóstico Diferencial , Feminino , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia
6.
Gene ; 716: 144031, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377314

RESUMO

Circular RNAs (circRNAs), a novel class of widespread and diverse endogenous RNAs, have been identified as critical regulators of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of circRNAs in HCC are largely unknown. In this study, we identified a novel circRNA, circ-IGF1R, in HCC tumour tissues and cell lines. Circ-IGF1R levels were found to be significantly upregulated in HCC tissues compared with levels in paired peritumoural tissues. The high expression levels of circ-IGF1R in HCC were associated with tumour size. Moreover, knocking down circ-IGF1R with siRNA significantly attenuated cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. Further investigation revealed that PI3K/AKT signalling pathway activation was involved in the oncogenic functions of circ-IGF1R in HCC. Our study suggests that circ-IGF1R may be a potential target for the prevention and treatment of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA/metabolismo , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
7.
Eur J Histochem ; 63(3)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31455073

RESUMO

RNA interference is a powerful approach to understand gene function both for therapeutic and experimental purposes. Since the lack of knowledge in the gene silencing of various hepatic cell lines, this work was aimed to compare two transfection agents, the liposome-based Lipofectamine™ RNAiMAX and the HepG2-specific, polymer-based GenMute™, in two cellular models of human hepatoma, HepG2 and Huh7.5. In the first part, we assessed transfection efficiency of a fluorescent Cy3-labeled negative control siRNA by cell imaging analysis; we found that cells treated with GenMute present a higher uptake of the fluorescent negative control siRNA when compared to Lipofectamine RNAiMAX-transfected cells, both in HepG2 and in Huh7.5 cells. In the second part, we evaluated GAPDH silencing with the two transfection reagents by RT-PCR similar GAPDH mRNA expression after each transfection treatment. Finally, we measured cell viability by the MTT assay, observing that cells transfected with GenMute have higher viability with respect to Lipofectamine RNAiMAX-administered cells. These results suggest that GenMute reagent might be considered the most suitable transfection agent for hepatic gene silencing.


Assuntos
Técnicas de Transferência de Genes , Lipídeos/química , Polímeros/química , RNA Interferente Pequeno/genética , Transfecção/métodos , Sequência de Bases , Carbocianinas/química , Carbocianinas/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Inativação Gênica , Gliceraldeído-3-Fosfato Desidrogenases/genética , Humanos , Metabolismo dos Lipídeos , Lipídeos/toxicidade , Lipossomos/química , Lipossomos/metabolismo , Lipossomos/toxicidade , Neoplasias Hepáticas/genética , Polímeros/metabolismo , Polímeros/toxicidade , Interferência de RNA
8.
Gene ; 719: 144044, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31400406

RESUMO

OBJECTIVE: Exosomes have been described as a messenger between cells' communication and contain various information (lipids, proteins, mRNAs, microRNAs, LncRNAs). It has been proved that Linc-ROR was enriched in exosomes released by HepG2 cells. Our aim was to investigate whether exosomes released by HepG2 cells could affect the biological behaviors of LO2 cells and whether Linc-ROR played an important role in this process. METHODS: Exosomes-derived from HepG2 cells were isolated and characterized. Real-time PCR assessed expression level of Linc-ROR in specimens of cancerous tissues and carcinoma-adjacent tissues. The Linc-ROR expression level in HepG2, Huh7, SMMC-7721, Bel-7402, LO2 cells and exosomes was detected by real-time PCR. Knockdown the expression of Linc-ROR in HepG2 by using effective siRNA. Cell counting method was used to test LO2 cells proliferative activities. Flow cytometry was performed to quantify the apoptosis rates of LO2 cells cocultured with exosomes. The expression levels of OCT4, NANOG, SOX2, P53 and CD133 were assessed by western blot. RESULTS: Linc-ROR was enriched in exosomes released by HepG2 cells. Exosomes derived from HepG2 cells promoted the proliferation and suppressed the apoptosis of LO2 cells suffering nutrient deficiency. Knockdown the expression of Linc-ROR in HepG2 or LO2 cells could significantly impaired the exosomes' effects on LO2 cells. In addition, the long-term coculture with exosomes would obviously change the biological behaviors of LO2 cells. CONCLUSIONS: Our experiments indicated the HepG2 cells could transfer its Linc-ROR to the LO2 cells via exosomes, then influenced the recipient cells.


Assuntos
Carcinoma Hepatocelular/patologia , Exossomos/metabolismo , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , Apoptose , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade
9.
Yonsei Med J ; 60(9): 842-853, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31433582

RESUMO

PURPOSE: Long intergenic non-protein coding RNA 665 (LINC00665) plays a vital role in the development of cancer. Its function in hepatocellular carcinoma (HCC), however, remains largely unknown. MATERIALS AND METHODS: The expressions of LINC00665, miR-186-5p, and MAP4K3 were determined by qRT-PCR. Cell viability and apoptosis were evaluated by MTT and flow cytometry, respectively. Autophagic puncta formation was observed by fluorescence microscopy. Bioinformatics analysis, luciferase reporter assay, RNA immunoprecipitation, and RNA pulldown were performed to identify associations among LINC00665, miR-186-5p, and MAP4K3. Western blot was utilized to examine the expressions of MAP4K3, Beclin-1, and LC3. Tumor growth was evaluated in a xenograft model. RESULTS: Elevations in LINC00665 were observed in HCC tissues and cells. The overall survival of HCC patients with high levels of LINC00665 was shorter than those with low levels. In vitro, LINC00665 depletion inhibited viability and induced apoptosis and autophagy. miR-186-5p interacted with LINC00665 and was downregulated in HCC tissues and cells. Upregulation of miR-186-5p inhibited viability and induced apoptosis and autophagy, which were attenuated by upregulation of LINC00665. MAP4K3 was found to possess binding sites with miR-186-5p and was upregulated in HCC tissues and cells. MAP4K3 depletion inhibited viability and induced apoptosis and autophagy, which were attenuated by miR-186-5p inhibitor. In vivo, miR-186-5p expression was negatively correlated with LINC00665 or MAP4K3 in HCC tissues, while LINC00665 was positively correlated with MAP4K3. LINC00665 knockdown suppressed tumor growth. CONCLUSION: LINC00665 was involved in cell viability, apoptosis, and autophagy in HCC via miR-186-5p/MAP4K3 axis, which may provide a new approach for HCC treatment.


Assuntos
Apoptose/genética , Autofagia/genética , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , Adulto , Idoso , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Feminino , Humanos , Neoplasias Hepáticas/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases , RNA Longo não Codificante/genética , Regulação para Cima
10.
Gene ; 712: 143965, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279708

RESUMO

Recently, we read the published article in GENE. Dong et al. presented the evaluation of the MDM2 40-bp insertion/deletion status in Hepatocellular carcinoma patients (Dong et al., 2012). The authors stated that the insertion allele showed a 521-bp band and the deletion allele showed a 481-bp band on agarose gel electrophoresis. While it seems that these reported sizes for insertion and deletion alleles of MDM2 are incorrect. Our analysis using the primers indicated that the length of insertion and deletion fragments will be 481 and 441 bps, respectively. Actually, 40-bp is added to the fragment length instead of reducing the 40-bp. In the 'UCSC In-Silico PCR' tool, the length of the amplified fragment using mentioned primers is 481-bp including the sequence of 40-bp insertion allele (5'-(A)5GCTGCA(GAAGG)2ATATAACTTTAT(A)7-3') (Reference SNP (rs) Report, n.d.). Therefore, the fragment including the deletion allele will be 441-bp.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Alelos , Predisposição Genética para Doença , Humanos , Mutação INDEL , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-mdm2/genética
11.
Gene ; 714: 143994, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31330233

RESUMO

Long non-coding RNA (lncRNA) potentially regulates tumorigenesis. LncRNA small nucleolar RNA host gene 1 (SNHG1) expression remains high in hepatocellular carcinoma cells; however, its biological mechanism in hepatocellular carcinoma remains unknown. In this study, SNHG1 expression in hepatocellular carcinoma cells was detected by qRT-PCR. Proliferative and migratory potentials of hepatocellular carcinoma cells were determined by CCK-8 and Transwell assay, respectively. Then, the nude mice model of xenograft was employed to verify the effect of SNHG1 on tumor formation in vivo. We identified the potential target of SNHG1 through bioinformatics and dual-luciferase reporter gene. Furthermore, Western blot and RIP assay was used for clarifying their interaction and functions in regulating the development of hepatocellular carcinoma. Our results indicated a high expression of SNHG1 in hepatocellular carcinoma cells. Downregulation of SNHG1 inhibited proliferative and migratory potentials of hepatocellular carcinoma cells in vitro and in vivo. Moreover, the expression of programmed cell death 4 (PDCD4) was positively regulated by SNHG1 through competing with miR-195-5p. These results indicated that SNHG1 participated in the development of hepatocellular carcinoma as a ceRNA to competitively bind to miR-195-5p and thus mediate PDCD4 expression.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Animais , Apoptose/genética , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
12.
Gene ; 714: 143992, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31330234

RESUMO

Increasing studies have demonstrated the important roles of circular RNAs (circRNAs) in human malignancies. Nevertheless, the molecular mechanisms and functions of circRNAs in hepatocellular carcinoma (HCC) are still not fully understood. In the present study, we evaluated circ_0021093 expression in 82 pairs of HCC tissues and 5 cell lines by qRT-PCR. The clinical implications of circ_0021093 were evaluated. In addition, the viability, apoptosis, migration and invasion capacities of different HCC cells were evaluated by gain-/loss-of-function experiments. Target prediction and dual-luciferase reporter experiments were performed to identify the molecular mechanisms of circ_0021093. Upregulation of circ_0021093 was found in HCC tumor samples and cells. Additionally, upregulated circ_0021093 was related to adverse clinical characteristics and an unfavorable prognosis. Furthermore, downregulated circ_0021093 attenuated cell growth, migration and invasion but increased cell apoptosis. By contrast, ectopically expressed circ_0021093 enhanced the abovementioned malignant biological behaviors. For mechanism exploration, circ_0021093 sponges of miR-766-3p were used in HCC cells. In addition, we found that metastasis-associated protein 3 (MTA3) was a direct target of miR-766-3p and that the oncogenic function of circ_0021093 was partly dependent on the miR-766-3p/MTA3 axis according to rescue assays. In conclusion, the circ_0021093/miR-766-3p/MTA3 regulatory axis may be an effective therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA/genética , Apoptose/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Regulação para Cima/genética
13.
Medicine (Baltimore) ; 98(28): e16245, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305404

RESUMO

RATIONALE: Primary splenic angiosarcoma (PSA) is a rare mesenchymal malignancy of the splenic vascular origin often with a dismal prognosis. Genomic profile may provide evidence for the solution of therapy. PATIENT CONCERNS: We reported a case of a 51-year-old woman with splenectomy 4 years ago and the postoperative histopathology diagnosis revealed "splenic hemangioma" with spontaneous rupture. Two years after the operation, the patient's rechecked abdominal computed tomography (CT) showed multiple hepatic occupations. DIAGNOSES: Pathological test suggested PSA hepatic metastasis. INTERVENTIONS: The patient was treated with trans-catheter arterial chemoembolization (TACE) and a pathological diagnosis of PSA was highly suspected in the hepatic biopsy. Four somatic alterations, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), MCL1 apoptosis regulator (MCL1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were detected in the tumor tissue using a Next generation sequencing (NGS) technology. The results prompted that the patient may get clinical benefit from using some agents for targeted therapy, Everolimus, Temsirolimus, or Copanlisib. OUTCOMES: The patient refused targeted therapy. As a result, the patient passed away within 51 months after splenectomy. LESSONS: PSA is an aggressive disease that often presented with a high propensity for metastasis and rupture hemorrhage. Some of these mutations were first discovered in PSA and these findings added new contents to the genomic mutation profile of PSA.


Assuntos
Hemangiossarcoma/cirurgia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Esplenectomia , Neoplasias Esplênicas/cirurgia , Classe I de Fosfatidilinositol 3-Quinases/genética , Evolução Fatal , Feminino , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-fos/genética , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/patologia
14.
Rev Soc Bras Med Trop ; 52: e20170427, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31271612

RESUMO

INTRODUCTION: HPA polymorphism has been associated with HCV presence and fibrosis progression in chronic hepatitis C. However, it is unknown if there is an association between HPA-1 polymorphism and hepatocellular carcinoma (HCC). Therefore, this study aimed to evaluate HPA-1 polymorphism in the presence of HCC. METHODS: PCR-SSP was used to perform HPA genotyping on 76 HCV-infected patients. RESULTS: There was no association between patients with and without HCC. There was significant difference in HPA-1 genotypic frequency distribution between HCC and F1/F2 fibrosis degree. CONCLUSIONS: The HPA-1a/1b polymorphism appears to be more associated with liver damage progression than with HCC presence.


Assuntos
Antígenos de Plaquetas Humanas/genética , Carcinoma Hepatocelular/virologia , Hepatite C Crônica/genética , Neoplasias Hepáticas/virologia , Carcinoma Hepatocelular/genética , Progressão da Doença , Feminino , Marcadores Genéticos , Genótipo , Hepatite C Crônica/virologia , Humanos , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Risco
15.
Neoplasma ; 20192019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31307202

RESUMO

The aim of study was to identify the downstream target genes of CX43 by Human Transcriptome Array. Therefore, a gene microarray was generated which consists of CX43-overexpressed hepatocellular carcinoma (HCC) cells transfected with the constructed plasmid and negative controls to identify candidate genes. Integrated bioinformatic analysis was used to clarify biological functions of the identified genes, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction network, and survival analysis. The candidate genes were further validated by qRT-PCR in liver cancer tissues and CX43-silenced HCC cells. We have found the mRNA and protein levels of CX43 significantly upregulated in HCC cells transfected with CX43 constructed plasmid. We identified 928 differentially expressed genes including 394 upregulated and 534 downregulated genes, enriched in the cancer related functions and pathways by GO and KEGG pathway analysis. The protein-protein interaction network revealed 9 hub genes in this study. Statistical analysis indicated that upregulation of RALA and SRC was associated with poor prognosis in liver cancer. The differential expression of 2 candidate genes were further validated in HCC cells and tissues. In conclusion, protein-coding genes RALA and SRC could be target genes of CX43 and therapeutic targets for hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular , Conexina 43 , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/fisiopatologia , Conexina 43/genética , Conexina 43/metabolismo , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(6): 679-684, 2019 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-31270046

RESUMO

OBJECTIVE: To explore the role of Long noncoding RNA UFC1 (lincRNA-UFC1) in modulating the metastasis and invasion of hepatocellular carcinoma (HCC) cells and the underlying mechanism. METHODS: Human HCC cell line Huh7 was infected with the lentiviral vector carrying lincRNA-UFC1 to obtain a cell line with lincRNA-UFC1 overexpression. A short hairpin RNA (shRNA) targeting lincRNA-UFC1 was delivered in human HCC BEL-7402 cells via a lentiviral vector to obtain a cell line with lincRNA-UFC1 knockdown. Expression levels of lincRNA-UFC1 in the two HCC cell lines were detected using real-time PCR, and the changes in the cell invasion and migration in response to lincRNA-UFC1 overexpression or knockdown were analyzed using Transwell and wound-healing assays. The expressions of GSK-3ß/ß-catenin-related proteins in the cells were detected with Western blotting. XAV-939, a GSK-3ß/ß-catenin inhibitor, was used for assessing the impact of lincRNAUFC1 overexpression on the invasion and migration of the HCC cells through Transwell and wound-healing assays. RESULTS: Overexpression of lincRNA-UFC1 significantly promoted the invasion and migration of Huh7 cells as compared with the control cells (P < 0.001), while lincRNA-UFC1 knockdown obviously suppressed the invasion and migration of BEL-7402 cells (P < 0.001). The results of Western blotting showed that the expressions of proteins associated with the cell invasion and migration, namely ß-catenin and P-GSK-3ß, were significantly upregulated in response to lincRNA-UFC1 overexpression, and were obviously lowered after lincRNA-UFC1 knockdown. Treatment of the cells with XAV-939 significantly reversed the effect of lincRNA-UFC1 overexpression on the cell invasion and migration (P < 0.001). CONCLUSIONS: lincRNA-UFC1 overexpresison promotes cell invasion and migration through the GSK-3ß/ß-catenin axis in HCC cells in vitro.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta , Humanos , Neoplasias Hepáticas/genética , Invasividade Neoplásica , Metástase Neoplásica , RNA Longo não Codificante , beta Catenina
17.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(7): 805-809, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31357803

RESUMO

Objective: To explore an effective long non-coding RNA (lncRNA) signature in predicting the prognosis of hepatocellular carcinoma through the analysis on RNA sequencing data of hepatocellular carcinoma patients and peritumoral tissues in the Cancer Genome Atlas (TCGA) database. Methods: The clinical characteristics and RNA sequencing data of 377 hepatocellular carcinoma patients were obtained from TCGA database by the end of February 2018. Then, differentially expressed lncRNAs between 50 pairs of tumor and peritumoral tissues were explored using student's t-test. Next, a lncRNA signature was established through LASSO Cox regression analysis. All the patients were divided into four groups (

Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA Longo não Codificante , Carcinoma Hepatocelular/terapia , Bases de Dados Genéticas , Humanos , Neoplasias Hepáticas/terapia , Prognóstico
18.
Anticancer Res ; 39(7): 3571-3578, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262881

RESUMO

BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cancer-selective, cell-death-inducing agent with little toxicity to normal cells. However, various human cancers and cancer cell lines have been reported to be resistant to TRAIL. Molecular clarification of resistance mechanism is needed. MATERIALS AND METHODS: Compound screening, proliferation assays, western blotting, and flow cytometry were used to examine the sensitizer activity of methyl transferase inhibitor BIX-01294 in combination with TRAIL, in hepatocellular carcinoma (HCC) cells. RNA sequencing analysis and single guide (sg)RNA-mediated gene deletion were used to investigate the role of survivin in sensitization. RESULTS: In HCC cells, BIX-01294 enhanced TRAIL sensitivity by reducing survivin expression at the RNA level. Small interference RNA-mediated gene knockdown demonstrated the mechanism of sensitization to be via the reduction of survivin. CONCLUSION: Euchromatin histone methyltransferase 2 (EHMT2) inhibition by BIX-01294 may be a potent anti-tumor therapeutic strategy for human HCC.


Assuntos
Azepinas/farmacologia , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quinazolinas/farmacologia , Survivina/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Survivina/genética
19.
Neoplasma ; 66(5): 792-800, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31305121

RESUMO

NF-kB activating protein (NKAP) is a highly conserved protein involved in transcriptional repression, immune cell development, maturation, T cell acquisition of functional competency and maintenance of hematopoiesis. Here we first explore the function of NKAP in hepatocellular carcinoma (HCC). We found that NKAP was highly expressed in HCC tissues and associated with a poor patient survival. CCK8 assay showed that NKAP knockdown significantly decreased cell viability of HuH7 and Hep3B HCC cell lines. Cell invasion, tested by transwell assays, was significantly inhibited by NKAP knockdown in HuH7 and Hep3B cells (P<0.05). Percentage of cell apoptosis was significantly increased by NKAP knockdown in HuH7 cells (6.5% to 12.5%) and in Hep3B cells (8.3% to 27.3%). Furthermore, western blot results indicated that NKAP silence upregulated the expression of pro-apoptotic proteins Bax and Caspase3-P17 while downregulated anti-apoptotic protein Bcl2. Finaly, AKT signaling pathway was evaluated to reveal the underlying mechanism of NKAP in HCC cells. It was suggested that NKAP knockdown decreased the phosphorylation level of AKT and the expression of its downstream members p70S6K and Cyclin D1. Furthermore, we demonstrated that NKAP knockdown also played an oncogenic role in human gastric cancer AGS and MKN45 cells. In conclusion, for the first time our study reveals that NKAP promotes the proliferation and invasion in HCC cell lines at least partly through AKT signaling pathway.


Assuntos
Carcinoma Hepatocelular , Proteínas Correpressoras , Neoplasias Hepáticas , Proteínas Nucleares , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/fisiopatologia , Linhagem Celular Tumoral , Proteínas Correpressoras/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
20.
Yonsei Med J ; 60(8): 727-734, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347327

RESUMO

PURPOSE: Hepatocellular carcinoma (HCC) is a common cancer worldwide. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA (lncRNA), has been reported to be aberrantly expressed in hypoxic cancer cells. MALAT1 plays a significant role in many malignancies, including HCC. The aim of this study was to explore the role of MALAT1 in hypoxic HCC cells and its underlying regulatory mechanism. MATERIALS AND METHODS: Quantitative reverse transcription PCR (qRT-PCR) assay was performed to detect the mRNA levels of MALAT1 and microRNA-200a (miR-200a) in HCC cells. Cell invasion and migration ability were evaluated by Transwell assay. Starbase v2.0 and luciferase reporter assay were employed to identify the association between MALAT1 and miR-200a. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. RESULTS: MALAT1 levels were significantly upregulated in HCC cells under hypoxia. Hypoxia promoted proliferation, migration, and invasion, and blocked apoptosis in Hep3B cells, which were weakened by knockdown of MALAT1. Starbase v2.0 showed that MALAT1 and miR-200a have a complementarity region, and luciferase reporter assay verified that MALAT1 interacted with miR-200a in Hep3B cells. Moreover, MALAT1 negatively regulated the expression of miR-200a. miR-200a levels were dramatically downregulated in HCC cells under hypoxia. Upregulation of miR-200a inhibited proliferation, migration, and invasion, and induced apoptosis in Hep3B cells under hypoxia. Interestingly, downregulation of miR-200a partially reversed the tumor-suppressive effect of knockdown of MALAT1 on Hep3B cells in hypoxic condition. CONCLUSION: LncRNA MALAT1 was involved in proliferation, migration, invasion, and apoptosis by interacting with miR-200a in hypoxic Hep3B cells, revealing a new mechanism of MALAT1 involved in hypoxic HCC progression.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Hipóxia Tumoral/genética , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Invasividade Neoplásica , RNA Longo não Codificante/genética , Regulação para Cima/genética
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