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1.
Cell Cycle ; : 1-16, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31650885

RESUMO

Lung cancer (LC) is one of the malignant tumors with growing morbidity and mortality. The involvement of runt-related transcription factor 1 (RUNX1) in LC patients has been elucidated. We intended to research mechanisms of RUNX1 and tartrate-resistant acid phosphatase 5 (ACP5) in LC. Firstly, ACP5 levels in LC tissues, paracancerous tissues, LC cells and tracheal epithelial cells were detected. RUNX1 overexpression plasmid and interference plasmid were constructed and transfected into 95C cells and A549 cells, respectively. The binding of RUNX1 to ACP5 promoter was tested. Additionally, the gain- and loss-of-function were performed to explore the effects of ACP5 and RUNX1 on LC biological process. The xenograft tumor in nude mice was constructed in vivo to verify in vitro results. Functional rescue experiment was performed by adding MAPK-specific activator P79350 to A549 cells with si-ACP5 to measure the effects of ERK/MAPK axis on LC progression. Consequently, we found ACP5 expression was higher in LC tissues and cells, and ACP5 silencing suppressed LC cell growth. Overexpression of ACP5 promoted malignant biological behavior of LC cells. RUNX1 could bind to ACP5 promoter, and overexpressed RUNX1 promoted ACP5 expression and LC cell growth. Moreover, ACP5 upregulated the ERK/MAPK axis and thus promoted LC progression. The results of xenograft tumor in nude mice showed that silencing ACP5 could inhibit the growth of LC cells in vivo. To conclude, silenced RUNX1 inhibits LC progression through the ERK/MAPK axis by binding to ACP5. This study may provide new approaches for LC treatment.

2.
J Exp Clin Cancer Res ; 38(1): 183, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053148

RESUMO

BACKGROUND: Acquired resistance to sorafenib greatly limits its therapeutic efficiency in the treatment of hepatocellular carcinoma (HCC). Increasing evidence indicates that long noncoding RNAs (lncRNAs) play important roles in the resistance to anti-cancer drugs. The present study aims to explore the involvement of lncRNA SNHG1 (small nucleolar RNA host gene 1) in sorafenib resistance and how SNHG1 is associated with overexpressed microRNA-21 (miR-21) and the activated Akt pathway, which have been demonstrated to mediate this resistance in HCC cells. METHODS: Sorafenib-resistant HCC (SR-HCC) cells were generated and their sorafenib-resistant properties were confirmed by cell viability and apoptosis assays. Potential lncRNAs were screened by using multiple bioinformatics analyses and databases. The expression of genes and proteins was detected by qRT-PCR, Western blot and in situ hybridization. Gene silencing was achieved by specific siRNA or lncRNA Smart Silencer. The effects of anti-SNHG1 were evaluated in vitro and in experimental animals by using quantitative measures of cell proliferation, apoptosis and autophagy. The binding sites of miR-21 and SNHG1 were predicted by using the RNAhybrid algorithm and their interaction was verified by luciferase assays. RESULTS: The Akt pathway was highly activated by overexpressed miR-21 in SR-HCC cells compared with parental HCC cells. Among ten screened candidates, SNHG1 showed the largest folds of alteration between SR-HCC and parental cells and between vehicle- and sorafenib-treated cells. Overexpressed SNHG1 contributes to sorafenib resistance by activating the Akt pathway via regulating SLC3A2. Depletion of SNHG1 enhanced the efficacy of sorafenib to induce apoptosis and autophagy of SR-HCC cells by inhibiting the activation of Akt pathway. Sorafenib induced translocation of miR-21 to the nucleus, where it promoted the expression of SNHG1, resulting in upregulation of SLC3A2, leading to the activation of Akt pathway. In contrast, SNHG1 was shown to have little effect on the expression of miR-21, which downregulated the expression of PTEN, leading to the activation of the Akt pathway independently of SNHG1. CONCLUSIONS: The present study has demonstrated that lncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib. These results indicate that SNHG1 may represent a potentially valuable target for overcoming sorafenib resistance for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , Sorafenibe/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cell Physiol Biochem ; 47(6): 2534-2543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29991059

RESUMO

BACKGROUND/AIMS: Assistance with tumor-associated vascularization is needed for the growth and invasion of non-small cell lung cancer (NSCLC). Recently, it was shown that placental growth factor (PLGF) expressed by NSCLC cells had a critical role in promoting the metastasis of NSCLC cells. However, the underlying molecular mechanisms remain elusive. METHODS: Here, we first established a NSCLC model in mice that allows us not only to isolate tumor cells from non-tumor cells in the tumor, but also to trace tumor cells in living animals. Levels of PLGF, its unique receptor Flt-1, as well as transforming growth factor ß1 (TGFß1) was examined in tumor cells and tumor-associated macrophages (TAM) by RT-qPCR. A transwell well co-culture system and HUVEC assay were applied to study the crosstalk between NSCLC cells and TAM. RESULTS: NSCLC cells produced and secreted PLGF to signal to tumor-associated macrophages (TAM) through surface expression of Flt-1 on macrophages. In a transwell co-culture system, PLGF secreted by NSCLC cells triggered macrophage polarization to a TAM subtype that promote growth of NSCLC cells. Moreover, polarized TAM seemed to secrete TGFß1 to enhance the growth of endothelial cells in a HUVEC assay. CONCLUSION: The cross-talk between TAM and NSCLC cells via PLGF/Flt-1 and TGFß receptor signaling may promote the growth and vascularization of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Comunicação Celular , Neoplasias Pulmonares , Macrófagos , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica , Fator de Crescimento Placentário/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia
4.
Oncol Res ; 26(3): 385-400, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28653608

RESUMO

Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop.

5.
Cell Physiol Biochem ; 44(2): 455-466, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29141252

RESUMO

BACKGROUND/AIMS: Lung cancer is one of the leading causes for cancer mortality. The poor therapeutic outcome of non-small cell lung carcinoma (NSCLC) is mainly due to late diagnosis and chemoresistance. In this study, we investigated the role of Musashi1 (MSI1) in NSCLC malignancy and chemoresistance. METHODS: Colony formation, MTT, glucose uptake and lactate production assays were employed to study lung cancer cell malignancy and chemoresistance. RT-PCR and Western blotting were performed to detect mRNA and protein expressions of genes. We used immunohistochemistry and Pearson correlation analysis to study the relationship of gene expression. RESULTS: We demonstrated that MSI1 was able to promote the proliferation and glucose metabolism of NSCLC cells, and to mediate the sensitivity to chemotherapy drugs in NSCLC cells. Importantly, we found that MSI1 could regulate the activity of Akt signaling. The regulation of NSCLC proliferation, glucose metabolism and chemoresistance by MSI1 was dependent on the modulation of the activity of the Akt signaling pathway. We also found that MSI1 was a target of miR-181a-5p, a microRNA involved in the regulation of cancer development. The expression levels of MSI1 and miR-181a-5p were negatively correlated in NSCLC. CONCLUSION: MSI1 promotes non-small cell lung carcinoma malignancy and chemoresistance via activating the Akt signaling pathway, which provides a new strategy for the therapy of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Regiões 3' não Traduzidas , Células A549 , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/toxicidade , Resistencia a Medicamentos Antineoplásicos , Glucose/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Consumo de Oxigênio/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Alinhamento de Sequência , Transdução de Sinais/efeitos dos fármacos
6.
Onco Targets Ther ; 9: 4983-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27563252

RESUMO

AIM: The clinical implications of transforming growth factor-beta-induced gene-h3 (beta-IGH3) protein expression in lung cancer remain unclear. This study investigated beta-IGH3 protein expression levels and biological function, as well as lung cancer prognosis. METHODS: Beta-IGH3 protein expression levels were measured in 236 lung cancers and were matched with adjacent noncancerous tissues by immunohistochemical staining. Subsequently, the relationship between beta-IGH3 protein expression, clinical-pathological parameters, and lung cancer prognosis was evaluated. RESULTS: Beta-IGH3 protein expression was significantly higher in lung cancer tissues compared with adjacent noncancerous tissues (61.86% vs 22.88%; P=0.01). Of the 236 enrolled cases, 146 (61.86%) showed high beta-IGH3 levels. Tumor size, clinical stage, and lymph node metastasis were significantly related to beta-IGH3 protein expression in univariate analysis (P=0.001, 0.044, and 0.029, respectively), whereas age, sex, and histological type were not (P=0.038, 0.756, and 0.889, respectively). Finally, a Cox regression model also identified beta-IGH3 as an independent prognostic factor (P=0.01). CONCLUSION: Beta-IGH3 is highly expressed in lung cancers and may be a potential target for lung cancer treatments.

7.
Oncotarget ; 6(30): 28867-81, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26311740

RESUMO

Sorafenib resistance remains a major obstacle for the effective treatments of hepatocellular carcinoma (HCC). Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation. Sorafenib-resistant HCC cells were shown to be refractory to sorafenib-induced growth inhibition and apoptosis. Akt and its downstream factors were highly activated and/or upregulated in sorafenib-resistant cells. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to sorafenib, while its induction had the opposite effect. Differential screening of miRNAs showed higher levels of miR-21 in sorafenib-resistant HCC cells. Exposure of HCC cells to sorafenib led to an increase in miR-21 expression, a decrease in PTEN expression and sequential Akt activation. Transfection of miR-21 mimics in HCC cells restored sorafenib resistance by inhibiting autophagy. Anti-miR-21 oligonucleotides re-sensitized sorafenib-resistant cells by promoting autophagy. Inhibition of miR-21 enhances the efficacy of sorafenib in treating sorafenib-resistant HCC tumors in vivo. We conclude that miR-21 participates in the acquired resistance of sorafenib by suppresing autophagy through the Akt/PTEN pathway. MiR-21 could serve as a therapeutic target for overcoming sorafenib resistance in the treatment of HCC.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/metabolismo , Niacinamida/análogos & derivados , PTEN Fosfo-Hidrolase/metabolismo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Niacinamida/farmacologia , Oligonucleotídeos/genética , Oligonucleotídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Tumour Biol ; 36(4): 2323-34, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25416439

RESUMO

Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but it also induces the activation of Akt, which contributes to the mechanisms for the resistance to sorafenib. Arsenic trioxide (ATO) is a currently clinically used anticancer drug and displays its anticancer activities by inhibiting Akt activation. Therefore, we hypothesized that ATO may potentiate the anti-cancer activities of sorafenib against HCC. The results have demonstrated that ATO synergized with sorafenib to inhibit the proliferation and promote the apoptosis of HCC cells by diminishing the increased activation of Akt by sorafenib. ATO was shown to inhibit the expression or activation of Akt downstream factors, including glycogen synthase kinase (GSK)-3ß, mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which regulate cell apoptosis and were upregulated or activated by sorafenib. Both sorafenib and ATO downregulated the expression of cyclin D1, resulting in HCC cells arrested at G0/G1 phase. ATO downregulated the expression of Bcl-2 and Bcl-xL and upregulated the expression of Bax, indicating that ATO could induce the apoptosis of HCC cells through the intrinsic pathways; but sorafenib showed little effects on these proteins of Bcl-2 family. ATO synergized with sorafenib to suppress the growth of HCC tumors established in mice by inhibiting the proliferation and inducing the apoptosis of HCC cells in situ. These results indicate that ATO may be a potential agent that given in combination with sorafenib acts synergistically for treating HCC.


Assuntos
Arsenicais/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Óxidos/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas de Neoplasias/biossíntese , Niacinamida/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe
9.
Cell Signal ; 26(5): 1030-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24486412

RESUMO

Sorafenib, the first-line systemic drug for advanced hepatocellular carcinoma (HCC), has demonstrated limited benefits with very low response rates. Thus it is essential to investigate the underlying mechanisms for the resistance to sorafenib and seek potential strategy to enhance its efficacy. Hypoxic cells inside solid tumors are extremely resistant to therapies as their survival ability is increased due to the cellular adaptive response to hypoxia, which is controlled by hypoxia-inducible factor (HIF)-1 and HIF-2. Sorafenib inhibits HIF-1α synthesis, making the hypoxic response switch from HIF-1α- to HIF-2α-dependent pathways and providing a mechanism for more aggressive growth of tumors. The present study has demonstrated that upregulation of HIF-2α induced by sorafenib contributes to the resistance of hypoxic HCC cells by activating the transforming growth factor (TGF)-α/epidermal growth factor receptor (EGFR) pathway. Blocking the TGF-α/EGFR pathway by gefitinib, a specific EGFR inhibitor, reduced the activation of STAT (signal transducer and activator of transcription) 3, AKT and ERK (extracellular signal-regulated kinase), and synergized with sorafenib to inhibit proliferation and induce apoptosis of hypoxic HCC cells. Transfection of HIF-2α siRNA into HCC cells downregulated the expression of VEGF (vascular endothelial growth factor), cyclin D1, HIF-2α and TGF-α, and inhibited the activation of EGFR. HIF-2α siRNA inhibited the proliferation and promoted the apoptosis of HCC cells in vitro, and synergized with sorafenib to suppress the growth of HCC tumors in vivo. The results indicate that targeting HIF-2α-mediated activation of the TGF-α/EGFR pathway warrants further investigation as a potential strategy to enhance the efficacy of sorafenib for treating HCC.


Assuntos
Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Receptores ErbB/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Fator de Crescimento Transformador alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Niacinamida/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Fator de Crescimento Transformador alfa/antagonistas & inibidores , Fator de Crescimento Transformador alfa/genética
10.
Tohoku J Exp Med ; 226(4): 275-85, 2012 04.
Artigo em Inglês | MEDLINE | ID: mdl-22499119

RESUMO

Hydrogen sulfide (H(2)S) displays an anti-apoptotic activity against myocardial ischemia reperfusion (MIR). Apoptosis repressor with caspase recruitment domain (ARC) is constitutively expressed in the heart and inhibits cell apoptosis when it is phosphorylated. Here, we investigated whether H(2)S could inhibit apoptosis by affecting ARC phosphorylation using cultured rat cardiomyocytes and a rat model of MIR. Primary cardiomyocytes were prepared from hearts of newborn rats and were pre-incubated with NaHS, a donor of H(2)S, for 60 min. Cardiomyocytes were subjected to hypoxia for 4 h, followed by reoxygenation for 2 h. The hypoxia and subsequent reoxygenation (H/R) significantly induced cell apoptosis, increased expression levels of Fas and FasL proteins, enhanced release of cytochrome c from mitochondria, and elevated caspase-3 activity, while H/R reduced ARC phosphorylation and increased the activity of calcineurin that dephosphorylates ARC. Pre-incubation with NaHS significantly attenuated the above effects through promoting ARC phosphorylation by reducing calcineurin activity and by increasing the activity of protein kinase casein kinase II (CK2) that phosphorylates ARC. In fact, TBB, a specific inhibitor of CK2, abolished the effects of NaHS. In rats undergoing MIR, NaHS significantly reduced the myocardial infarct size, cell apoptosis, calcineurin activity, and the expression levels of Fas, FasL and cleaved caspase-3 proteins, while NaHS increased ARC phosphorylation. In contrast, DL-propargylglycine, an inhibitor of cystathionine γ-lyase, the main enzyme for H(2)S production in hearts, showed opposite effects to NaHS. The results indicate that H(2)S inhibits apoptosis of cardiomyocytes induced by MIR through enhancing ARC phosphorylation.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Cardiotônicos/farmacologia , Sulfeto de Hidrogênio/farmacologia , Proteínas Musculares/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Caseína Quinase II/metabolismo , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , L-Lactato Desidrogenase/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/citologia , Miócitos Cardíacos/enzimologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Ratos , Ratos Wistar
11.
Invest New Drugs ; 30(2): 508-17, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21080209

RESUMO

Liver metastasis is the major obstacle for prolonging the survival of colon cancer patients. Low-molecular-weight heparin (LMWH), a common drug for venous thromboembolism, has displayed beneficial effects in improving the survival of cancer patients, though the mechanism remains unclear. This study aimed to investigate the effects of LMWH on hepatic metastasis of colon cancer and its underlying molecular mechanism by targeting the interaction of the chemokine receptor CXCR4 and its ligand CXCL12 (formerly known as stromal cell-derived factor 1α, SDF-1α), as the CXCR4-CXCL12 axis has been shown to regulate the interaction of cancer cells and stroma. Experimental results revealed that LMWH (Enoxaparin, 3500-5500 Da) inhibited the CXCL12-stimulated proliferation, adhesion and colony formation of human colon cancer HCT-116 cells that highly expressed CXCR4. Interestingly, LMWH or an anti-CXCR4 blocking antibody diminished the migrating and invading abilities of HCT116 cells stimulated by the recombinant CXCL12 protein or liver homogenates which contained endogenous CXCL12 protein. Although LMWH did not significantly inhibit the growth of subcutaneous colon tumors, it significantly suppressed the formation of hepatic metastasis established by intrasplenic injection of colon cancer cells in nude Balb/c mice and also downregulated the expression of CXCL12 in hepatic sinusoidal endothelial cells. The results suggest that LMWH inhibits the formation of hepatic metastasis of colon cancer by disrupting the interaction of CXCR4 and CXCL12, supporting that perioperative administration of LMWH may help to prevent the seeding and subsequent growth of hepatic metastases of colon cancer cells.


Assuntos
Antineoplásicos/farmacologia , Quimiocina CXCL12/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Enoxaparina/farmacologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/prevenção & controle , Receptores CXCR4/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Células Endoteliais/imunologia , Células Endoteliais/patologia , Células HCT116 , Células HT29 , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Sci ; 103(3): 528-34, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22145922

RESUMO

The hypoxic microenvironment inside solid tumors, including hepatocellular carcinoma (HCC), is a major cause of tumor resistance to chemotherapy. The recently identified hypoxia-inducible factor (HIF)-2 executes the hypoxia response. Its expression feature and transcriptional targets indicate a possible dominance of HIF-2 in regulating genes in HCC. The aim of the present study was to determine whether transfection of siRNA targeting HIF-2α could enhance the efficacy of doxorubicin, the most commonly used drug in the treatment of HCC. Transfection of HIF-2 siRNA into human HCC cells downregulated the expression of HIF-2α, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-α, and cyclin D1, but had little effect on the expression of HIF-1α, fms-related tyrosine kinase-1 (Flt-1), the glucose transporter (GLUT)-1, and lactate dehydrogenase A (LDHA). Doxorubicin itself only downregulated VEGF expression. Furthermore, HIF-2 siRNA inhibited proliferation, induced cell cycle arrest at the G(0)/G(1) phase, and acted synergistically with doxorubicin to inhibit the growth of human HCC cells in vitro. Transfection of HIF-2 siRNA also downregulated tumoral expression of HIF-2α, VEGF, TGF-α, and cyclin D1 in vivo, and acted synergistically with doxorubicin to suppress the growth of HepG2 tumors established in immunodeficient mice by inhibiting cell proliferation, tumor angiogenesis and microvessel perfusion. The results of the present study suggest that targeting HIF-2α with siRNA warrants investigation as a potential strategy to enhance the efficacy of doxorubicin in the treatment of HCC.


Assuntos
Antineoplásicos/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma Hepatocelular/terapia , Doxorrubicina/uso terapêutico , Terapia Genética/métodos , Neoplasias Hepáticas/terapia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , RNA Interferente Pequeno/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
13.
Clin Dev Immunol ; 2011: 695834, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22013483

RESUMO

B7-H4 is one of the most recently identified members of B7 superfamily of costimulatory molecules serving as an inhibitory modulator of T-cell response. B7-H4 is broadly expressed in human peripheral tissues and inducibly expressed in immune cells. The expression of B7-H4 has been observed in various types of human cancer tissues, and its soluble form has been detected in blood samples from cancer patients. However, its precise physiological role is still elusive, as its receptor has not been identified and the expression levels are not consistent. This paper summarizes the pertinent data on the inhibitory role of B7-H4 in antitumor immunity and its association with cancer progression and survival in human patients. The paper also discusses the clinical significance of investigating B7-H4 as potential markers for cancer diagnosis and prognosis, and as therapeutic targets.


Assuntos
Biomarcadores Tumorais/metabolismo , Imunossupressão , Neoplasias/diagnóstico , Neoplasias/imunologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo , Antígenos de Neoplasias/imunologia , Transformação Celular Neoplásica , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunidade , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/genética , Neoplasias/mortalidade , Prognóstico , Análise de Sobrevida , Evasão Tumoral , Microambiente Tumoral , Inibidor 1 da Ativação de Células T com Domínio V-Set/genética , Inibidor 1 da Ativação de Células T com Domínio V-Set/imunologia
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