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ABSTRACT: Statins have been confirmed with protective effect to microvessels in diabetic retinopathy, implicated as reducing vascular permeability, maintaining endothelial junction integrity and improving blood perfusion, which are surrogate markers of vascular 'normalization', but no data are currently available on efficacy of statins on tumor endothelial functions. Since statins have been shown to exhibit a biphasic dose-related response on biological behaviour of microvessels, we sought to determine whether statins with bipolar concentrations can ameliorate vessel dysfunction and then increase efficiency of chemotherapeutics in Lewis lung carcinoma and B16F10 melanoma models. Our in vitro study showed that simvastatin reduces hypoxia-induced endothelium leakage in human umbilical vein endothelial cells (HUVEC) in a concentration-dependent manner. In tumor-bearing mice, low-dose simvastatin (0.2 mg/kg) induced upregulation of endothelial NO synthase (eNOS) skewed vessels to a pericyte-coated and stable pattern, while high-dose simvastatin (10 mg/kg) remarkably deceased reactive oxygen species (ROS)-induced hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression, attenuating VEGF-drived tumor vessel hyperpermeability. These changes ultimately improved intratumoral perfusion and decreased tumor hypoxia. Administration of cisplatin and cyclophosphamide to the simvastatin-treated mice resulted in slower tumor growth. Collectively, simvastatin may promote tumor vessel normalization and show clinical benefit when used in combination with chemotherapeutics.
International Journal of Oncology 04/2013; 42(4):1325-36. · 2.40 Impact Factor
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ABSTRACT: Vascular endothelial growth factor 165 (VEGF165)-mediated autocrine stimulation of tumor cells enhances the progression to a malignant phenotype. VEGF165b competes with VEGF165 and binds to vascular endothelial growth factor receptor (VEGFR), resulting in inhibition of downstream signal transduction
pathways. This study was designed to investigate the role of VEGF165b in the migration and invasion of human lung adenocarcinoma A549 cells. The full-length of VEGF165b was constructed and cloned into an expression plasmid (pVEGF165b), and then transfected into A549 cells. Dimethylthiazolyl- 1 -2, 5-diphenyltetrazolium bromide (MTT) assay was used to detect
the effect of VEGF165b on proliferation of transfected cells. Reverse transcription polymerase chain reaction (RT-PCR) was employed to examine
the effect of VEGF165b on the expression of VEGF165 in transfected cells. Wound-healing assays were used to investigate the effect of VEGF165b on migration of transfected cells. Matrix metalloproteinase (MMPs) activity assay and in vitro invasion assay were used to determine the role of VEGF165b in invasion of transfected cells. There was no significant change in proliferation of A549 cells after transfection of pVEGF165b, but the expression of VEGF165, migration and invasion in A549 cells were inhibited. Furthermore, exogenous VEGF165b inhibited the activity of MMP9 in the supernatant of A549 cells and the subsequent invasion capacity of those cells. We
therefore conclude that exogenous VEGF165b can inhibit the expression of VEGF165, as well as the migration and invasion of A549 cells, but has no effect on the proliferation of A549 cells.
Key wordsVEGF165b–non-small cell lung cancer–migration; invasion
Journal of Huazhong University of Science and Technology 04/2012; 31(5):619-624. · 0.38 Impact Factor
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ABSTRACT: ObjectiveThe aim of this study was to explore the relationship between VEGF expression and vasculogenic mimicry of tumor in vitro.
MethodsWe observed the ability to form vasculogenic mimicry in several cell lines follow as LO2 cell, hepG2 cell, SMMC-7721 cell
and A549 cell in three-dimensional cultures; we detected the expression of VEGF in the level of mRNA and protein by polymerase
chain reaction (PCR) and western blot in those cell lines.
ResultsHepG2 cell and A549 cell had the ability to form vasculogenic mimicry in three-dimensional cell cultures, while LO2 cell and
SMMC-7721 cell hadn’t the ability. The rates of VEGF165/GAPDH were 0.212 ± 0.011,0.208 ± 0.013, 0.117 ± 0.009 and 0.214 ± 0.012 respectively, and the rates of VEGF121/GAPDH were 0.186 ± 0.018, 0.192 ± 0.014, 0.050 ± 0.010, 0.196 ± 0.017 in LO2 cell, hepG2 cell, SMMC-7721 cell and A549 cell,
separately. The expression of VEGF gene in mRNA and protein levels in HepG2 cell, LO2 cell and A549 cell were significantly
higher than that in SMMC-7721 cell (P < 0.05).
ConclusionThe cell lines which the expression of VEGF gene is low don’t have the ability to form vasculogenic mimicry and the high expression
of VEGF gene cann’t form vasculogenic mimicry at all, while the expression of VEGF gene in the cell lines is high in the cell
lines which can form vasculogenic mimicry. VEGF has impact on the formation vasculgenic mimicry. Only the cells which the
expression of VEGF is high have the potential to form vasculogenic mimicry. But, it doesn’t play a unique key role in vasculogenic
mimicry.
The Chinese-German Journal of Clinical Oncology 04/2012; 8(11):655-658.
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ABSTRACT: Vascular endothelial growth factor 165 (VEGF(165))-mediated autocrine stimulation of tumor cells enhances the progression to a malignant phenotype. VEGF(165)b competes with VEGF(165) and binds to vascular endothelial growth factor receptor (VEGFR), resulting in inhibition of downstream signal transduction pathways. This study was designed to investigate the role of VEGF(165)b in the migration and invasion of human lung adenocarcinoma A549 cells. The full-length of VEGF(165)b was constructed and cloned into an expression plasmid (pVEGF(165)b), and then transfected into A549 cells. Dimethylthiazolyl- 1 -2, 5-diphenyltetrazolium bromide (MTT) assay was used to detect the effect of VEGF(165)b on proliferation of transfected cells. Reverse transcription polymerase chain reaction (RT-PCR) was employed to examine the effect of VEGF(165)b on the expression of VEGF(165) in transfected cells. Wound-healing assays were used to investigate the effect of VEGF(165)b on migration of transfected cells. Matrix metalloproteinase (MMPs) activity assay and in vitro invasion assay were used to determine the role of VEGF(165)b in invasion of transfected cells. There was no significant change in proliferation of A549 cells after transfection of pVEGF(165)b, but the expression of VEGF(165), migration and invasion in A549 cells were inhibited. Furthermore, exogenous VEGF(165)b inhibited the activity of MMP9 in the supernatant of A549 cells and the subsequent invasion capacity of those cells. We therefore conclude that exogenous VEGF(165)b can inhibit the expression of VEGF(165), as well as the migration and invasion of A549 cells, but has no effect on the proliferation of A549 cells.
Journal of Huazhong University of Science and Technology 10/2011; 31(5):619-24. · 0.38 Impact Factor
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ABSTRACT: Several large randomized clinical trials show that chemotherapy in combination with interferon-α (IFN-α) seems superior to single-agent chemotherapy, such as dacarbazine (DTIC) in melanoma, but the molecular mechanism of this better efficacy is unclear. IFN-α has antiangiogenic activity and could downregulate expression of regulator of G-protein signalling-5 (RGS5) recognized as a novel pericyte marker and a master gene loss of which results in pericyte maturation, vascular normalization, and consequent marked reductions in tumor hypoxia and vessel leakiness in pancreatic carcinoma. Here, we investigated the molecular mechanism of the effects of this combination therapy on melanoma tumor growth. In B16 tumor-bearing mice, the addition of IFN-α to DTIC treatment significantly reduced tumor volume, compared with control or DTIC alone. Consistently, Digital Radiography data showed less chaotic vessel morphology and a decrease in microvessel density and mean vessel diameter in the combinational treatment. Furthermore, the combination therapy showed a remarkable reduction in tumor hypoxia, downregulated RGS5 expression, and increased mature pericyte coverage. Our data suggest that the combination of IFN-α and DTIC therapy more efficiently inhibits tumor growth by normalizing tumor vasculature. This study shows a previously unrecognized role of IFN-α in melanoma vascular normalization and suggests that pericyte including its novel marker RGS5 is an important target of IFN-α.
Journal of immunotherapy (Hagerstown, Md.: 1997) 03/2011; 34(3):320-6. · 3.20 Impact Factor
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ABSTRACT: Rho and Rho-associated kinase play an important role in focal adhesion, stress fiber formation and cell motility. Fasudil is a kind of Rho kinase inhibitor. The effect and precise molecular mechanism of fasudil on the biology behavior of lung cancer cell A549 remains unclear. The cytotoxic effect of fasudil on A549 cell was measured by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Wound-healing assay was used to evaluate the effect of fasudil on migration activity of A549 cells. The invasion activity of A549 cells was detected by transwell chamber assay. The expression of MMPs was measured by gelatin zymography. RT-PCR and western blot were used to investigate the molecular change of A549 cells after treated with fasudil. Fasudil-inhibited proliferation of A549 cells in a concentration-dependent manner, decreased the migration and invasion activity. After treated with fasudil, the expression of MMP-2 and MMP-9 was significantly inhibited compared with the control group. Furthermore, the expression of RhoA and VEGF of A549 cell treated with fasudil was significantly down-regulated. Our findings indicate that fasudil might have a therapeutic potential for lung cancer though inhibiting cell proliferation, migration, invasion, MMPs activity and down-regulating the expression of RhoA and VEGF.
Medical Oncology 03/2010; 28(2):565-71. · 2.14 Impact Factor
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ABSTRACT: Loss of the RASSF2A expression induced by methylation-mediated silencing has been reported in several human cancers, but the methylation status of RASSF2A in hepatocellular carcinoma (HCC) is rarely studied so far. In this study, we investigated the RASSF2A expression and its methylation status in a cohort of 45 hepatitis B virus-associated HCC tissues and their adjacent non-carcinoma tissues by using RT-PCR and MS-PCR. Promoter methylation of RASSF2A was found in 31 (68.9%) out of 45 HCC tissues and 12 (40%) out of 30 adjacent normal tissues, respectively (P<0.05). The methylation status of PASSF2A was closely associated with the loss of RASSF2A expression and elevated serum alpha-fetoprotein level, but not significantly with clinical stage, hepatic fibrosis and K-ras mutation. It was concluded that aberrant methylation of the RASSF2A gene with the subsequent loss of RASSF2A expression plays an important role in the pathogenesis of HCC.
Journal of Huazhong University of Science and Technology 06/2009; 29(3):309-12. · 0.38 Impact Factor
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ABSTRACT: The effects of Oxymatrine (Oxy) on the proliferation and apoptosis of human esophageal carcinoma Eca109 cell line and the mechanism were investigated. The human esophageal carcinoma Eca109 cells were cultured in vitro. The Oxy-induced apoptosis of Eca 109 cells was assayed by using flow cytometry. The expressions of p-ERK(1/2), Cyclin D1, p21(waf/cip1), Bax and Bcl-2 were detected by Western blot. Flow cytometry revealed that Oxy could induce the apoptosis of Eca109 cells. Western blot showed that Oxy of different concentrations suppressed the expressions of p-ERK(1/2), Cyclin D1 and Bcl-2, but up-regulated the expression of p21(waf/cip1) and Bax, and the ratio of Bax/Bcl-2 was increased. It was suggested the Oxy could induce the apoptosis of Eca109 cells, which might be related to the upregulation of p21(waf/cip1) and the downregulation of p-ERK(1/2), Cyclin D1 and p21(waf/cip1). The possible pathway may be related to Bcl-2/Bax.
Journal of Huazhong University of Science and Technology 07/2008; 28(3):314-6. · 0.38 Impact Factor
