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1.
基质金属蛋白酶及其抑制剂在乳腺癌转移、浸润中的作用   总被引:7,自引:2,他引:7  
目的 :探讨基质金属蛋白酶 (MMP 2、MMP 9)及其抑制剂 (TIMP 1、TIMP 2 )与乳腺癌的关系。方法 :应用免疫组化S P法检测乳腺癌中MMP 2、MMP 9、TIMP 1、TIMP 2的表达。结果  30例乳腺癌患者中MMP 2阳性表达 14例 ,占 46 7% ,MMP 9阳性表达 16例占 5 3 3% ,TIMP 1阳性表达 4例 ,占 13 3% ,TIMP 2阳性表达 3例 ,占 10 0 %。MMP 2、MMP 9的表达与乳腺癌的淋巴结状况、肿瘤大小相关 ,与年龄、月经状况无关。结论 :MMP 2、MMP 9的表达可以作为估计乳腺癌预后及术后综合治疗的生物学指标  相似文献   

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3.
目的: 研究细胞外基质蛋白酶诱导因子(EMMPRIN)和肝细胞生长因子(HGF)在非小细胞肺癌(NSCLC)组织中的表达及其临床意义。方法: 免疫组织化学方法检测77例NSCLC组织中EMMPRIN与HGF的表达,分析其与患者吸烟情况、肿瘤大小、组织学类型、组织分化程度、淋巴结转移和预后的关系。 结果:77例NSCLC组织中EMMPRIN与HGF的阳性表达率分别为68%和44%。EMMPRIN与HGF的表达均与淋巴结转移呈正相关(r=0.371和0.339,P<0.01),与患者术后生存时间呈负相关(P<0.01)。EMMPRIN与HGF的表达均与患者吸烟、肿瘤大小、组织学类型和组织分化程度无关(P>0.05)。EMMPRIN与HGF的表达之间呈正相关(r=0.281,P<0.01)。结论: EMMPRIN和HGF的表达与NSCLC的淋巴结转移和预后密切相关,它们的高表达提示NSCLC患者预后不良。  相似文献   

4.
Objective and Design: Hydroxamic-and carboxylic- acid based matrix metalloproteinase inhibitors (MMPIs) were compared for their potency against various MMPs, pharmacodynamic properties and in vivo efficacy in a model of cartilage degeneration. Materials and Methods: The MMPIs were evaluated for their ability to inhibit human MMPs using the quenched fl uorescence assay. The ability of the MMPIs to inhibit the degeneration of the knee joint was evaluated in rats injected intraarticularly with iodoacetate. The amount of MMPI in the plasma and cartilage was determined using liquid chromatography/mass spectrometry/mass spectrometry (LC/ MS/MS). Plasma protein binding was measured by ultrafi ltration and unbound MMPI was quantitated using HPLC. Results: The hydroxamic acid based inhibitor PGE-3321996 and the carboxylic acids PGE-2909492 and PGE-6292544 were potent MMP-13 inhibitors, but only the hydroxamic acid PGE 3321996 demonstrated signifi cant inhibition of knee degeneration in the rat iodoacetate model. Both of the carboxylic acids demonstrated superior pharmacokinetic properties and established much higher plasma concentrations than the hydroxamic acid. However, neither of the carboxylic acids was detectable in the cartilage, whereas, the hydroxamic acid was present in both the cartilage and the plasma. The carboxylic acid based MMPIs also demonstrated higher plasma protein binding (>99 %) than the hydroxamic acid (79 %). Conclusions: Carboxylic acid-based MMPIs were identifi ed that had superior in vivo plasma exposure compared to a hydroxamic acid inhibitor but lacked in vivo effi cacy in the rat iodoacetate model of cartilage degeneration. The lack of in vivo effi cacy of the carboxylic acid based MMPIs were probably due to their lack of cartilage penetration which was related to their physicochemical properties. Received 12 April 2005; returned for revision 24 July 2005; accepted by J. Skotnicki 20 October 2005  相似文献   

5.
己烯雌酚对肿瘤生长,转移的影响及机制探讨   总被引:5,自引:0,他引:5  
目的:研究己烯雌酚(DES)对实验性肿瘤转移的影响。方法:利用自发性Lewis肺癌(LLC)及实验性B16黑色素瘤(B16M)转移模型研究DES对肿瘤生长、转移的影响。结果:发现预先用DES处理的小鼠对其移植的LLC生长和自发性肺转移均有抑制作用,且DES剂量与肿瘤的生长、转移呈直线负相关(r〉0.80,P〈0.01);B16M实验性肺转移也明显减少;小鼠接种LLC后给予DES对LLC也有抑制作用  相似文献   

6.
目的: 研究细胞外基质金属蛋白酶诱导因子(EMMPRIN)和内皮素转化酶(ECE)在非小细胞肺癌(NSCLC)组织中表达的临床意义。 方法: 用免疫组织化学方法检测77例NSCLC组织中EMMPRIN和ECE的表达情况,分析其与肿瘤大小、癌的组织学类型、组织分化程度、淋巴结转移和预后的关系。 结果: 77例NSCLC组织中EMMPRIN和ECE的阳性表达率分别为66%和45%。EMMPRIN和ECE的表达均与淋巴结转移呈正相关(均P<0.01,r=0.371和0.467),两者表达阳性组术后生存期均明显短于阴性组(均P<0.01)。NSCLC组织中EMMPRIN和ECE的表达之间呈正相关(P<0.05,r=0.243)。EMMPRIN和ECE的表达与肿瘤大小、癌组织学类型和组织分化程度均无相关性(P>0.05)。 结论: EMMPRIN和ECE的表达与NSCLC的淋巴结转移和预后密切相关,它们的高表达提示非小细胞肺癌患者预后不良。  相似文献   

7.
Angiogenesis, a multi-step process which involves endothelial cell proliferation, adhesion, migration, and basement membrane (BM) degradation, is essential for tumor metastasis. Here we show that recombinant human prothrombin kringle-2 (rk-2) inhibited bovine capillary endothelial cell migration with an IC50 (concentration for half maximal inhibition) of 38 nM and inhibited adhesion to extracellular matrix (ECM) proteins. Because tumor metastasis requires angiogenesis, we examined whether rk-2 could inhibit metastases induced by injection of B16F10 melanoma cells into mice. The results revealed that the metastatic tumors in mouse lung were markedly decreased in a dose-dependent manner and acute lung injury induced by B16F10 melanoma metastasis was diminished by systemic rk-2 treatment. In immunohistochemical analysis, rk-2 reduced expression of vascular endothelial growth factor, which is a potent angiogenic activator and neovascularization in the mouse lung. Also, rk-2 diminished the expression of matrix metalloproteinase-2 and -9 in the mouse lung which induces tumor metastasis and angiogenesis. These data suggest that inhibition of B16F10 melanoma metastasis by rk-2 was caused by inhibition of neovascularization and reduction of matrix metalloproteinase expression.  相似文献   

8.
A series of pseudo-peptide analogs of the Arg-Gly-Asp (RGD) sequence of fibronectin have been synthe-sized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have been examined. The partially modified retro pseudo-peptide of RGD, Rrev-COCH2CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (Rrev-COCH2CH2-D, FC-303 ) achieved more potent inhibition of lung metastasis of melanoma cells than FC-63. Among the analogs, FC-336, a p-xylylendiamine derivative having two FC-303 moieties, showed the most potent inhibitory effect on experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma or colon 26 M3.1 cells in a dose-dependent manner. Multiple administrations of FC-336 after tumor inoculation also showed efficient therapeutic potency against spontaneous lung metastasis of B16-BL6 melanoma in mice. Furthermore, FC-336 effectively inhibited the invasion, migration and adhesion of tumor cells in vitro, but its inhibitory effects were not more than those of RGDS peptide. Zymography analysis revealed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indicate that the pseudo-peptides of the RGD sequence, possessing the inhibitory property of the degradation by MMPs differently from original RGD-containing peptides, may be advantageous and useful in preventing tumor metastasis. © Rapid Science 1998  相似文献   

9.
<正>1 PTP4A3基因的概述PTP4A3基因编码一种属于蛋白酪氨酸磷酸酶(protein tyrosine phosphatases,PTPs)家族的蛋白,其相对分子质量大约为22 k D[1]。目前发现编码促肝细胞再生磷酸酶(phosphatases of regenerating livers,PRL)家族的基因包括PTP4A1、PTP4A2和PTP4A3,它们分别位于染色体6q12、1q35.2和8q24.3位  相似文献   

10.
目的 研究血管内皮生长因子C(VEGF-C)与基质金属蛋白酶(MMP)-2、MMP-9在乳腺癌组织中的表达及三者在乳腺癌淋巴结转移中的作用.方法 应用免疫组织化学SP法对84例乳腺癌(有腋淋巴结转移者52例,无腋淋巴结转移者32例)的VEGF-C、MMP-2和-9以及血管内皮透明质酸受体-1(LYVE-1)的表达进行检测,统计分析VEGF-C、MMP-2和-9与乳腺癌淋巴管生成的关系.利用重组质粒表达载体介导的短发夹式干扰RNA(shRNA)靶向沉默乳腺癌MCF-7细胞株中VEGF-C基因,PCR检测VEGF-C、MMP-2和-9的表达.结果 VEGF-C与MMP-2和-9在乳腺癌组织中均呈过表达,分别为83.3%(70/84)、89.3%(75/84)和75.0%(63/84),且在腋淋巴结转移组[94.2%(49/52)、98.1%(51/52)和88.5%(46/52)]比无淋巴结转移组[65.6%(21/32)、75.0%(24/32)和53.1%(17/32)]明显高表达(P<0.05);淋巴管密度在腋淋巴结转移组及无转移组的表达有统计学意义(P<0.05),随着VEGF-C与MMP-2和-9表达强度增加,淋巴管数量也增加(P<0.05);转染重组质粒后MCF-7细胞株的VEGF-C及MMP-2和-9的mRNA表达水平下调,抑制率分别为95.0%、53.0%和77.0%(P<0.05).结论 VEGF-C与MMP-2和-9协同促进乳腺癌组织的淋巴管新生和乳腺癌淋巴结转移.  相似文献   

11.
目的:观察PPAR α、γ配体对巨噬细胞、泡沫细胞细胞外基质金属蛋白酶诱导因子(EMMPRIN)表达的影响。方法:体外诱导THP-1单核细胞转化为巨噬细胞、泡沫细胞,分别加入PPAR α配体氯贝特(clofibrate)、PPARγ配体吡格列酮(pioglitazone)共同培养,应用Real-time RT-PCR和Western blotting测定巨噬细胞、泡沫细胞中EMMPRIN基因和蛋白表达,ELISA测定细胞培养上清液MMP-9浓度,Zymgraphy法测定MMP-9活性。结果:氯贝特和吡格列酮均能显著抑制巨噬细胞和泡沫细胞EMMPRIN的表达,此抑制作用与PPAR α、γ配体抑制MMP-9分泌及活性的趋势一致。结论:PPAR α、γ配体均可抑制巨噬细胞、泡沫细胞EMMPRIN的表达,下调EMMPRIN可能是PPARs配体抑制粥样斑块局部MMPs产生的机制之一。  相似文献   

12.
It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase, and that such degradation is regulated by metalloproteinase inhibitors (TIMP). Therefore, the balance between collagenase and TIMP is an important factor for tissue destruction in inflammatory joints. In the present study the effects of cytokines on collagenase and TIMP production in chondrocytes as well as the effects of cytokines on TIMP production in connective tissue cells were studied. IL-1 beta inhibited TIMP production in endothelial cells while enhancing TIMP production in synovial cells and chondrocytes. In addition, tumour necrosis factor-alpha (TNF-alpha) significantly inhibited and IL-6 significantly enhanced TIMP production in endothelial cells, synovial cells and chondrocytes. In the chondrocyte supernatant, collagenase activity/TIMP ratio was significantly elevated by the addition of either IL-1 beta or TNF-alpha to the cells, whereas the ratio was significantly decreased by IL-6. These results suggest that the cytokine effects on TIMP production are different among the different cell types, and that either IL-1 beta or TNF-alpha induce cartilage matrix degradation by disrupting the collagenase/TIMP balance, while, on the other hand, IL-6 protects the tissue through an opposite effect.  相似文献   

13.
目的:观察强力霉素对损伤动脉组织中基质金属蛋白酶(MMP)活性的抑制作用,并探讨强力霉素对血管平滑肌细胞增殖、动脉内膜增生、管腔重构的影响。方法:球囊导管扩张动脉的方法建立大鼠颈总动脉损伤模型。治疗组用强力霉素30 mg·kg-1·d-1干预。明胶酶谱法测定损伤动脉组织中MMPs的活性。用HE染色、VVG染色、免疫组化标记α-actin和增殖细胞核抗原的方法观察损伤动脉内膜厚度、管腔重构及平滑肌细胞增殖的情况。结果:①强力霉素治疗组MMP-9活性在术后24 h、3 d分别比对照组低26.3%、34.5%(P<0.01);MMP-2活性在术后7 d比对照组低40.0%(P<0.01)。②强力霉素治疗使术后7 d内膜平滑肌细胞增殖率(43.23%±1.06%)显著低于对照组(62.76%±1.02%)(P<0.01);使术后14 d、28 d新生内膜厚度比对照组分别少32.0%、38.8%(P<0.01),而管腔面积比对照组多58.0%、90.4%(P<0.01) 。结论:强力霉素可以显著降低血管损伤后MMPs活性,抑制内膜平滑肌细胞的增殖、新生内膜增生以及管腔重构,提示它可能具有防治PTCA术后再狭窄的作用。  相似文献   

14.
目的:探讨大鼠肺纤维化发生发展中基质金属蛋白酶1(MMP1)、MMP3、基质金属蛋白酶组织抑制剂1(TIMP1)及miR-29的表达和作用以及活性维生素D3[1,25(OH)_2D_3]处理对这些基因表达的影响。方法:雄性SD大鼠随机分为预防组和治疗组。预防组分为对照组Ⅰ、模型组Ⅰ和给药组Ⅰ,治疗组分为对照组Ⅱ、模型组Ⅱ和给药组Ⅱ。模型组Ⅰ/Ⅱ和给药组Ⅰ/Ⅱ经气管注入博莱霉素,对照组Ⅰ/Ⅱ经气管注入生理盐水。预防组和治疗组分别于术后第2和14天腹腔注射给药,给药组给予活性维生素D3,模型组给予活性维生素D3溶剂,对照组给予生理盐水。预防组的各组分别于术后第14、21、28天处死大鼠取材,治疗组的各组分别于术后第21和28天处死大鼠取材。实时定量PCR检测大鼠肺组织中miR-29a及TIMP1 mRNA表达水平,免疫组织化学检测组织中MMP1、MMP3和TIMP1的表达水平。结果:模型组Ⅰ/Ⅱ和给药组Ⅰ/Ⅱ中的MMP1、MMP3和TIMP1的表达均明显高于相同时间点对照组Ⅰ/Ⅱ中的表达,而miR-29a的表达明显低于相应的对照组Ⅰ/Ⅱ;给药组Ⅰ/Ⅱ中MMP1、MMP3和TIMP1的表达均低于相应时间点的模型组Ⅰ/Ⅱ的表达,而给药组Ⅰ/Ⅱ中miR-29a的表达则高于模型组Ⅰ/Ⅱ中的表达。结论:MMP1、MMP3、TIMP1和miR-29在大鼠肺纤维化发生发展中具有重要作用,活性维生素D3可以促进miR-29表达,抑制MMP1、MMP3、TIMP1的表达;可能是通过miR-29调节包括MMP1、MMP3、TIMP1在内的多种靶基因来发挥抑制纤维化的作用。  相似文献   

15.
背景:以往促进骨髓间充质干细胞软骨分化的研究,多将胰岛素样生长因子1作为辅助因子与其他细胞因子联合应用,而胰岛素样生长因子1单独应用能否促进骨髓间充质干细胞分泌软骨特异性胶原仍存在争议,其对骨髓间充质干细胞软骨分化及软骨胶原纤维稳定性的影响尚不清楚。 目的:观察胰岛素样生长因子1对骨髓间充质干细胞软骨分化以及基质金属蛋白酶表达的影响。 方法:构建含有胰岛素样生长因子1基因完整编码区的表达载体,稳定转染至大鼠骨髓间充质干细胞,设为胰岛素样生长因子1稳定转染组,同时设未转染组作对照。 结果与结论:MTT检测结果显示,实验成功筛选得到胰岛素样生长因子1稳定过表达的骨髓间充质干细胞,转染后4 d,细胞增殖能力显著增强(P < 0.05)。RT-PCR,Western blot法及免疫细胞化学检测结果显示,与未转染组相比,胰岛素样生长因子1稳定转染组细胞胰岛素样生长因子1,Ⅱ型胶原 mRNA和蛋白的表达水平均显著升高(P < 0.01),基质金属蛋白酶1,2,3 mRNA表达显著降低(P < 0.01)。结果证实,单独应用胰岛素样生长因子1能够有效促进骨髓间充质干细胞的增殖以及软骨分化,并维持软骨胶原纤维的稳定性。  相似文献   

16.
This study has examined the response of a rabbit model of inflammatory bowel disease to methylprednisolone. Colitis was induced in the colon of rabbits with 40 mg trinitrobenzenesulphonic acid in 25% ethanol (TNBS). The effect of methylprednisolone (0.5 mg/kg/day) on the development of colitis was determined at one week, by examining the colon's macroscopic and microscopic appearance, the distribution of matrix metalloproteinases (MMPs) and by measuring eicosanoid production. Although there was no difference in the area of ulcerated colonic tissue in the treated and untreated TNBS animals, the increase in polymorphonuclear leucocytes was significantly reduced in TNBS rabbits given methylprednisolone. The only difference in the distribution of MMPs was a reduction in the number of polymorphonuclear leucocytes containing gelatinase B. The release of immunoreactive PGE2 and LTB4, but not 6-keto PG F , was increased in the TNBS animals and was unchanged by methylprednisolone. These results show that methylprednisolone does not modify the injury produced by TNBS in this model despite reducing the infiltration of polymorphonuclear leucocytes. Hence it suggests that these cells do not contribute to the injury observed, are not the source of the eicosanoids and that gelatinase B is not required in the healing process in this model.  相似文献   

17.
We examined the effects of roxithromycin, a 14-membered ring macrolide antibiotic, on tumor angiogenesis, tumor growth and metastasis of mouse B16BL6 melanoma cells. The inhibitory effect of roxithromycin on angiogenesis using mouse dorsal air sac model was dose-dependent, and 100 mg/kg of roxithromycin administered intraperitoneally twice a day reduced the dense capillary network area to about 20% of the control. Administration of roxithromycin histologically reduced the development of microvessels and mononuclear cell infiltration. In vivo tumor growth studies demonstrated that intraperitoneal administration of roxithromycin at 20 mg/kg/day and 50 mg/kg/day reduced tumor size of B16BL6 melanoma to about 56% and 33% (experiment 1), 71% and 48% (experiment 2) of that in the respective controls. Roxithromycin also significantly inhibited pulmonary metastasis of B16BL6 cells in a spontaneous system. The inhibitory activities of roxithromycin on angiogenesis, tumor growth and metastasis were compared with those of a potent angiogenesis inhibitor, TNP-470. These data demonstrated that roxithromycin has potent antiangiogenic and antitumor effects and might have possible therapeutic applications.  相似文献   

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19.
Increased intake of vitamin E has been suggested to be protective against prostate cancer in men, but the effects of vitamin E on prostate growth and function remain poorly defined. The purpose of this study was to determine the effects of vitamin E deficiency on pubertal growth and maturation of the prostate in the rat. Animals were placed on a vitamin E deficient diet at 28 days of age and were followed for 15 and 26 weeks. Vitamin E deficient rats had a circulating vitamin E level of less than 1% of control animals and experienced a decrease in body and testis weight. The deficiency did not alter the weights of the ventral and dorsal lobes of the prostate. However, there was an increase in weight, DNA, and protein contents of the lateral lobe in control and vitamin E deficient rats from 15 to 26 weeks of treatment, but these increases were significantly lower in vitamin E deficient 26-week treated rats. The volume of secretion per milligram tissue was greater in the ventral than lateral or dorsal lobes. The volume of secretion and activity of the secretory 26 kDa protease in the ventral prostate was lower in vitamin E deficient rats at 15 weeks, but not at 26 weeks of treatment. In contrast, the relative protein content of lateral lobe secretion increased in both control and vitamin E deficient rats from 15 to 26 weeks of treatment. The lateral, but not ventral or dorsal, lobes of both control and vitamin E deficient rats were affected by chronic prostatitis as evidenced by infiltration of inflammatory cells. The lateral lobes also showed markedly elevated activities of the matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9). These data indicate that vitamin E deficiency does not alter the growth of the prostatic lobes, nor the onset and extent of lateral lobe specific prostatitis, but it may delay some differentiated functions such as secretion of specific proteins in the ventral lobe. Thus, the effects of vitamin E in the prostate of the rat appear to be selective.  相似文献   

20.
Fibromodulin, a member of the small leucine-rich proteoglycan family, has been recently suggested as a biologically significant mediator of fetal scarless repair. To assess the role of fibromodulin in the tissue remodeling, we constructed an adenoviral vector expressing human fibromodulin cDNA. We evaluated the effect of adenovirus-mediated overexpression of fibromodulin in vitro on transforming growth factors and metalloproteinases in fibroblasts and in vivo on full-thickness incisional wounds in a rabbit model. In vitro, we found that Ad-Fibromodulin induced a decrease of expression of TGF-β1 and TGF-β2 precursor proteins, but an increase in expression of TGF-β3 precursor protein and TGF-β type II receptor. In addition, fibromodulin overexpression resulted in decreased MMP-1 and MMP-3 protein secretion but increased MMP-2, TIMP-1, and TIMP-2 secretion, whereas MMP-9 and MMP-13 were not influenced by fibromodulin overexpression. In vivo evaluation by histopathology and tensile strength demonstrated that Ad-Fibromodulin administration could ameliorate wound healing in incisional wounds. In conclusion, although the mechanism of scar formation in adult wounds remains incompletely understood, we found that fibromodulin overexpression improves wound healing in vivo, suggesting that fibromodulin may be a key mediator in reduced scarring.
Mariam A. Stoff-KhaliliEmail:
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