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1.
Human giant larvae-1 (Hugl-1) is a human homologue of Drosophila tumor suppressor lethal (2)-giant larvae and has been reported to be involved in the development of human malignancies. Previous studies performed by our group demonstrated that Hugl-1 inhibits glioma cell proliferation in an intracranial model of nude mice. However, the exact molecular mechanisms underlying the participation of Hugl-1 in glioma invasion and migration, and in the depolarizing process remain largely unknown. Utilizing the U251-MG cells with stable expression of Hugl-1, the present study used wound healing, Transwell invasion and western blot assays to explore the role and specific mechanism of Hugl-1 in glioma invasion and migration. The results of the present study demonstrated that overexpression of Hugl-1 decreased cell-cell adhesion and increased cell-cell extracellular matrix adhesion. In addition, overexpression of Hugl-1 promoted pseudopodia formation, glioma cell migration and invasion. The molecular mechanism of action involved the negative regulation of N-cadherin protein levels by Hugl-1. Overexpression or knockdown of N-cadherin partially suppressed or enhanced the effects of Hugl-1 on glioma cell migration and invasion, respectively. Furthermore, Hugl-1 inhibited cell proliferation, while promoting cell migration, which suggests that it may serve a two-sided biological role in cellular processes. Taken together, these results suggest that Hugl-1 promotes the migration and invasion of malignant glioma cells by decreasing N-cadherin expression. Thus, Hugl-1 may be applied in the development of targeted and personalized treatment. 相似文献
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Zhang H Zhu W Su X Wu S Lin Y Li J Wang Y Chen J Zhou Y Qiu P Yan G Zhao S Hu J Zhang J 《Journal of neuro-oncology》2012,109(1):53-62
Malignant glioma is the most devastating and aggressive tumor in brain, characterized by rapid proliferation and diffuse invasion. Chemotherapy and radiotherapy are the pivotal strategies after surgery; however, high drug resistance of malignant glioma and the blood-brain barrier usually render chemotherapy drugs ineffective. Here, we find that triptolide, a small molecule with high lipid solubility, is capable of inhibiting proliferation and invasion of malignant glioma cells effectively. In both investigated malignant glioma cell lines, triptolide repressed cell proliferation via inducing cell cycle arrest in G0/G1 phase, associated with downregulation of G0/G1 cell cycle regulators cyclin D1, CDK4, and CDK6 followed by reduced phosphorylation of retinoblastoma protein (Rb). In addition, triptolide induced morphological change of C6 cells through downregulation of protein expression of MAP-2 and inhibition of activities of GTPases Cdc42 and Rac1/2/3, thus significantly suppressing migratory and invasive capacity. Moreover, in an in vivo tumor model, triptolide delayed growth of malignant glioma xenografts. These findings suggest an important inhibitory action of triptolide on proliferation and invasion of malignant glioma, and encourage triptolide as a candidate for glioma therapy. 相似文献
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Baogang Zhang Feng Gu Chunhua She Hua Guo Wenliang Li Ruifang Niu Li Fu Ning Zhang Yongjie Ma 《International journal of cancer. Journal international du cancer》2009,125(3):585-595
Malignant gliomas have a tendency to invade diffusely into surrounding healthy brain tissues, thereby precluding their successful surgical removal. The serine/threonine kinase Akt2 is well known as an important regulator of cell survival and growth. In this study, we show that siRNA‐mediated depletion of Akt2 inhibited migration and invasion of glioma cells. In addition, we demonstrate the mechanisms by which Akt2 functions to promote cell migration and invasion. Phosphorylation of cofilin, a critical step of actin polymerization, and phosphorylation of Girdin, essential for the integrity of the actin cytoskeleton and cell migration, were impaired. Furthermore, epidermal growth factor‐induced ACAP1 phosphorylation and integrin β1 phosphorylation were also blocked, consistent with defects in adhesion. Thus, Akt2 regulates both cell adhesion and cytoskeleton rearrangement during migration. Decreased MMP‐9 expression in Akt2 knocked‐down glioma cells was subsequently confirmed by Western blotting, consistent with the decreased invasion in vitro and in vivo. These results suggest that Akt2 contributes to glioma cells migration and invasion by regulating the formation of cytoskeleton, influencing adhesion and increasing expression of MMP‐9. Our immunohistochemistry results by using human gliomas tissue sections also indicated that Akt2 expression was closely related with the malignancy of gliomas. This is coincident with our in vivo and in vitro results from cell lines. All of these results indicate that Akt2 is a critical factor in gliomas invasion. This study identifies that Akt2 is a potentially antiinvasion target for therapeutic intervention in gliomas. © 2009 UICC 相似文献
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Jun Xie Yan Li Yijun Huang Pengxin QiuMinfeng Shu Wenbo ZhuYanqiu Ou Guangmei Yan 《Cancer letters》2009
Malignant gliomas are common and aggressive brain tumors in adults. The rapid proliferation and diffuse brain migration are main obstacles to successful treatment. Here we show that pentobarbital, a central depressant introduced clinically a century ago, is capable of suppressing proliferation and migration of C6 malignant glioma cells in a concentration-dependent manner. Pentobarbital also leads to a G1 phase cell cycle arrest accompanied by suppressed G1 cell cycle regulatory proteins Cyclin D1, Cyclin D3, CDK2 and phosphorylated Rb. In addition, noticeable morphological changes and interrupted α-tubulin microtubule assembly are induced by pentobarbital exposure. Intracellular signal pathways involved in the effect of pentobarbital is concerned with inactivation of ERK, c-Jun and Akt. Together, these findings suggest anti-proliferation and anti-migration effects of pentobarbital on malignant gliomas, most likely by arresting cell cycle and interfering microtubule. ERK, c-Jun MAPK and PI3K/Akt are possible signaling pathways involved. 相似文献
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Numerous studies have revealed the chemopreventive and hepatoprotective activities of dietary and synthetic organosulfur compounds. We previously showed that synthetic allylthiopyridazine derivatives, designated as K compounds, induced apoptosis in SK-Hep-1 hepatocarcinoma cells. In order to extend our program to pursue the chemopreventive potential of these compounds, we investigated the effects of the K compounds on invasive and migrative properties of the SK-Hep-1 cells in this study. Here, we show that 3-methoxy-6-allylthiopyridazine (K6) and 3-propoxy-6-allylthiopyridazine (K17) efficiently inhibit SK-Hep-1 cell invasion and migration. A prominent downregulation of matrix metalloproteinase (MMP)-2, but not MMP-9, was observed, presenting MMP-2 as a potential target molecule for the anti-invasive and anti-migrative activities of the compounds. Since hepatocarcinoma is characterized as a hypervascular tumor, we examined the effect of the compounds on angiogenesis of human umbilical vein endothelial cells (HUVECs). The K compounds exerted anti-angiogenic activity, supporting that the development of these compounds would be a promising approach for treatment of hepatocarcinoma. Taken in conjunction with the fact that hepatocellular carcinoma is one of the most lethal malignancies, our findings may be critical to the chemopreventive potential of these synthetic organosulfur compounds for hepatocarcinoma. 相似文献
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Glioblastoma multiforme is the most aggressive type of brain tumor with a strong ability to invade and migrate into surrounding normal brain tissues, leading to high tumor recurrence and mortality. Most of class-3 semaphorins, especially SEMA3A, SEMA3B and SEMA3F, have been reported to have strong tumor inhibition ability, but the role of SEMA3G in tumor biology is largely unknown. We report here that SEMA3G possesses anti-migration and anti-invasion ability. To determine the potential effects of SEMA3G on migratory and invasive ability, we generated stable SEMA3G expression U251MG cells. We found that stably overexpressed SEMA3G inhibited the migratory and invasive behavior of U251MG cells. In addition, treatment with SEMA3G conditioned media also decreased the migratory and invasive ability of parental U251MG cells. Furthermore, SEMA3G also inhibited the activity of MMP2, an index of tumor invasion ability. Thus, our results suggest that SEMA3G inhibited tumor cell migration and invasion, which may be obtained through cell autonomous or paracrine mechanisms, and SEMA3G is a potential target for antitumor migration and invasion. 相似文献
8.
目的:探讨瘦素(leptin)对人脑胶质瘤U87MG细胞迁移及侵袭能力的影响及其机制。方法:Leptin处理U87MG细胞,采用细胞划痕实验检测U87MG细胞的迁移能力,Transwell实验检测U87MG细胞的侵袭能力,RT-PCR及Western blot-ting法检测U87MG细胞中MMP-2及MMP-9 mRNA和蛋白的表达。结果:Leptin明显促进U87MG细胞迁移能力[(152.42±3.29)vs(83.24±2.61)μm,P<0.05]和侵袭能力[(31.78±5.04)vs(17.03±2.41)个细胞,P<0.05],leptin能显著上调U87MG细胞中MMP-2、MMP-9 mRNA[(0.76±0.04)vs(0.35±0.02),(0.84±0.02)vs(0.41±0.06);均P<0.05]及蛋白[(0.79±0.03)vs(0.23±0.01),(0.81±0.05)vs(0.39±0.03);均P<0.05]的表达。MMP抑制剂GM6001(10μmol/ml)可以逆转leptin对U87MG细胞迁移[(82.05±2.98)vs(81.76±3.25)μm,P>0.05]和侵袭能力[(19.23±2.46)vs(18.02±1.98)个细胞,P>0.05]的影响。结论:Leptin可以促进人脑胶质瘤U87MG细胞的侵袭及迁移,其机制可能与上调MMP-2、MMP-9的表达有关。 相似文献
9.
Lipinski CA Tran NL Menashi E Rohl C Kloss J Bay RC Berens ME Loftus JC 《Neoplasia (New York, N.Y.)》2005,7(5):435-445
Glioblastoma multiforme is extraordinarily aggressive due to the propensity of cells to migrate away from the tumor core into the surrounding normal brain. In this report, we investigated the role of proline-rich tyrosine kinase 2 (Pyk2) and FAK with regard to influencing glioma cell phenotypes. Expression of Pyk2 stimulated glioma cell migration, whereas expression of FAK inhibited glioma cell migration and stimulated cell cycle progression. Pyk2 autophosphorylation was necessary, but not sufficient, to stimulate cellular migration. The N-terminal domain of Pyk2 is required for stimulation of migration as an N-terminally deleted variant of Pyk2 failed to stimulate migration, whereas expression of an autonomous Pyk2 N-terminal domain inhibited cell migration. Substitution of the C-terminal domain of Pyk2 with the corresponding domain of FAK stimulated cell migration as effectively as wild-type Pyk2; however, substitution of the N-terminal domain of Pyk2 with that of FAK inhibited cell migration, substantiating that the N-terminal domain of Pyk2 was required to stimulate migration. Silencing of Pyk2 expression by RNA interference significantly inhibited glioma migration. Cell migration was restored on re-expression of Pyk2, but expression of FAK in Pyk2 knockdown cells failed to restore migration. We conclude that Pyk2 plays a central role in the migratory behavior of glioblastomas. 相似文献
10.
目的:探讨YM155对人骨肉瘤细胞系F5M2的生物学恶性行为的影响。方法:体外培养人骨肉瘤细胞系F5M2,不同浓度YM155处理人骨肉瘤细胞系F5M2,细胞克隆实验检测骨肉瘤细胞增殖能力的变化,采用迁移和侵袭实验检测骨肉瘤细胞迁移、侵袭能力的变化,透射电镜观察YM155作用下细胞结构的改变。结果:YM155具有抑制骨肉瘤细胞增殖的效果。YM155作用于骨肉瘤细胞后,细胞伪足减少,人骨肉瘤细胞F5M2细胞迁移、侵袭能力下降。结论:YM155能够有效抑制人骨肉瘤细胞F5M2迁移、侵袭恶性生物学行为,为临床应用提供了一定的理论依据。 相似文献
11.
Hae Kyung Lee Susan Finniss Simona Cazacu Efrat Bucris Amotz Ziv-Av Cunli Xiang Kevin Bobbitt Sandra A. Rempel Laura Hasselbach Tom Mikkelsen Shimon Slavin Chaya Brodie 《Oncotarget》2013,4(2):346-361
MicroRNAs (miRNAs) have emerged as potential cancer therapeutics; however, their clinical use is hindered by lack of effective delivery mechanisms to tumor sites. Mesenchymal stem cells (MSCs) have been shown to migrate to experimental glioma and to exert anti-tumor effects by delivering cytotoxic compounds. Here, we examined the ability of MSCs derived from bone marrow, adipose tissue, placenta and umbilical cord to deliver synthetic miRNA mimics to glioma cells and glioma stem cells (GSCs). We examined the delivery of miR-124 and miR-145 mimics as glioma cells and GSCs express very low levels of these miRNAs. Using fluorescently labeled miRNA mimics and in situ hybridization, we demonstrated that all the MSCs examined delivered miR-124 and miR-145 mimics to co-cultured glioma cells and GSCs via gap junction–dependent and independent processes. The delivered miR-124 and miR-145 mimics significantly decreased the luciferase activity of their respected reporter target genes, SCP-1 and Sox2, and decreased the migration of glioma cells and the self-renewal of GSCs. Moreover, MSCs delivered Cy3-miR-124 mimic to glioma xenografts when administered intracranially. These results suggest that MSCs can deliver synthetic exogenous miRNA mimics to glioma cells and GSCs and may provide an efficient route of therapeutic miRNA delivery in vivo. 相似文献
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Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells 总被引:9,自引:0,他引:9
Roth W Wild-Bode C Platten M Grimmel C Melkonyan HS Dichgans J Weller M 《Oncogene》2000,19(37):4210-4220
Cellular resistance to multiple proapoptotic stimuli and invasion of surrounding brain tissue by migrating tumor cells are main obstacles to an effective therapy for human malignant glioma. Here, we report that the Wnt family of embryonic differentiation genes modulate growth of malignant glioma cells in vitro and in vivo and inhibit cellular migration in vitro. sFRPs (soluble Frizzled-related proteins) are soluble proteins that bind to Wnt and interfere with Wnt signaling. We find that sFRP-1 and sFRP-2 are produced by the majority of longterm and ex vivo malignant glioma cell lines. Glioma cells that ectopically express sFRPs exhibit increased clonogenicity and enhanced resistance to serum starvation. In contrast, sFRPs do not modulate glioma cell susceptibility to apoptosis induced by the cytotoxic cytokines, CD95 (Fas/APO-1) ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), or various cytotoxic drugs. sFRP-2 strongly promotes the growth of intracranial glioma xenografts in nude mice. In contrast, enhanced expression of sFRPs inhibits the motility of glioma cells in vitro. sFRP-mediated effects on glioma cells are accompanied by decreased expression and activity of matrix metalloproteinase-2 (MMP-2) and decreased tyrosine phosphorylation of beta-catenin. Thus, sFRPs promote survival under non-supportive conditions and inhibit the migration of glioma cells. We suggest that the regulation of these cellular processes involves expression of MMP-2 and tyrosine phosphorylation of beta-catenin. These data support a function for Wnt signaling and its modulation by sFRPs in the biology of human gliomas. Oncogene (2000) 19, 4210 - 4220 相似文献
15.
Hideho Okada Jun Yoshida Masahiro Sokabe Takashi Wakabayashi Masatoshi Hagiwara 《International journal of cancer. Journal international du cancer》1996,66(2):255-260
We have reported high expression of CD44H in human glioma cells. To investigate the role of CD44H in the invasion of human glioma, we established a CD44-anti-sense-gene-expression glioma cell line named U-251A1. The expression of CD44H in the G-418-selected U-251A1 cells was reduced to 20% of that in the parental U-251SP cells, as determined by flow-cytometry analysis. We first examined the migratory responses of U-251A1 cells in vitro by time-lapse video-microscopic sparse cell-migration assay on hyaluronic acid or on chondroitin 6 sulfate. U-251A1 cells did not show significant differences in motility on any substrate, while U-251SP and other CD44H-positive glioma cells showed dose-dependent increase of migration specifically on hyaluronic acid. To examine the physiologic function of CD44H in gliomas in vivo, U-251A1 and its control cells, U-251S1, which retain CD44-sense-expression vector, were injected stereotactically into the brains of nude mice. U-251A1 cells were localised in the region of the injection site, with relatively well demarcated borders between tumour and brain tissue, while the control cells demonstrated a cell-infiltration pattern. Our data suggest that CD44H may be required for infiltration of glioma cells through its interaction with hyaluronic acid, a major component of the brain extracellular matrix. © 1996 Wiley-Liss, Inc. 相似文献
16.
A. J. A. Terzis H. Arnold T. Fiskerstrand H. Refsum P. M. Ueland R. Bjerkvig 《International journal of cancer. Journal international du cancer》1993,54(1):112-118
The present study describes the effects of 2 folate antagonists, methotrexate (MTX) and the lipophilic antifolate trimetrexate (TMX) on 2 permanent human glioma cell lines (GaMg and D-54Mg) grown as monolayers and as multicellular tumor spheroids. In addition, the effects of drug exposure on tumor cell invasion was studied using a three-dimensional organ co-culture system. In monolayer cultures, TMX was a more potent inhibitor of cell growth than MTX, especially towards the GaMg cell line. The 2 drugs, however, showed similar cytotoxicity as assessed by the plating efficiency assay. Reduced ability of directional migration of cells on a plastic surface was seen by either antifolate usually at concentrations to 10-fold higher than those exerting a cytotoxic effect in the plating efficiency assay. TMX was somewhat more potent than MTX as an inhibitor of spheroid growth. When tumor spheroids were exposed to MTX or TMX at concentrations that caused 65 to 70% inhibition of cell migration, there was a latent period of 4 to 5 days before inhibition of spheroid growth ensued. Invasion was investigated in a co-culture system, where tumor spheroids were confronted with fetal rat brain cell aggregates. Neither drug reduced tumor cell invasion, although histological examination revealed toxic effects both in GaMg and in D-54Mg spheroids. We conclude that spheroids from human glioma cells were less sensitive to the antifolates than monolayers. For both drugs a latency period was observed before inhibition of spheroid growth. The spheroids retained their ability to invade normal brain tissue when exposed to levels of folate antagonists inhibiting spheroid growth. 相似文献
17.
Glioblastoma is the most aggressive form of primary brain tumor with a tendency to invade surrounding healthy brain tissues, rendering tumors of this type largely incurable. Aquaporin-4 (AQP4) is a key molecule involved in maintaining water and ion homeostasis in the central nervous system and has been recently reported to play a role in cell migration in addition to its well-known function in brain edema. Increased AQP4 expression has been demonstrated in glioblastoma multiforme (GBM), suggesting that it is also involved in malignant brain tumors. Here, we identify a novel role for aquaporin-4 in glioblastoma cell migration and invasion. In the present study, we used small-interference RNA technology and a pharmacological inhibitor to knock down the expression of AQP4, which resulted in speci?c and massive impairment of glioblastoma cell migration and invasion in vitro and in vivo. In addition, we demonstrated the possible mechanisms by which AQP4 functions in the process of glioblastoma cell invasion. The downregulation of matrix metalloprotease-2 (MMP-2) expression in LN229 cells with AQP4 reduction coincided with decreased cell invasive ability. Furthermore, our study showed that AQP4 may also be involved in the regulation of glioblastoma cell adhesion. The expression of β-catenin and connexin 43 were increased in AQP4-downregulated LN229 cells consistent with their enhanced cell-cell adhesion ability. In summary, our results indicate that AQP4 is involved in the control of glioblastoma cell migration and invasion and may be a potential therapeutic target for glioblastoma cell in?ltration. 相似文献
18.
The phosphorylation of EphB2 receptor regulates migration and invasion of human glioma cells 总被引:10,自引:0,他引:10
Nakada M Niska JA Miyamori H McDonough WS Wu J Sato H Berens ME 《Cancer research》2004,64(9):3179-3185
Eph receptor tyrosine kinases and their ligands, ephrins, mediate neurodevelopmental processes such as boundary formation, axon guidance, vasculogenesis, and cell migration. We determined the expression profiles of the Eph family members in five glioma cell lines under migrating and nonmigrating conditions. EphB2 mRNA was overexpressed in all five during migration (1.2-2.8-fold). We found abundant EphB2 protein as well as strong phosphorylation of EphB2 in migrating U87 cells. Confocal imaging showed EphB2 localized in lamellipodia of motile U87 cells. Treatment with ephrin-B1/Fc chimera stimulated migration and invasion of U87, whereas treatment with a blocking EphB2 antibody significantly inhibited migration and invasion. Forced expression of EphB2 in U251 cells stimulated cell migration and invasion and diminished adhesion concomitant with the tyrosine phosphorylation of EphB2. U251 stably transfected with EphB2 showed more scattered and more pronounced invasive growth in an ex vivo rat brain slice. In human brain tumor specimens, EphB2 expression was higher in glioblastomas than in low-grade astrocytomas or normal brain; patterns of phosphorylated EphB2 matched the expression levels. Laser capture microdissection of invading glioblastoma cells revealed elevated EphB2 mRNA (1.5-3.5-fold) in 7 of 7 biopsy specimens. Immunohistochemistry demonstrated EphB2 localization primarily in glioblastoma cells (56 of 62 cases) and not in normal brain. This is the first demonstration that migrating glioblastoma cells overexpress EphB2 in vitro and in vivo; glioma migration and invasion are promoted by activation of EphB2 or inhibited by blocking EphB2. Dysregulation of EphB2 expression or function may underlie glioma invasion. 相似文献
19.
目的:探讨miR-1471对胶质瘤细胞增殖、侵袭和迁移能力的影响及其机制。方法:体外培养人胶质瘤细胞U251,将miR-1471模拟物或阴性对照分别转染至细胞中,记为miR-1471组和阴性对照(NC组),同时设置对照组。qRT-PCR检测转染效果。CCK8检测各组细胞增殖能力。Transwell实验检测各组细胞侵袭能力。划痕实验检测各组细胞迁移能力。qRT-PCR和Western blot检测转移黏附基因(metadherin, MTDH)及Wnt/β-catenin信号通路相关基因和蛋白的表达。结果:与对照组和NC组比较,miR-1471组细胞增殖活性均显著降低(P<0.05),侵袭细胞数均显著减少(P<0.05),划痕间距明显较大,细胞中MTDH、Wnt1和β-catenin mRNA和蛋白表达水平均显著降低(P<0.05)。结论:miR-1471能抑制人胶质瘤细胞U251的增殖、侵袭和迁移能力,其作用机制可能与下调MTDH表达,抑制Wnt/β-catenin信号通路的激活有关。 相似文献
20.
Satoshi Takahashi Hisafumi Yamada-Okabe Kenji Hamada Shigeki Ohta Takeshi Kawase Kazunari Yoshida Masahiro Toda 《Journal of neuro-oncology》2011,103(2):267-276
To identify molecular therapeutic targets for glioma, we performed gene expression profiling by using a complementary DNA
(cDNA) microarray method and identified the urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) as
a gene expressed highly in glioma tissue compared with the normal brain tissue. The uPARAP is an endocytic receptor for collagen.
In certain cell types, uPARAP occurs in a complex with the urokinase plasminogen activator receptor (uPAR) where it fulfills
other functions in addition to collagenolysis. Quantitative PCR analysis using a cDNA panel revealed higher expression levels
of uPARAP in glioma tissue compared with normal brain tissue. Western blot analysis revealed that the uPARAP protein was expressed
in glioma samples and two glioma cell lines, KNS42 and KNS81, but not expressed in control tissue from the normal brain. Introduction
of small interfering RNA-targeted uPARAP into the two different glioma cell lines, KNS42 and KNS81, resulted in downregulation
of uPARAP expression, and it significantly suppressed glioma cell migration and invasion in vitro. Control glioma cells showed
small cell bodies, whereas uPARAP siRNA-treated glioma cells exhibited large and flat morphology. Most of the polymeric actin
in the control glioma cells was concentrated in the lamellipodia that are observed in mobile cells. In contrast, in the uPARAP
siRNA-treated glioma cells, polymeric actin became organized in stress fibers and the lamellipodia disappeared, characteristic
of immobile cells. Our present study suggests that uPARAP may be involved in glioma cell invasiveness through actin cytoskeletal
rearrangement. downregulation of uPARAP may be a novel anti-invasion therapeutic strategy for malignant gliomas. 相似文献