基质金属蛋白酶-2和基质金属蛋白酶-9在胶质瘤侵袭和转移中的作用

胶质瘤是一种中枢神经系统恶性肿瘤,病死率高。胶质瘤细胞的侵袭和转移是其致死的重要原因之一,而基质金属蛋白酶通过溶解细胞外基质实现侵袭和转移。基质金属蛋白酶(mat r i x metalloproteinase,MMP)是锌离子依赖性蛋白水解酶,广泛分布于人体各组织和器官,参与细胞外基质的降解和重塑,调节细胞粘着,在肿瘤细胞的侵袭中起着重要作用。本文就基质金属蛋白酶-2和基质金属蛋白酶-9在胶质瘤中的侵袭作用及其机制进行综述。     

基质金属蛋白酶-9、金属蛋白酶抑制因子-1及CD147在食管鳞状细胞癌组织中的表达

目的探讨基质金属蛋白酶-9（MMP-9）、金属蛋白酶抑制因子-1（TIMP-1）及CD147在食管鳞状细胞癌（鳞癌）的表达及意义。方法选择2005年1月～2007年1月在新乡医学院第一附属医院胸心外科行食管癌根治术切除的标本52例，术后均经病理证实为食管鳞癌。采用免疫组织化学方法检测食管癌组织及癌旁正常食管组织中MMP-9、TIMP-1及CD147的表达。结果食管鳞癌组织中MMP-9、TIMP-1及CD147的阳性表达率分别为73．0％、44．2％和80．8％，与癌旁正常食管组织（23．1％、30．8％、19．2％）比较有显著性差异（P〈0．05）。鳞癌组织中MMP-9阳性表达率与TIMP-1无明显相关性（P〉0．05），与CD147成正相关（r=0．457，P〈0．05）。MMP-9阳性表达率与肿瘤浸润及淋巴结转移有关（P〈0．05）。结论食管鳞癌组织中MMP-9／TIMP—1失衡参与了其侵袭转移过程，CD147可能作为涛导剂促进了MMP-9的表达。     

基质金属蛋白酶-2和-9基因多态性与结直肠癌的相关性

目的探讨基质金属蛋白酶（matrix metalloproteinase，MMP）-2和-9基因启动子区多态性与结直肠癌的关系。方法应用变性高效液相色谱法和限制性片段长度多态性分析方法分别检测126例结直肠癌患者和126名正常对照者的MMP-2—1306C/T和MMP-9—1562C／T多态性，分析其基因型与结直肠癌发病风险及临床病理参数的相关性。结果MMP-2—1306C／C基因型频率在结直肠癌组中显著高于对照组（P〈0．05），与CT＋TT基因型携带者比较，CC基因型携带者患结直肠癌的风险约增加2倍（OR：1．959；95％CI：1．055～3．637）。而且在结直肠癌中，MMP-2—1306C／T多态性与肿瘤的浸润深度之间差异有统计学意义（P〈0．05），CC基因型的肿瘤更容易浸润到外膜。MMP-9—1562C／T多态性的基因型及等位基因频率在结直肠癌组和对照组间的分布差异无统计学意义（P〉0．05）。结论MMP-2—1306C／T多态性可能与中国人群结直肠癌的遗传易感性相关，且CC基因型的肿瘤更易浸润到外膜。     

基质金属蛋白酶MMP—2，MMP—9与肺癌的侵袭和转移

基质金属蛋白酶MMP 2和MMP 9是降解Ⅳ型胶原最主要的酶 ,在肺癌的侵袭转移中起重要作用。MMPs在各型肺癌中的表达均有明显增加 ,MMP 2 ,MMP 9的表达水平与肺癌预后具相关性。目前开发合成的数种MMP抑制剂已进入临床实验阶段     

急性心肌梗死患者PCI术前后血清基质金属蛋白酶-2与基质金属蛋白酶-9的相关性

目的: 探讨急性心肌梗死(AMI)患者在急诊经皮冠状动脉介入(PCI)术治疗前后血清基质金属蛋白酶-2 (MMP-2)和基质金属蛋白酶-9 (MMP-9)变化的相关性.方法: 应用酶图(SDS-PAGE zymograph)和Western blot的方法检测56例行PCI术治疗的AMI患者及20例冠状动脉造影正常者术前及术后第1~7 天血清中MMP-2和MMP-9的酶活性及蛋白表达水平,并分析MMP-2和MMP-9变化的相关性.结果: AMI患者PCI术前及术后血清MMP-2和MMP-9的酶活性及蛋白表达水平较对照组明显升高(P<0.01),PCI术患者在术后第1天血清MMP-2和MMP-9的酶活性及蛋白表达水平显著升高,并在术后第3天达高峰(P<0.01),第5天开始明显下降(P<0.05).经Spearman相关性分析表明,各组血清MMP-2的酶活性与MMP-9的酶活性呈正相关(P<0.01);各组血清MMP-2的表达水平与MMP-9的表达水平亦呈正相关(P<0.01).结论: 血清MMP-2和MMP-9酶活性及蛋白表达水平的增加可能是AMI患者心肌缺血再灌注损伤的机制之一.MMP-2和MMP-9是AMI病程进展中同样重要的炎性标志物.     

膝关节炎软骨基质金属蛋白酶2、基质金属蛋白酶9表达与MRI表现的相关性

BACKGROUND: Matrix metalloproteinases (MMPs) have been shown to break the balance between the production and degradation of extracellular matrix by degrading collagen, gelatin, elastin and other macromolecules, which is the leading cause of bone and cartilage damage in rheumatic arthritis. OBJECTIVE: To determine the expression levels of MMP-2 and MM-9 in the rabbit knee osteoarthritis cartilage, and to analyze whether they are related to the early MRI performance. METHODS: Fifty healthy Japanese white rabbits free from osteoarthritis were enrolled and randomly divided into control group (n=10) and model group (n=40). The anterior and posterior cruciate ligament amputation was adopted to establish the model of osteoarthritis. Subsequently, MRI examination and the expression levels of MMP-2 and MMP-9 were detected at 1, 3, 5 and 7 weeks (n=10 at each time point), respectively. RESULTS AND CONCLUSION: MRI examination showed that more damaged cartilage appeared with time in the rabbit model of osteoarthritis, and significantly different from MRI classification (P < 0.05). The expression levels of MMP-2 and MMP-9 mRNA in the model group were always significantly higher than those in the control group (P < 0.05); MMP-2 level reached the highest at 3 weeks after modeling (P < 0.01), and then presented a slight decline; MMP-9 level peaked at 5 weeks after modeling (P < 0.01) and slightly decreased at 7 weeks. MRI classification of cartage injury and expressions of MMP-2 (R2=0.119, P=0.119) and MMP-9 (R2= 0.466, P=0.466) were shown to have the correlation. These results illustrate that the serum levels of MMP-2 and MMP-9 are related to the early destruction of articular cartilage in patients with osteoarthritis, and can be used as predictors for early osteoarthritis. 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

血清基质金属蛋白酶2与代谢综合征的相关性研究

目的 比较代谢综合征(MS)患者与健康对照人群血清基质金属蛋白酶2(MMP-2)水平,探讨MMP-2水平与MS疾病组成成分及相关危险因素的关系.方法 2009年7月至10月于广州市海珠区龙凤社区及素社社区进行流行病学调查,筛选出MS组75例和对照组82例.采用ELISA法检测MS组及对照组血清MMP-2水平.对MS组患者的血清MMP-2水平与MS各组成成分及相关危险因素进行相关性分析.结果 与对照组比较,MS组血清MMP-2水平显著降低[(216.6±51.6) μg/L比(232.9±49.8) μg/L,P＜0.05].MS患者的血清MMP-2水平与三酰甘油(TG)、体质量指数(BMI)、腰围(WC)和舒张压(DBP)呈负相关(r=-0.217、-0.188、-0.191、-0.199,均P＜0.05),与年龄呈正相关(r=0.263,P＜0.05).结论 MS患者MMP-2水平的降低可能参与心血管系统细胞外基质沉积的病理过程.     

不同组织微环境中人胃癌异种移植瘤侵袭性及基质金属蛋白酶谱表达的差异

目的 探讨组织微环境对癌细胞侵袭性影响机制中基质金属蛋白酶表达的意义。方法 取人胃腺癌组织移植于裸小鼠皮下,成瘤后进行皮下和腹腔内传代接种,形态学观察2处异种移植瘤侵袭性的不同并用免疫组织化学链霉素抗生物素蛋白-过氧化物酶法检测基质金属蛋白酶(MMP)-2、MMP-7、MMP-9、MMP-13、TM1-MMP、TM2-MMP、TM3-MMP 7种MMPs在瘤组织中的表达。结果 人胃癌裸小鼠皮下异种移植瘤呈膨胀性生长,侵袭性不明显;除MMP-7外,其他6种MMPs在皮下移植瘤细胞及间质中均无表达。腹腔内移植瘤呈侵袭性生长、纤维间质增多,多种MMPs均在侵袭前沿的肿瘤细胞及间质中表达。同一瘤株来源的人胃癌细胞在裸小鼠不同组织环境中所呈现的侵袭性及MMPs表达差异均有显著性。结论 (1)肿瘤细胞与相邻的间质细胞之间存在相互诱导作用,组织环境对肿瘤侵袭表型可有决定性的影响。(2)MMPs的表达与肿瘤细胞生长方式及侵袭性有密切联系;肿瘤侵袭前沿的间质细胞产生的MMPs也可能参与肿瘤细胞的侵袭过程。     

蒿甲醚对人胶质瘤细胞侵袭、转移及基质金属铁蛋白酶-2、9活性的影响

目的研究蒿甲醚对U251人胶质瘤细胞侵袭、转移能力以及基质金属铁蛋白酶-2、9活性的影响。方法将浓度为200μmol/L的蒿甲醚孵育U251胶质瘤细胞24h。利用划痕修复试验及Transwell小室建立体外迁移及侵袭模型,观察蒿甲醚对U251人胶质瘤细胞迁移及侵袭能力的影响。利用基于荧光抑制的明胶的酶动力性实验检测蒿甲醚对U251人胶质瘤细胞的基质金属铁蛋白酶-2、9活性改变。结果在200μmol/L的蒿甲醚处理下,U251胶质瘤细胞的侵袭和转移能力明显降低,同时基质金属铁蛋白酶-2、9活性受到显著抑制。结论蒿甲醚抑制人U251胶质瘤细胞侵袭和转移能力可能与下调MMP-2和MMP-9的蛋白酶活性相关。     

可调控型反义基质金属蛋白酶9表达抑制人黑色素瘤细胞侵袭转移表型的研究

目的 探讨基质金属蛋白酶(MMP)-9与肿瘤转移的相关性。方法 利用基因重组技术构建反义MMP—9 cDNA四环素可调控型表达载体,用脂质体法转染反义MMP—9至转移性人黑色素瘤细胞株WM451(高表达MMP—9)。检测转染后细胞MMP—9表达水平的改变以及体外生长、侵袭、裸鼠体内成瘤及自发转移能力的变化。结果 转染反义基因后,WM451细胞MMP—9的表达及活性明显下降,同时MMP—2的表达也受到一定抑制,细胞生长速度、体外侵袭能力及棵鼠体内成瘤性及自发转移能力均受到一定程度抑制;运用四环素可以抑制四环素负调控逆转录病毒载体上的外源基因的表达。结论 反义MMP—9基因下调MMP—9的表达,可使人黑色素细胞转移能力受到一定程度的抑制,说明MMP—9在人黑色素瘤细胞转移过程中起重要作用。同时,四环素负调控逆转录病毒载体可以调控外源基因的表达。     

上调分子伴侣mortalin经由MAPK-ERK信号转导通路促进卵巢癌细胞增殖

目的 通过获得稳定表达mortalin的卵巢癌细胞株（A2780、A2780/cis）,检测mortalin与卵巢癌细胞增殖的关系及可能机制。方法 CCK-8实验检测mortalin过表达组和对照组细胞增殖的变化;通过流式细胞术检测mortalin过表达对卵巢癌细胞周期的影响;Western blotting检测mortalin上调表达后,卵巢癌细胞中MAPK/ERK和JNK/SAPK信号通路蛋白的变化。 结果 Mortalin上调表达促进卵巢癌细胞A2780和A2780/cis的增殖。Mortalin通过加快卵巢癌细胞由G₁期快速过渡到G₂/M期,促进细胞增殖,且MAPK/ERK信号通路参与该过程。结论 Mortalin上调表达促进了卵巢癌细胞的增殖,与其对MAPK-ERK信号通路的激活有关。     

METTL3 promotes the proliferation and invasion of esophageal cancer cells partly through AKT signaling pathway

Methyltransferase-like 3 (METTL3) is identified as a methyltransferase responsible for N⁶-methyladenosine (m⁶A) modification of mRNA, miRNA and lncRNA. Emerging evidences suggest that METTL3 is involved in tumorigenesis and progression of multiple tumor types. However, the functional role of METTL3 in esophageal cancer (EC) remains unclear. We used specific shRNA to down-regulate the METTL3 expression, and used pcDNA3.1-METTL3 cDNA plasmid to up-regulate the METTL3 expression in Eca-109 and KY-SE150 cells. Biological functions of METTL3 were performed by CCK-8, colony formation, apoptosis analysis, transwell and wound healing assays. Finally, an in-depth mechanism study was performed by an AKT inhibitor. METTL3 knockdown reduced the proliferation, clonality, migration and invasion of Eca-109 and KY-SE150 cells, and induced cell apoptosis, which may be mediated by activation of the mitochondrial apoptotic pathway. Further, METTL3 overexpression promoted the proliferation, clonality, migration and invasion of Eca-109 and KY-SE150 cells, and inhibited cell apoptosis. In addition, METTL3 regulated the expression of Wnt/β-catenin and AKT signaling pathway components. A double-effect inhibitor (BEZ235) inhibited AKT and mTOR phosphorylation and hindered the effect of METTL3 overexpression on the proliferation and migration of Eca-109 and KY-SE150 cells. Our data suggest that METTL3 plays a carcinogenic role in human EC progression partially through AKT signaling pathways, suggesting that METTL3 may serve as a potential therapeutic target for EC therapy.     

NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway

Neurensin-2 (NRSN2), a small neural membrane protein which localized in small vesicles in neural cells. Recent report suggested that Neurensin-2 might play a suppressive role in tumor. While the biological functions and molecular mechanisms in cancer progression remain unknown. We retrieved Oncomine Database and found that NRSN2 is commonly highly expressed in non-small cell lung cancer (NSCLC). We examined the levels of NRSN2 in 18 pairs of NSCLC and adjacent tissues and found that NRSN2 was overexpressed in malignant tissues. Both loss and gain of function experiments in NSCLC cell lines suggest that NRSN2 promotes cell growth, but no effects in cell invasion. Further investigation show that NRSN2 could affect phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling. Taken together, our findings suggest that NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway.     

miR-1179 promotes cell invasion through SLIT2/ROBO1 axis in esophageal squamous cell carcinoma

MiR-1179, a new identified miRNA highly associated with metastasis of colorectal cancer which was never reported in esophageal squamous cell carcinoma (ESCC). Here we measured the expression levels of miR-1179 and the candidate target gene in tissues from 40 patients with ESCC. Transwell, Dual-luciferase reporter assay and immunocytochemistry assay were employed to detect the function role of miR-1179 in vitro. We found that miR-1179 was up-regulated in human ESCC tumor tissues. Bioinformatics analysis indicated that SLIT2 acting as a new potential target of miR-1179 which was confirmed by luciferase reporter assay. Down-regulation of miR-1179 suppressed cell invasion in vitro with an increasing level of SLIT2 and ROBO1, besides, the up-regulation of SLIT2 decreased cell invasion through ROBO1. Taken together, these findings will shed light the role to mechanism of miR-1179 in regulating cell invasion via SLIT2/ROBO1 axis.     

SRPX2 promotes cell migration and invasion via FAK dependent pathway in pancreatic cancer

Sushi repeat-containing protein, X-linked 2, abbreviated as SRPX2, is a candidate downstream target protein for E2A-HLF and involved in disorders of language cortex and cognition. Recent studies have demonstrated that elevated SRPX2 exhibits crucial roles in gastric cancer, however, underlying clinical significance and biological function of SRPX2 in pancreatic ductal adenocarcinoma (PDAC), remains unclear. Data from Oncomine database showed that higher SRPX2 expression is more commonly observed in PDAC compared with normal pancreatic duct, similar results were also found in 12 matched PDAC tissue samples, 7 PDAC cell lines and a tissue microarray containing 81 PDAC specimens as demonstrated by real-time quantitative PCR and immunohistochemistry, respectively. Besides, higher SRPX2 expression was closely correlated with advanced TNM stage. Silencing of endogenous SRPX2 expression reduced abilities of cell migration and invasion of PDAC cells. Further studies revealed that SRPX2 expression in PDAC tissues significantly correlated with the phosphorylation levels of FAK, indicating that FAK dependent pathway may be account for the effect of SRPX2 on cell migration and invasion in PDAC. Collectively, this study reveals that frequently elevated SRPX2 contributes to cell migration and invasion in PDAC and SRPX2-related pathways might be a potential therapeutic target for PDAC.     

Stress-induced phosphoprotein 1 promotes pancreatic cancer progression through activation of the FAK/AKT/MMP signaling axis

BackgroundDependent on the extent of adenosine triphosphate (ATP) hydrolysis and/or ATP/ADP exchange, the stress-induced phosphoprotein 1 (STIP1) mediates molecular interaction and complex formation between the molecular chaperones heat shock protein (Hsp)70 and Hsp90. The overexpression of STIP1 is increasingly being documented in various human malignancies, including ovarian, cholangiocellular, renal and gastric cancers. However, the role of STIP1 in pancreatic cancer (PANC) and probable molecular mechanism remains largely unexplored.Methods & resultsIn the present study, using clinical samples (n = 88) and human PANC cell lines PANC-1, Capan-2, SW1990, and BxPC-3, we demonstrated that STIP1 is aberrantly expressed in human PANC tissues or cell lines compared to adjacent non-tumor pancreas samples or human pancreatic duct epithelial cells (HPDEC), respectively. Clinicopathological correlation studies revealed significant positive correlation between high STIP1 expression and lymph node involvement (p = 0.001), cancer metastasis (p = 0.002), microvascular invasion (p = 0.002), advance TNM stage (p = 0.024), perineural invasion (PNI; p = 0.013), and cancer-related death (p = 0.002) among patients with PANC. Univariate and multivariate analyses indicate that STIP1overexpression is an independent prognostic factor of PANC. Furthermore, STIP1 knockdown significantly inhibit the migration and invasive ability of PANC-1 and SW1990 cells, while downregulating N-cadherin and Vimentin, but upregulating E-cadherin mRNA expression levels, concurrently. We also demonstrated that STIP1 knockdown suppressed p-FAK, p-AKT, MMP2, MMP9, and Slug protein and mRNA expression levels, thus, indicating, at least in part, a role for STIP1 in the activation of FAK/AKT/MMP signaling.ConclusionTaken together, our results demonstrate a critical role for STIP1 in cancer metastasis, disease progression and poor prognosis, as well as, provide evidence suggestive of the therapeutic efficacy of STIP1-mediated targeting of the FAK/AKT/MMP signaling axis in patients with PANC.     

SASH1 inhibits proliferation and invasion of thyroid cancer cells through PI3K/Akt signaling pathway

The SASH1 (SAM- and SH3-domain containing 1) gene, a member of the SLY-family of signal adapter proteins, has an important regulatory role in tumorigenesis, but its implication in thyroid carcinoma has not been yet investigated. In this study, we investigated the role of SASH1 in proliferation and invasion of thyroid cancer cells and the underlying mechanism. Our results demonstrated that SASH1 is down-regulated in thyroid cancer cells. Overexpression of SASH1 inhibits thyroid cancer cell proliferation, migration and invasion with decreased epithelial-mesenchymal transition (EMT). Mechanistically, overexpression of SASH1 inhibits thyroid cancer cell proliferation and invasion through down-regulation of PI3K and Akt phosphorylation. Taken together, the present study showed that the loss or inhibition of SASH1 expression may play an important role in thyroid cancer development, invasion, and metastasis and that SASH1 may be a potential therapeutic target for the treatment of thyroid cancer.