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1.
Hepatology ; 78(5): 1402-1417, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36811396

RESUMO

BACKGROUND AIMS: Regulatory T cells (Tregs) are an obstacle to PD-1 blockade-mediated antitumor efficacy. However, the behaviors of Tregs response to anti-PD-1 in HCC and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues to the tumor are still unclear. APPROACH RESULTS: Here, we determine that PD-1 monotherapy potentially augments the accumulation of tumor CD4 + Tregs. Mechanistically, anti-PD-1 mediates Tregs proliferation in lymphoid tissues rather than in the tumor. Increased peripheral Tregs burden replenishes intratumoral Tregs, raising the ratio of intratumoral CD4 + Tregs to CD8 + T cells. Subsequently, single-cell transcriptomics revealed that neuropilin-1 (Nrp-1) supports Tregs migration behavior, and the genes of Crem and Tnfrsf9 regulate the behaviors of the terminal suppressive Tregs. Nrp-1 + 4-1BB - Tregs stepwise develop to the Nrp-1 - 4-1BB + Tregs from lymphoid tissues into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with the 4-1BB agonist to enhance the antitumor response. Finally, a combination of the Nrp-1 inhibitor and the 4-1BB agonist in humanized HCC models showed a favorable and safe outcome and evoked the antitumor effect of the PD-1 blockade. CONCLUSION: Our findings elucidate the potential mechanism of anti-PD-1-mediated intratumoral Tregs accumulation in HCC and uncover the tissue adaptation characteristics of Tregs and identify the therapeutic potential of targeting Nrp-1 and 4-1BB for reprogramming the HCC microenvironment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linfócitos T CD8-Positivos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neuropilina-1/genética , Receptor de Morte Celular Programada 1/genética , Linfócitos T Reguladores , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
Hepatology ; 70(1): 198-214, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30810243

RESUMO

Tumor-associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, resulting in immunosuppression. Specifically, TREM-1-positive (TREM-1+ ) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8+ T cells and induced CD8+ T-cells apoptosis. Biological and functional assays showed that TREM-1+ TAMs had higher expression of programmed cell death ligand 1 (PD-L1) under hypoxic environment. However, TREM-1+ TAMs could abrogate spontaneous and PD-L1-blockade-mediated antitumor effects in vivo, suggesting that TREM-1+ TAM-induced immunosuppression was dependent on a pathway separate from PD-L1/programmed cell death 1 axis. Moreover, TREM-1+ TAM-associated regulatory T cells (Tregs) were crucial for HCC resistance to anti-PD-L1 therapy. Mechanistically, TREM-1+ TAMs elevated chemokine (C-C motif) ligand 20 expression through the extracellular signal-regulated kinase/NF-κß pathway in response to hypoxia and tumor metabolites leading to CCR6+ Foxp3+ Treg accumulation. Blocking the TREM-1 pathway could significantly inhibit tumor progression, reduce CCR6+ Foxp3+ Treg recruitment, and improve the therapeutic efficacy of PD-L1 blockade. Thus, these data demonstrated that CCR6+ Foxp3+ Treg recruitment was crucial for TREM-1+ TAM-mediated anti-PD-L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM-1+ TAMs attracting CCR6+ Foxp3+ Tregs, and TREM-1+ TAMs endowed HCC with anti-PD-L1 therapy resistance.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/fisiologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos , Humanos , Hipóxia/metabolismo , Terapia de Imunossupressão , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Microambiente Tumoral
3.
Cancer Cell Int ; 19: 179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337986

RESUMO

BACKGROUND: Multi-drug resistance is the major cause of chemotherapy failure in hepatocellular carcinoma (HCC). YAP, a critical effector of the Hippo pathway, has been shown to contribute to the progression, metastasis and invasion of cancers. However, the potential role of YAP in mediating drug resistance remains obscure. METHODS: RT-qPCR and western blot were used to assess YAP expression in HCC cell lines. CCK-8 assays, flow cytometry, a xenograft tumour model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on multi-drug resistance, intracellular ROS production and the autophagy of HCC cells in vitro and in vivo. Autophagy inhibitor and rescue experiments were carried out to elucidate the mechanism by which YAP promotes chemoresistance in HCC cells. RESULTS: We found that BEL/FU, a typical HCC cell line with chemoresistance, exhibited overexpression of YAP. Moreover, the inhibition of YAP by shRNA or verteporfin conferred the sensitivity of BEL/FU cells to chemotherapeutic agents through autophagy-related cell death in vitro and in vivo. Mechanistically, YAP silencing significantly enhanced autophagic flux by increasing RAC1-driven ROS, which contributed to the inactivation of mTOR in HCC cells. In addition, the antagonist of autophagy reversed the enhanced effect of YAP silencing on cell death under treatment with chemotherapeutic agents. CONCLUSION: Our findings suggested that YAP upregulation endowed HCC cells with multi-drug resistance via the RAC1-ROS-mTOR pathway, resulting in the repression of autophagy-related cell death. The blockade of YAP may serve as a promising novel therapeutic strategy for overcoming chemoresistance in HCC.

4.
Int J Med Sci ; 16(9): 1271-1282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588193

RESUMO

Nanosecond pulsed electric fields (nsPEFs) is emerged as a potential curative modality to ablate hepatocellular carcinoma (HCC). The application of local ablation is usually limited by insufficiency of liver function. While baicalin, a flavonoid isolated from Scutellaria baicalensis Georgi, has been proven to possess both anti-tumor and protective effects. Our study aimed to estimate different responses of hepatic cancer cells and hepatocytes to the combination of nsPEFs and baicalin. Cell viability, apoptosis and necrosis, mitochondrial transmembrane potential (MTP) and reactive oxygen species (ROS) were examined by CCK-8, FCM, JC-1 and fluorescent probe, respectively. After treatment by nsPEFs, most hepatocytes died by apoptosis, nevertheless, nearly all cancer cells were killed through necrosis. Low concentration of baicalin synergically enhanced nsPEFs-induced suppression and necrosis of HCC cells, nevertheless, the application of baicalin protected normal hepatocytes from the injury caused by nsPEFs, owing to elevating mitochondrial transmembrane potential and reducing ROS generation. Our work provided an advantageous therapy for HCC through the enhanced combination treatment of nsPEFs and baicalin, with which could improve the tumor-ablation effect and alleviate the injury of hepatic tissues simultaneously.


Assuntos
Carcinoma Hepatocelular/terapia , Terapia por Estimulação Elétrica/métodos , Flavonoides/farmacologia , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/terapia , Animais , Carcinoma Hepatocelular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Flavonoides/efeitos adversos , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
5.
Biochem Biophys Res Commun ; 420(1): 29-35, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22390936

RESUMO

Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the protein phosphatases family and has a dual function in cell cycling. The function of this gene has been studied in several kinds of cancers, but its role in human hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we found that CDKN3 was frequently overexpressed in both HCC cell lines and clinical samples, and this overexpression was correlated with poor tumor differentiation and advanced tumor stage. Functional studies showed that overexpression of CDKN3 could promote cell proliferation by stimulating G1-S transition but has no impact on cell apoptosis and invasion. Microarray-based co-expression analysis identified a total of 61 genes co-expressed with CDKN3, with most of them involved in cell proliferation, and BIRC5 was located at the center of CDKN3 co-expression network. These results suggest that CDKN3 acts as an oncogene in human hepatocellular carcinoma and antagonism of CDKN3 may be of interest for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Proteínas Inibidoras de Quinase Dependente de Ciclina/biossíntese , Fosfatases de Especificidade Dupla/biossíntese , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Adulto , Proliferação de Células , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Fosfatases de Especificidade Dupla/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Adulto Jovem
6.
J Surg Oncol ; 102(7): 802-8, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20886556

RESUMO

BACKGROUND AND OBJECTIVES: Identification and characterization of loss of heterozygosity (LOH) can determine putative tumor suppressor genes (TSGs) and provide a variety of molecular markers for hepatocellular carcinoma (HCC). This study aimed to investigate LOH status on chromosomes 4q, 6q, 8p, 9p, and 17p, and to explore their clinical significances in HCC post-liver transplantation. METHODS: A total of 37 patients with HCC who underwent liver transplantation were enrolled. LOH was examined using 34 microsatellite markers located on 4q13-3q5, 6q27, 8p22-p23, 9p21-p22, and 17p12-p13. RESULTS: The frequency of LOH at each microsatellite locus ranged from 23% to 75%, with a mean value of 53.1%. Frequencies of LOH on 4q, 6q, 8p, 9p, and 17p were 62% (23 of 37), 30% (11 of 37), 49% (18 of 37), 46% (16 of 35), and 68% (25 of 37), respectively. LOHs on certain chromosomal regions were significantly associated with age, AFP level, tumor size, tumor multiplicity, histological grade, and metastatic recurrence. CONCLUSIONS: LOH on 17p13.1 correlated to metastatic HCC recurrence, while LOH on 4q and 8p was found to be associated with progression of HCC. Thus, potential novel biomarkers or TSGs for prognosis and treatment of HCC may harbor on these regions.


Assuntos
Carcinoma Hepatocelular/genética , Cromossomos Humanos Par 17/genética , Neoplasias Hepáticas/genética , Transplante de Fígado , Perda de Heterozigosidade , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Carcinoma Hepatocelular/secundário , Carcinoma Hepatocelular/terapia , DNA de Neoplasias/genética , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
7.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 39(5): 506-10, 2010 09.
Artigo em Zh | MEDLINE | ID: mdl-20936726

RESUMO

OBJECTIVE: To investigate the loss of heterozygosity (LOH) at mitofusin-2 (Mfn2) gene in hepatocellular carcinoma (HCC) and its clinicopathological significance. METHODS: Four high polymorphic microsatellite markers flanking Mfn2 were selected for LOH analysis in 29 cases of HCC. RESULT: The frequencies of LOH on D1S2667, D1S2740, D1S434 and D1S228 were 21%, 23%, 21% and 22%, respectively. LOH at Mfn2 was closely correlated with tumor size, age, capsule, differentiation and t HBV infection (P<0.05), not with gender, thrombosis, cirrhosis and serum AFP levels (P>0.05). CONCLUSION: LOH at Mfn2 gene in HCC is associated with the clinicopathological features of patients.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Perda de Heterozigosidade , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Adulto , Idoso , Feminino , GTP Fosfo-Hidrolases , Humanos , Masculino , Pessoa de Meia-Idade
8.
Cancer Lett ; 495: 1-11, 2020 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-32949680

RESUMO

As a promising method for local tumor treatment, nanosecond pulsed electric field (nsPEF) ablation elicits a potent anti-tumor immune response. However, the mechanism of the nsPEF-mediated anti-tumor immune response and its effects on the tumor microenvironment remains unclear. Here, we demonstrated that nsPEF treatment increased the level of membrane PD-L1 in liver cancer cells. Furthermore, nsPEF induced the release of PD-L1-associated extra-cellular vesicles, leading to the dysfunction of CD8+ T cells, which could potentially be reversed by PD-L1 blockade. Biological and functional assays also demonstrated that nsPEF treatment resulted in the increased PD-L1 level and dysfunction of infiltrated CD8+ T cells in tumor tissues in vivo, indicating the long term antitumor efficacy of nsPEF treatment. A combination of nsPEF treatment and PD-L1 blockade effectively inhibited tumor growth and improved the survival of the tumor-bearing mouse. In conclusion, nsPEF treatment induced the translocation and release of PD-L1 and contributed to the dysfunction of infiltrated CD8+ T cells, resulting in tumor progression at later stages. The combination of nsPEF treatment and PD-L1 blockade is a promising therapeutic strategy for liver cancer.


Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Hepáticas/terapia , Animais , Linhagem Celular Tumoral , Terapia Combinada , Terapia por Estimulação Elétrica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Hepáticas/metabolismo , Camundongos , Transporte Proteico , Resultado do Tratamento , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Biol Sci ; 15(6): 1139-1147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223275

RESUMO

Holliday Junction Recognition Protein (HJURP) is involved in various cancers including hepatocellular carcinoma (HCC). Current studies have showed that HJURP is correlated with HCC proliferation. However, the role of HJURP in HCC Epithelial-to-Mesenchymal Transition remains unclear. In this study, we found that HJURP knockdown significantly reduced the migration and invasion abilities of HCC cells both in vivo and in vitro by interacting with Sphingosine kinase1 (SPHK1). Conversely, HJURP overexpression enhanced these biological abilities. Moreover, high HJURP expression is related to poor prognosis of HCC patients. In conclusion, HJURP plays an important role in tumor metastasis by upregulating SPHK1. And high HJURP expression may predict a lower disease-free survival rate and higher possibility of microvascular invasion in HCC patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/fisiologia , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/patologia , Metástase Neoplásica/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Regulação para Cima
10.
J Exp Clin Cancer Res ; 38(1): 445, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31666106

RESUMO

In the publication of our publication [1], we have noticed there is a wrong label in Fig. 1e, in which the position of "HCC" and "Adjacent" should be transposed.

11.
Medicine (Baltimore) ; 97(22): e10826, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29851790

RESUMO

Insulinoma is a rare type tumor and its genetic features remain largely unknown. This study aimed to search for potential key genes and relevant enriched pathways of insulinoma.The gene expression data from GSE73338 were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified between insulinoma tissues and normal pancreas tissues, followed by pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. The expressions of candidate key genes were validated by quantitative real-time polymerase chain reaction (RT-PCR) in insulinoma tissues.A total of 1632 DEGs were obtained, including 1117 upregulated genes and 514 downregulated genes. Pathway enrichment results showed that upregulated DEGs were significantly implicated in insulin secretion, and downregulated DEGs were mainly enriched in pancreatic secretion. PPI network analysis revealed 7 hub genes with degrees more than 10, including GCG (glucagon), GCGR (glucagon receptor), PLCB1 (phospholipase C, beta 1), CASR (calcium sensing receptor), F2R (coagulation factor II thrombin receptor), GRM1 (glutamate metabotropic receptor 1), and GRM5 (glutamate metabotropic receptor 5). DEGs involved in the significant modules were enriched in calcium signaling pathway, protein ubiquitination, and platelet degranulation. Quantitative RT-PCR data confirmed that the expression trends of these hub genes were similar to the results of bioinformatic analysis.The present study demonstrated that candidate DEGs and enriched pathways were the potential critical molecule events involved in the development of insulinoma, and these findings were useful for better understanding of insulinoma genesis.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Insulinoma/genética , Análise em Microsséries/métodos , Neoplasias Pancreáticas/genética , Fenômenos Biológicos/genética , Carcinogênese/genética , Biologia Computacional/métodos , Regulação para Baixo , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Insulinoma/patologia , Neoplasias Pancreáticas/patologia , Mapas de Interação de Proteínas/genética , Regulação para Cima
13.
J Exp Clin Cancer Res ; 37(1): 215, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30180906

RESUMO

BACKGROUND: Plant homeodomain finger protein 8 (PHF8) serves an activator of epithelial-mesenchymal transition (EMT) and is implicated in various tumors. However, little is known about PHF8 roles in hepatocellular carcinoma (HCC) and regulating E-cadherin expression. METHODS: PHF8 expression pattern was investigated by informatic analysis and verified by RT-qPCR and immunochemistry in HCC tissues and cell lines. CCK8, xenograft tumor model, transwell assay, and tandem mCherry-GFP-LC3 fusion protein assay were utilized to assess the effects of PHF8 on proliferation, metastasis and autophagy of HCC cells in vitro and in vivo. ChIP, immunoblot analysis, rescue experiments and inhibitor treatment were used to clarify the mechanism by which PHF8 facilitated EMT, metastasis and autophagy. RESULTS: PHF8 upregulation was quite prevalent in HCC tissues and closely correlated with worse overall survival and disease-relapse free survival. Furthermore, PHF8-knockdown dramatically suppressed cell growth, migration, invasion and autophagy, and the expression of SNAI1, VIM, N-cadherin and FIP200, and increased E-cadherin level, while PHF8-overexpression led to the opposite results. Additionally, FIP200 augmentation reversed the inhibited effects of PHF8-siliencing on tumor migration, invasion and autophagy. Mechanistically, PHF8 was involved in transcriptionally regulating the expression of SNAI1, VIM and FIP200, rather than N-cadherin and E-cadherin. Noticeably, E-cadherin degradation could be accelerated by PHF8-mediated FIP200-dependent autophagy, a crucial pathway complementary to transcriptional repression of E-cadherin by SNAI1 activation. CONCLUSION: These findings suggested that PHF8 played an oncogenic role in facilitating FIP200-dependent autophagic degradation of E-cadherin, EMT and metastasis in HCC. PHF8 might be a promising target for prevention, treatment and prognostic prediction of HCC.


Assuntos
Caderinas/genética , Carcinoma Hepatocelular/genética , Histona Desmetilases/genética , Neoplasias Hepáticas/genética , Proteínas Tirosina Quinases/genética , Fatores de Transcrição/genética , Idoso , Autofagia/genética , Proteínas Relacionadas à Autofagia , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Fatores de Transcrição da Família Snail/genética
15.
Mol Cancer Ther ; 12(1): 94-103, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23136185

RESUMO

It has been shown that Ring finger protein 43 (RNF43) is overexpressed in colorectal cancer and mediates cancer cell proliferation; however, its role in hepatocellular carcinoma (HCC) remains unknown. In this study, we found that RNF43 was frequently overexpressed in HCCs, and this overexpression was correlated with positive vascular invasion, poor tumor differentiation, and advanced tumor stage. Functional studies showed that knockdown of RNF43 could induce apoptosis and inhibit proliferation, invasion, colony formation, and xenograft growth of HCCs. Microarray-based gene profiling showed a total of 229 genes differentially expressed after RNF43 knockdown, many of which are involved in oncogenic processes such as cell proliferation, cell adhesion, cell motility, cell death, DNA repair, and so on. These results suggest that RNF43 is involved in tumorigenesis and progression of HCCs and that antagonism of RNF43 may be beneficial for HCC treatment.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Oncogênicas/metabolismo , Adulto , Idoso , Animais , Carcinoma Hepatocelular/patologia , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica/metabolismo , Proteínas de Ligação a DNA/genética , Matriz Extracelular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/patologia , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Proteínas Oncogênicas/genética , Fenótipo , RNA Interferente Pequeno/genética , Transcriptoma/efeitos dos fármacos , Carga Tumoral , Ubiquitina-Proteína Ligases , Adulto Jovem
16.
PLoS One ; 6(9): e24671, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21935436

RESUMO

BACKGROUND: Regulatory T cells (Tregs) are highly prevalent in tumor tissue and can suppress effective anti-tumor immune responses. However, the source of the increased tumor-infiltrating Tregs and their contribution to cancer progression remain poorly understood. METHODOLOGY/PRINCIPAL FINDING: We here investigated the frequency, phenotype and trafficking property of Tregs and their prognostic value in patients with hepatocellular carcinoma (HCC). Our results showed that FoxP3(+) Tregs highly aggregated and were in an activated phenotype (CD69(+)HLA-DR(high)) in the tumor site, where they can suppress the proliferation and INF-γ secretion of CD4(+)CD25(-) T cells. These tumor-infiltrating Tregs could be selectively recruited though CCR6-CCL20 axis as illustrated by (a) high expression of CCR6 on circulating Tregs and their selective migration to CCR6 ligand CCL20, and (b) correlation of distribution and expression between tumor-infiltrating Tregs and intratumoral CCL20. In addition, we found that the number of tumor-infiltrating Tregs was associated with cirrhosis background (P = 0.011) and tumor differentiation (P = 0.003), and was an independent prognostic factor for overall survival (HR = 2.408, P = 0.013) and disease-free survival (HR = 2.204, P = 0.041). The increased tumor-infiltrating Tregs predicted poorer prognosis in HCC patients. CONCLUSIONS: The CCL20-CCR6 axis mediates the migration of circulating Tregs into tumor microenvironment, which in turn results in tumor progression and poor prognosis in HCC patients. Thus, blocking CCL20-CCR6 axis-mediated Treg migration may be a novel therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Quimiocina CCL20/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Receptores CCR6/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Células Cultivadas , Quimiocina CCL20/genética , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Receptores CCR6/genética
17.
J Hepatobiliary Pancreat Sci ; 18(6): 806-14, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21584707

RESUMO

BACKGROUND: Tri-iodothyronine (T3) has been shown to be a hepatic mitogen. The aim of this study was to evaluate the effect of T3 on liver regeneration after 50% partial liver transplantation (pLT) in rats. METHODS: Immediately after pLT, a single dose of T3 (4 mg/kg body weight) was administered. Liver/body weight ratio (LBWR), hepatocyte proliferation (Ki-67), biochemical parameters, and changes in cell cycle related proteins were evaluated. RESULTS: T3 promoted liver regeneration as shown by an increased liver/body weight ratio and Ki-67 proliferation index after pLT. On the transcriptional level, T3-treated rats had an increased expression of cyclin D1 and cyclin A as demonstrated by real time RT-PCR and Western blot. CONCLUSIONS: Exogenous administration of T3 significantly improved liver regeneration after pLT, and therefore it may represent a promising strategy to improve the clinical outcome after living donor liver transplantation in the future.


Assuntos
Hepatopatias/cirurgia , Regeneração Hepática/efeitos dos fármacos , Transplante de Fígado , Doadores Vivos , Tri-Iodotironina/análogos & derivados , Animais , Modelos Animais de Doenças , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tri-Iodotironina/farmacologia
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