摘要
脑胶质瘤是颅内最常见的恶性肿瘤,因其呈侵袭性生长,手术很难彻底切除,目前以手术、化疗、放疗作为常规的治疗方案,五年生存率低。
肝细胞生长因子(HGF)及其受体(c-Met)在许多肿瘤均有过表达,与肿瘤发生、发展、转移、侵袭及预后密切相关。研究已发现,HGF能促进胶质瘤细胞的增殖,血管生成,侵袭转移,其表达水平与脑胶质瘤的分级、血管密度及不良预后密切相关。在已筛查的HGF抑制物中,格尔德霉素(GDM)对HGF的抑制效力最显著,并在肝癌、肺癌、黑色素瘤等中观察到了GDM通过抑制HGF对肿瘤侵袭生长的抑制作用。
本实验采用Western blot法、MTT法、流式细胞术及Transwell小室侵袭实验检测了HGF在胶质瘤中的表达及其对胶质瘤细胞增殖、细胞周期、凋亡、侵袭的影响。应用ELISA法、RT-PCR法分析了GDM对胶质瘤中HGF含量和HGF及c-Met mRNA表达的影响。同时给予外源性HGF后,通过MTT法、流式细胞术观测了GDM对HGF促进胶质瘤细胞增殖、抑制细胞凋亡作用的影响,通过Transwell小室侵袭实验观察了GDM对胶质瘤细胞侵袭作用的影响。最后通过明胶酶谱法、RT-PCR法及琼脂糖凝胶电泳探讨了GDM抑制胶质瘤细胞侵袭能力的机制。所得结果如下:1.肝细胞生长因子可显著促进人脑胶质瘤U87和U251细胞的增殖,抑制细胞凋亡并增强胶质瘤细胞侵袭能力;2.格尔德霉素以剂量依赖方式抑制人脑胶质瘤U87和U251细胞的增殖、促进细胞凋亡并使胶质瘤细胞发生G2/M期阻滞,对胶质瘤细胞生长具有显著的抑制作用,同时显著降低了其侵袭能力;3.格尔德霉素部分逆转了肝细胞生长因子促人脑胶质瘤U87和U251细胞的增殖作用,逆转了肝细胞生长因子抑制细胞凋亡作用,并基本上抑制了肝细胞生长因子促进胶质瘤细胞侵袭能力;4.肝细胞生长因子可显著增加人脑胶质瘤U87和U251细胞中MMP-2、MMP-9活性,增加c-Met、MT1-MMP及u-PA基因的表达,而格尔德霉素可显著降低胶质瘤细胞中肝细胞生长因子的含量及其mRNA水平的表达,且明显逆转肝细胞生长因子对胶质瘤c-Met、MT1-MMP及u-PA基因的表达增加趋势,降低胶质瘤细胞MMP-2、MMP-9活性。推测格尔德霉素可能通过抑制HGF-Met通路,降低该通路后续基因MT1-MMP及u-PA基因的表达,并降低MMP-2、MMP-9活性,从而抑制胶质瘤细胞侵袭能力。
正由于HGF/c-Met系统在肿瘤发展中所起的重要作用,最近成了新的肿瘤研究热点。本实验把GDM-HGF-Met系统-胶质瘤侵袭生长联系起来,在国内外首次探讨GDM通过抑制HGF-Met系统影响胶质瘤侵袭生长,具有首创性。
Gliomas are the most common tumors of the central nervous system。Due to the extreme infiltrative and invasive property of gliomas, surgery is rarely effective, that is after surgical removal tumours recur predominantly within 1 cm of the resection cavity.Current therapy with surgery, radiation, and chemotherapy rarely, if ever, cures the disease and infrequently prolongs life for more than 1 year.The development of novel treatment strategies is therefore imperative. Hepatocyte growth factor (HGF) is a multifunctional growth factor that is linked to the initiation and/or progression of numerous malignancies, and that is known to be overexpressed in many malignancies including glioma. HGF binding promotes tumor proliferation,migration, invasion, and angiogenesis.Geldanamycin(GDM) is a benzoquinone ansamycin antibiotic. GDM is the most powerful inhibitor screened in all the HGF inhibitors . GDM can inhibiti cell growth and promote cell apoptosis by disrupting of Hsp90 function.
Objective:
1. To illuminate the effect of GDM on the expression level and rule of HGF, c-Met mRNA and protein of human malignant glioma cells. To identify the relationship between GDM and HGF/C-Met.
2.To identify the effect of GDM on the proliferation, cell cycle , apoptosis and invasion of glioma cells.
3. To identify the affect of GDM on the activities and expression of catabolic enzymes in the ECM of glioma cell.
4. To investigate the effect of GDM on the proliferation, apoptosis ang invasion of glioma cells caused by HGF.
5. To investigate the possible mechanism of GDM inhibit glioma invasion.
The research work of this experiment:
1. The expression of HGF protein and effect of behaviors in human glioma cells
Methods:The expression of HGF protein were examined by Western blot methods.The inhibitory rates of growth of glioma cells were examined by MTT essays. The cell apoptosis of glioma cells were examined by Flow cytometry analysis.
Result:
Western blot showed that: HGF protein was expressed at higher level in U87and U251 glioma cells.
MTT: U87and U251 glioma cells dealed with HGF, the cell proliferation was slightly higher than normol groups in 24 h ,while significantly higher in 48 h(P<0.05),if the time was prolonged to 72 h , the stimulation was slightly weaker.
Flow cytometry analysis : U87and U251 glioma cells were dealed with HGF, the percent of apoptosis was significantly lower than normal groups.
2. The effect of GDM in glioma behaviors and correlated with HGF
Methods: The inhibitory rates of growth of glioma cells were examined by MTT essays. The cell cycle and apoptosis of glioma cells were examined by Flow cytometry analysis. Transwell chamber was used to observe glioma cells invasion ability.
Result:
MTT showed that :The OD value of U87 and U251 glioma cells dealed with GDM that concentrations above 250 nmol/L was lower than normal groups, among, 500 and 1000 nmol/L of U87 glioma cells dealed with GDM especially striking in 48 and 72 h(P<0.05或P<0.01),while1000 nmol/L of U251 glioma cells especially striking (P<0.01) ,they both displayed inhibitory action tendency increasing with the raise GDM concentrations; The OD value of U87 glioma cells dealed with GDM that concentrations above 250 nmol/L was significantly lower than HGF groups(P<0.05或P<0.01), and the OD value of U251 glioma cells dealed with different concentrations GDM was all significantly decreased in 48 and 72 h(P<0.05或P<0.01); The OD value of U87 glioma cells dealed with HGF+GMD was obviously higher than GDM groups in 24 h, and the OD value of U87 glioma cells dealed with HGF+GMD at 500 nmol/L was no statistically significant compared with GDM groups in 48 h, the OD value of U87 glioma cells dealed with HGF+GMD at 50 and 1000nmol/L was both significantly lower than GDM groups in 72 h (P<0.05或P<0.01).While the OD value of U251 glioma cells dealed with GDM at 250~1000 nmol/L was no statistically significant compared with GDM groups in 48 h .
Flow cytometry analysis showed that :The percent of G0/G1 phase and apoptosis of U87 glioma cells dealed with HGF was significantly decreased and the percent of G2/M and S phase significantly increased compared with normal groups in 24 h(P<0.05). The percent of G0/G1 phase was significantly increased and the percent of G2/M phase and apoptosis significantly decreased , the percent of S phase obviously increased compared with normal groups in 24 h(P<0.05). The percent of G2/M phase of U251 glioma cells dealed with GDM at 500 and 1000 nmol/L were significantly higher than normal groups in 48 h(P<0.05) , the percent of G0/G1 and S phase of U251 glioma cells dealed with GDM at four different concentrations was all significantly decreased(P<0.05),but the percent of G2/M phase was significantly increased(P<0.05);The apoptosis rate of U87 and U251 dealed with GDM at four different concentrations was all significantly higher than normal and HGF groups (P<0.05), the apoptosis rate of U87 and U251 dealed with HGF+GDM at 500 and1000 nmol/L was no statistically significant compared with GDM groups.
Transwell chamber invasion experimenta showed that : The invasion ability of U87and U251 glioma cells dealed with HGF was significantly increased compared with normal groups(P<0.05); The numbers of U87 and U251 glioma cells dealed with GDM through the reconstituted basement membrane was significantly lower than normal and HGF groups in 48 h(P<0.05); The numbers of two kinds of glioma cells dealed with HGF+GDM through the reconstituted basement membrane was obviously lower than normal and HGF groups in 48 h(P<0.05),and close to GDM groups.
3. Possible mechanism of GDM inhibit the invasion ability of glioma cells
Methods: The effect of HGF content in glioma dealed with GDM was detected by ELISA method; The effect on expression level of HGF mRNA in glioma dealed with GDM was detected by RT-PCR method ; The effect of c-Met、uPA and MT1-MMP mRNA of glioma cells dealed with GDM was detected with RT-PCR methods;The activities of MMP-2 and MMP-9 of glioma cells were examined by zymogram methods.
Result:
ELISA methods showed that:The HGF content in the supernatant liquid of two kinds of glioma cellsdealed with GDM was significantly lower than normal groups in 48 h(P<0.05).
RT-PCR result : Compared with normal groups ,the expression of HGF mRNA in two kinds of glioma cells dealed with HGF was both obviously increased(P<0.05), the expression of HGF mRNA in two kinds of glioma cells dealed with GDM was both significantly decreased(P<0.05); The expression of HGF mRNA in two kind of glioma cells dealed with HGF+GDM was significantly lower than HGF groups(P<0.05),the expression of HGF mRNA in U251 glioma cells dealed with HGF+GDM was slightly higher than GDM groups,and was no statistically significant,but the expression of HGF mRNA in U87 glioma cells dealed with HGF+GDM was significantly higher than GDM groups(P<0.05); The expression of c-Met,MT1-MMP and u-PA mRNA in two kinds of glioma cells dealed with HGF was obviously increased compared with normal groups(P<0.05), the expression of in GDM groups was obviously decreased compared with normal groups(P<0.05), the expression of three kinds of genes in HGF+GDM groups was significantly decreased compared with HGF groups(P<0.05); The expression of c-Met and MT1-MMP mRNA in U87 glioma cells dealed with HGF+GDM was slightly higher than GDM groups,and was no statistically significant, the expression of u-PA mRNA in U87 glioma cells was significantly increased compared with GDM groups(P<0.05),but the expression of c-Met and MT1-MMP mRNA in U251 glioma cells dealed with HGF+GDM was significantly higher than GDM groups(P<0.05), the expression of u-PA mRNA was no statistically significant compared with GDM groups.
Zymogram methods showed that: The activities of MMP-2 and MMP-9 in U87 and U251 human glioma cells dealed with HGF were significantly increased compared with those of normal group(P<0.05); The activities of MMP-2 and MMP-9 in two kinds of glioma cells dealed with GDM were significantly decreased compared with those of HGF group(P<0.05); The activities of MMP-2 and MMP-9 in two kinds of glioma cells dealed with HGF+GDM were significantly decreased compared with HGF group(P<0.05); The activities of MMP-2 and MMP-9 in U87 glioma cells dealed with HGF+GDM were significantly higher than GDM group compared with GDM group(P<0.05),while the activities of MMP-2 and MMP-9 in U251 glioma cells were no statistically significant compared with GDM groups.
Conclusions:
1. HGF can significantly promote proliferation,inhibit apoptosis and strengthen invasion ability in U87 and U251 glioma cells.
2. GDM can inhibit proliferation with dose-dependence, promote apoptosis,make cell cycle arrest in G2/M phase,and decrease invasion ability in U87 and U251 glioma cells.
3. GDM can partly reverse the proliferation ability caused by HGF , reverse the apoptosis inhibition ability caused by HGF ,and inhibit the invasion ability enhanced by HGF in U87 and U251 glioma cells.
4. HGF can significantly increase the activities of MMP-2 and MMP-9, increase c-Met,MT1-MMP and uPA mRNA expression in U87 and U251 glioma cells, while GDM can greatly decrease HGF protein content and HGF mRNA expression in two kinds of glioma cells , significantly reverse the expression increasing tendency of c-Met,MT1-MMP and u-PA mRNA in two kinds of glioma cells dealed with HGF ,decrease the activities of MMP-2 and MMP-9 of glioma cells.
GDM might inhibit HGF-Met signal pathway, accordingly decrease the expression of MT1-MMP and u-PA mRNA, depress the activities of MMP-2 and MMP-9, inhibit the invasion ability of glioma ultimately.
引文
[1]Yamamoto S,Wakimoto H,Aoyagi M,et al.Modulation of motility and proliferation of glioma cells by hepatocyte growth factor[J].Jpn J Cancer Res,1997, 88(6):564-77.
[2]Abounader R,Laterra J.Scatter factor / hepatocyte growth factor in brain tumor growth and angiogenesis[J].Neuro-oncol,2005,7(4):436-51.
[3]Beckner ME,Chen X,An J,et al.Proteomic characterization of harvested pseudopodia with differential gel electrophoresis and specific antibodies[J].Lab Invest,2005,83(3):316-27.
[4]Brockmann,Papadimitriou A,Brandt M,et al.Glioblastoma and cerebral microvascular endothelial cell migration in response to tumor-associated growth factors[J].Neurosurgery,2003,52(6):1391-9.
[5]Abounader R,Ranganathan S,Lal B,et al.Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression[J].J Natl Cancer Inst,1999,9(18): 1548-56.
[6]Abounader R,Lal B,Luddy C,et al. In vivo targeting of SF/HGF and c-met expression via U1 snRNA/ribozyme inhibits glioma growth and angiogenesis and promotes apoptosis[J].FASEB J,2002,16(1):108-10.
[7]Brockmann,Papadimitriou A,Brandt M,et al.Inhibition of intracerebral glioblastoma growth by local treatment with the scatter factor / hepatocyte growth factor-antagonist NK4[J].Clin Cancer Res,2003,9(12):4578-85.
[8]Zagzag D,Nomura M,Friedlander D R,et a.Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion[ J ].J Cell Physiol,2003,196(2):394-402.
[9]Nomura M,Nomura N,Newcomb E W ,et al.Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells[ J ].J Cell Physiol,2004, 201(3): p. 374-84.
[10]Moolten FL,Bucher NLR.Regeneration of rat liver:transfer of humoral agents by cross circulation[J].Science,1967,158:272-274.
[11]Stoker M,M Perryman.An epithelial scatter factor released by embryo fibroblasts[J].JCell Sci,1985,77:209-23.
[12]Nakamura T . [Molecular characterization of hepatocyte growth factor (HGF)] [J].Seikagaku,1989,61(10):1243-7.
[13]OkigakiM.Biochemistry,1992,31(40):9555.
[14]Cooper CS,Park M,Blair DP,et al. Molecular Cloning of a new transforming gene from a chemically transformed human cell line[J].Nature,1984,311 (6) :29.
[15]Bottaro DP,Rubin JS,Falet to DL,et al.Identification of hepatocyte growth factor receptor as the c-met proto-oncogene product[J].Science,1991,251 (2):802-4.
[16]Wendy M M,Meng,Lun Liu,et al.Immediate earlydetection ofurokinase receptor after partial hepato-ctomy and its implication for initiation of liver regen-eration [J].Hepatology,1995,21(6):1695-1701.
[17]Bussolino F,Direnzo M F,Ziche M ,et al.Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth[J].J Cell Biol,992,119(3):629-641.
[18]Schmidt C,Bladt F,Goedecke S, et al.Scatter factor/hepatocyte growth factor is essential for liver development[J].Nature,1995,373(6516):699-702.
[19]Yamamoto K,Morishita R,Hayashi S,et a1.Contribution of Bcl-2,but not Bcl-xL and Bax,to antiapoptotic actions of hepatocyte growth factor in hypoxia-conditioned human endothelial cells[J].Hypertension,2001,37(5):1341.
[20]Xiao GH,J effers M,Bellacosa A,et al.Anti-apoptotic signaling by hepatocyte growt h factor/ Met via t he phosphatidylinositol 3-kinase/ Akt and mitogen-activated protein kinase pat hways [J].Proc Natl Acad Sci USA,2001,98 (1):247.
[21]Sengupta S,SellersLA,Cindrova T,et al.Cyclooxygenase-2-selective nonsteroidal anti- inflammatory drugs inhibit hepatocyte growth factor/ scatter factor-induced angiogenesis[J].CancerRes,2003,63:835l-8359.
[22]Miyagawa S,SawaY,Fukuda K,et al.Angiogenic gene cell therapy using suicide gene system regulates the effect of angiogenesis in infareted Rat heart[J].Transplantation,2006,81(6):902-907.
[23]Ebens A,Brose K,Leonardo ED,et al.Hepatocyte growth factor/ scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons [J ].Neuron,1996,17(6):1157-1172.
[24]Miyazawa T,Matsumoto K,Ohmichi H.Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor : a novel neurotrophic factor[J].J Cereb Blood Flow Metab,1998,18(4):345-8.
[25]Tsuzuki N,Miyazawa T,Mautsumoto K,et al.Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats[J].Neuro Res,2001, 23(4):417.
[26]Birchmeier C,birchmeier W,Gheraid IE,et al.Met,metastasis,motility and more[J].Nat Rev Mol Cell Biol,2003,4(12):915-925.
[27]Qian C N,guo X,cao B,et al.Met protein expression level correlates with survival in patientswith late-stage nasopharynegeal carcinoma[J].CancerRes,2002, 62(2):589-596.
[28]Chen BK,Ohtsuki Y,Furihata M,et al.Overexpression of c-Met protein in human thyroid tumors correlated with lymph node metastasis and clinicopathologic stage[J ].Pathol Res Pract,1999,195 (6):4272433.
[29]Trorato M,Villari D,Bartolone L,et al.Expression of the hepatocyte growth factor and c-met in normal thyroid ,nonneoplastic,and neoplastic nodules[J].Thyroid,1998,8 (2):1252131.
[30]Perugini RA,McDade TP,Vittimberga FJ Jr,et al.The molecular and cellular biology of pancreatic cancer[J].Crit Rev Eukaryot Gene Expr,1998,8(324):377-393.
[31]Birchmeier C,birchmeier W,Gheraid IE.et al.Met,metastasis,motility and more[J].Nat Rev Mol Cell Bio,l 2003,4(12):915-925.
[32]Maulik G,Kijima T,Ma PC,et al.Modulation of the c-Met/Hepatocyte growth factor pathway in small cell lung cancer [ J ].Clin Cancer Res,2002,8 (2):620-627.
[33]Long LS,Han K,Li M,et al.Met receptor are expression and oncogenic ki-Ras Mutation cooperate to enhance tumorigenicity[J].Mol Cancer Res,2003,1(5):393-401.
[34]Ishiki Y,Ohnishi H,Muto Y,et al.Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo[J].Hepatology,1992,16:1227.
[35]Paranjpe S,Bowen W C,Bell A W,et al.Cell cycle effects resulting from inhibition of hepatocyte growth factor and its receptor c-Met in regenerating rat livers by RNAinterference[J ].Hepatology,2007,45 (6):1471-1477.
[36]Nakopoulou L,Gakiopoulou H,Keramopoulos A,et al.c-Met tyrosine kinase receptor expression is associated with abnormalβ-catenin expression and favourable prognostic factors in invasive breast carcinoma[J ].Histopathology,2000,36 (4):313-325.
[37]Gaggioli C,Deckert M,Robert G,et al.HGF induces fibronectin mat rix synt hesis in melanoma cells t hrough MAP kinase-dependent signaling pat hway and induction of Egr21[J].Oncogene,2005,24 (8):1423-1433.
[38]Monvoisin A,Bisson C,Si Tayeb K,et al.Involvement of matrix metallop- roteinasetype -3 in hepatocyte growth factor induced invasion of human hepatocellular carcinoma cells[J ].Int J Cancer,2002,97 (2):1572162.
[39]Kachra Z,Beaulieu E,Delbecchi L.Expression of matrix metalloproteinases and their inhibitors in human brain tumors[J].Clin Exp Metastasis,1999,17(7):555-66.
[40]Nishimura K,Mat sumiya K,Miura H,et al.Effect s of hepatocyte growt h factor on urokinase-type plasminogen activator (uPA) and uPA receptor in DU145 prostate cancercells[J ].Int J Androl,2003,26 (3):175-179.
[41]Ishizawa K,Kubo H,Yamada M.Hepatocyte growth factor induces angiogenesis in injured lungs through hmobilizing endothelial progenitor cells[J].Biochem Biophys Res Commun.2004,324(l):276-80.
[42]Maulik G,Shrikhande A,KijimaT.Role of the Hepatocyte growth factor receptor,c-Met,in oncogenesis and potential for therapeutic inhibition[J] . Cytokine Growth Factor.Rev2002,13(l):41-59.
[43]Stiver SI.Angiogenesis and it s role in t he behavior ofast rocytic brain tumors [J ].Front Biosci,2004,9 (9):3105-3123.
[44]Dong G,Chen Z,Li ZY,et al.Hepatocyte growth factorPscatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma[J ].Cancer Res,2001,61 (15):5911-5918.
[45]Fan S,Gao M,Meng Q,et al.Role of NF-kB signaling in hepatocyte growth,factor/scatter factor-rmediated cell protection[J].Oncogene,2005,24:1749-1766.
[46]Nakagmai N,Morishita R,Yamamoto K,et al.Mitogenic and Antiapoptotic Actions ofHepatocyte Growth Through ERK,STAT3,andAkt in Endothelial Cells[J].Hypertension,2001,2:581-586.
[47]Marte BM,Downward J.PKB/Akt:connecting phosphoinositide3-kinase to cellSurvival and beyond[J].Trends Biochem Sci,1997,22:355-358.
[48]Datta SR,Dudek H,Tao X,et al.Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery[J].Cell,1997,91:231-241.
[49]Bardelli A,Longati P,AlberoD,et al.HGF receptor associates with the anti-apoptotic protein BAG-1 and prervent cell death [J].EMBOJ,1996,15:6205-6212.
[50]Cardone MH,Roy N,Stennicke HR,et al.Regulation of cell death protease caspase-9 by phosphorylation[J].Science,1998,282:1318-1321.
[51]Asselin E,Mills GB,Tsang BK.XIAP regulates Akt activity and caspase-3- dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells[J].Cancer Res,2001,61:1862–1868.
[52]Datta SR,Dudek H,Tao X,et al.Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery[J].Cell,1997,91:231-241.
[53]Brunet A,Bonni A,Zigmond MJ,et al.Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor[J].Cell,1999,96:857-868.
[54]Zhou H,Li XM,Meinkoth J,et al.Akt regulates cell survival and apoptosis at a postmitochondrial level[J].J Cell Biol,2000,151:483–494.
[55]Zhang R,Luo R,Miao R,et al.Hsp90-Akt phosphorylates ASK-1 and ASK-1mediated apoptosis[J].Oncogene,2005,24(24):3954-3963.
[56]Jeong SJ,Pise-Masison CA,Radonovich MF,et al.Activated AKT regulates NF-kappaB activation,p53 inhibition and cell survival in HTLV-1-transformed cells[J].Oncoge- ne,2005,24:6719-6728.
[57]Laterra J,Nam M,Rosen E,et al.Scatter factor / hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo[J].Lab Invest,1997,76(4):565-77.
[58]Kermorgant S,Zicha D,Parker P J.PKC controls HGF-dependent c-Met traffic,signalling and cell migration[J ].EMBO J,2004,23 (19):3721-3734.
[59]Wen J,Matsumoto K,Taniura N,et al.Inhibition of colon cancer growth and metastasis by NK4 gene repetitive delivery in mice[J ].Biochem Biophys Res Commun,2007,358(1):117-123.
[60]Purin,Khramtsov A,Ahmed S,et al.A selective small molecule inhibitor of c-Met,PHA665752 , inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts[ J].Cancer Res,2007,67(8):3529-3534.
[61]Ma P C,Jagadeeswaran R,Jagadeesh S,et al.Functional expression and mutation of c-Met and its therapeutic inhibiton with SU11274 and small interfering RNA in Non-Small Cell LungCancer[J].CancerRes,2005,65(4):1479-1488.
[62]MorottiA,Mila S,Accornero P,et al.K252a inhibits the oncogenic p roperties of Met, the HGF recep tor [ J ].Oncogene,2002,21(32):4885– 93.
[63]Zou H Y,Li Q,Lee J H,et al.An orally available small molecule inhibitor of c-Met,PF22341066,exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms[J ].Cancer Res,2007,67 (9):4408-4417.
[64]Cassinelli G,Lanzi C,Petrangolini G,et al.Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1 [ J ].Mol Cancer Ther,2006,5 (9):2388-2397.
[65]Martens T,Schmidtn O,Eckerich C,et al.A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo[J].Clin CancerRes,2006,12(20):6144-6152.
[66]Dharmawardana PG,Peruzzib,Giubellinoa,et al.Molecular targeting of growth factor receptor-bound 2 (Grb2) as ananti-cancer strategy[J].AnticancerDrugs,2006, 17(1):13-20.
[67]Chu S H,Zhu Z A,Yuan X H,et al.In vitro and in vivo potentiating the cytotoxic effect of radiation on human U 251 gliomas by the c2Met antisense oligodeoxynucleotides [J ].JNeurooncol,2006,80 (2):143-149.
[68]Chu SH,Zhang H,Ma Y B,et al.c-Met antisense oligode oxynucleotides as a novel therapeutic agent forglioma:in vitro andin vivo studies of uptake,effects,and toxicity[ J].J Surg Res,2007,141(2),284-288.
[69]Sawada K,Radjabia R,Shinomiyan,et al.C-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion[J].CancerRes,2007,67(4):1670-1679. [70Cao B,Su Y,Oskarsson M,et al.Neutralizing monoclonal antibodies to hepatocyte growthfactor/scatter factor (HGF/SF) display antitumor activity in animalmodes[J].ProcN- atlAcad Sci USA,2001,98(13):7443-7448.
[71]Bedin M,Gaben AM,Saucier C,et al.Geldanamycin,an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest[J].Int J Cancer 2004,109:643–652.
[72]Megumi Senju.Naoko.Sueoka.Akemi Sato.Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines[J].J Cancer Res Clin Oncol,2006,132:150–158.
[73]Carcer G.Heat shock protein 90 regulates the metaphase–anaphase transition in a polo-like kinase-dependent manner[J ].Cancer Res,2004,64:5106–5112.
[74]Niikura Y,Ohta S,Vandenbeldt KJ,et al.17-AAG, an Hsp90 inhibitor,causes kinetochore defects:a novel mechanism by which 17-AAG inhibits cell proliferation. [J ].Oncogene,2006,25:4133–4146.
[75]Neckers L.Hsp90 inhibitors as novel cancer chemotherapeutic agents [J].Trends Mol Med,2002,8:55–61.
[76]Hostein I,Robertson D,DiStefano F,et al.Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis[J]. Cancer Res,2001,61:4003–4009.
[77]Nimmanapalli R,O’Bryan E,Bhalla K.Geldanamycin and its analogue 17-allylamino- 17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts[J].Cancer Res,2001,61:1799–1804.
[78]Kim S,Kang J,Hu W,et al.Geldanamycin decreases Raf-1 and Akt levels and induces apoptosis in neuroblastomas[J].Int J Cancer,2003,103:352–359.
[79]Georgakis G V,Li Y,Rassidakis G Z,et al.Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin's lymphoma cells down- regulates Akt kinase,dephosphorylates extracellular signal-regulated kinase,and induces cell cycle arrest and cell death[J].Clin Cancer Res,2006, 12(2):584-90.
[80]Webb C,PHose C,DKoochekpour S,et al.The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasminproteolytic network[J].Cancer Res,2000,60(2):342-9.
[81]Maulik G,Madhiwala P,Brooks S,et al.Activated c-Met signals through PI3K with dramatic effects on cytoskeletal functions in small cell lung cancer[J].J Cell Mol Med,2002,6(4):539-53.
[82]Russell JS,Burgan W,Oswald KA ,et al.Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino- 17-demethoxygeldanamycin:a multitarget approach to radiosensitization[J].Clin Cancer Res,2003,9:3749–3755.
[83]Gupta AK,Cerniglia GJ,Mick R,et al.Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3 K using LY294002[J].Int J Radiat Oncol Biol Phys,2003,56:846–853.
[84]Pietras RJ,Poen JC,Gallardo D,et al.Monoclonal antibody to HER-2/neu receptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene[J].Cancer Res,1999,59:1347-1355.
[85]Lee JM,Bernstein A.P53 mutations increase resistance to ionizing radiation[J].Proc Natl Acad Sci USA,1993,90(12):5742-5746.
[86]李霞,邓华瑜,陈黎.GA对乳腺癌MDA-MB-435s细胞端粒酶活性的影响[J].重庆医科大学学报,2006,05.
[87]Lin K,Rockliffe N,Johnson G G.Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells[J].Oncogene,2008,27(17):2445-55.
[88]Shintani S,Zhang T,Aslam A,et al.P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines[J].Int J Oncol,2006,29(5):1111-7.
[89]Nimmanapalli R,O'Bryan E,Kuhn D,et al.Regulation of 17-AAG-induced apoptosis: role of Bcl-2,Bcl-XL,and Bax downstream of 17-AAG-mediated down-regulation of Akt,Raf-1,and Src kinases[J].Blood,2003,102(1):269-75.
[90]Georgakis G V,Li Y,Younes A.The heat shock protein 90 inhibitor 17-AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt,Bid and activating caspase 9[J].Br J Haematol, 2006,135(1):68-71.
[91]Liao ZY,SH Zhang,YS Zhen.Synergistic effects of geldanamycin and antitumor drugs[ J ].Yao Xue Xue Bao,2001,36(8):569-75.
[92]Bagatell R,Beliakoff J,David C L,et al.Hsp90 inhibitors deplete key anti-apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin[ J ].Int J Cancer,2005,113(2):179-88.
[93]Solar P,Horvath V,Kleban J,et al.Hsp90 inhibitor geldanamycin increases the sensitivity of resistant ovarian adenocarcinoma cell line A2780cis to cisplatin[ J ].Neoplasma,2007,54(2):127-30.
[94]Kamal A,Thao L,Sensintaffar J,et al.A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors[ J ].Nature,2003,425(6956): 407-10.
[95]Mandler R,Kobayashi H,Davis M Y,et al.Modifications in synthesis strategy improve the yield and efficacy of geldanamycin-herceptin immunoconjugates. Bioconjug Chem.2002,13(4):786-91.
[96]EgorinMJ,Zuhowski EG,RosenDM,et al.Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) in CD2F1 mice1[ J ].200l,47(4):291-302.
[97]Braga-Basaria M,Hardy E,Gottfried R,et al.17-Allylamino- 17-demethoxygelda- namycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels[ J ].J Clin Endocrinol Metab,2004,89(6):2982-8.
[98]Blagosklonny MV.p53 from complexity to simplicity:mutant p53 stabilization, gain-of-function,and dominant-negative effect[ J ].FASEB J,2000,14(13): 1901-7.
[99]Clarke PA,Hostein I,Banerji U,et al.Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17- demethoxy- geldanamycin,an inhibitor of the hsp90 molecular chaperone[ J ].Oncogene,2000,19(36):4125-33.
[100]Xu W,Mimnaugh E,Rosser M F,et al.Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90[ J ].J Biol Chem,2001,276(5):3702-8.
[101]Ochel HJ,Schulte TW,Nguyen P,et al.The benzoquinone ansamycin geldanamycinstimulates p roteolytic degradation of focal adhesion kinase[ J ].Mol GenetMetab,1999,66 (1) :24-30.
[102]Yu W,Rao Q,Wang M,et al.The Hsp90 inhibitor 17-allylamide-17- demethoxyge- ldanamycin induces apoptosis and differentiation of Kasumi-1 harboring the Asn822Lys KIT mutation and down-regulates KIT protein level[ J ].Leuk Res,2006,30(5):575-82.
[103]Wang K,Ma Q Y,Ren Y,et al.[Geldanamycin inhibits proliferation and motility of human HER2/neu-overexpressing breast cancer cell line SKBr3] [ J ].Nan Fang Yi Ke Da Xue Xue Bao,2007,27(10):1480-4.
[104]George P,Bali P,Cohen P,et al.Cotreatment with 17-allylamino- demethoxygeld- anamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3[ J ].Cancer Res,2004,64(10):3645-52.
[105]George P,Bali P,Annavarapu S,et al.Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3[ J ].Blood,2005, 105(4):1768-76.
[106]Beliakoff J,Bagatell R,Paine-Murrieta G,et al.Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors[ J ].Clin Cancer Res,2003,9(13):4961-71.
[107]Radujkovic A,Schad M,Topaly J,et al.Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL--Inhibition of P-glycoprotein function by 17-AAG[ J ].Leukemia,2005,19(7):1198-206.
[108]Workman P.Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone[ J ].Cancer Lett,2004,206(2):149-57.
[109]Price JT,Quinn J M,Sims N A,et al.The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin,enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line[ J ].Cancer Res,2005, 65(11):4929-38.
[110]Schwock J,Pham N A,Cao M P,et al.Efficacy of Hsp90 inhibition for induction of apoptosis and inhibition of growth in cervical carcinoma cells in vitro and in vivo[ J ].Cancer Chemother Pharmacol,2008,61(4):669-81.
[111]高志军,赵春临,乔军波.HSP90抑制剂17-DMAG对胃癌细胞株SGC-7901增殖及凋亡的影响[ J ].世界华人消化杂志,2008,16(29):3269-3273.
[112]Tsutsumi S,Neckers L.Extracellular heat shock protein 90:a role for a molecular chaperone in cell motility and cancer metastasis[ J ].Cancer Sci,2007, 98:1536-1539.
[113]Johnson A J,Wagner A J,Cheney C M,et al.Rituximab and 17-allylamino-17- demethoxygeldanamycin induce synergistic apoptosis in B-cell chronic lymphocytic leukaemia[ J ].Br J Haematol,2007,139(5):837-44.
[114]Strik HM,Weller M,Frank B,et al.Heat shock protein expression in human gliomas[ J ].Anticancer Res ,2000,20:4457–62.
[115]Ferrarini M,Heltai S,Zocchi MR,et al.Unusual expression and localization of heat-shock proteins in human tumor cells[ J ].Int J Cancer,1992,51:613–9.
[116]Zagzag D,Nomura M,Friedlander DR,et al.Geldanamycin inhibits migration ofglioma cells in vitro:a potential role for hypoxia-induciblefactor (HIF-1alpha) in glioma cell invasion [ J ].J Cell Physiol,2003,196:394–402.
[117]Yang J,Yang J M,Iannone M,et al.Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin[ J ].Cancer Res,2001,61(10):4010-6.
[118]Nomura N,Nomura M,Newcomb E W, et al.Geldanamycin induces G2 arrest in U87MG glioblastoma cells through downregulation of Cdc2 and cyclin B1[J].Biochem Pharmacol,2007,73(10):1528-36.
[119]Nurse P.Universal control mechanism regulating onset of M-phase[J].Nature, 1990,344:503–8.
[120]Nishiyama A,Tachibana K,Igarashi Y,et al.A nonproteolytic function of the proteasome is required for the dissociation of Cdc2 and cyclin B at the end of M phase[J].Genes Dev 2000,14:2344–57.
[121]Whitesell L, Sutphin P, An WG, et al. Geldanamycin-stimulated destabilization of mutated p53 is mediated by the proteasome in vivo[J]. Oncogene 1997;14:2809–16.
[122]Ling YH,Liebes L,Jiang JD,et al.Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines[J].Clin Cancer Res,2003,9:1145–1154.
[123]Nabha SM,Mohammad RM,Dandashi MH,et al.Combretastatin-A4 prodrug inducesmitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspaseactivation and poly (ADPribose) polymerase cleavage[J].Clin Cancer Res.2002.8:2735–2741.
[124]Ruth AC，Roninson IB．Effects of the multidrug transporter Pglycoprotein on cellularresponses to ionizing radiation[J]．Cancer Res，2000，60：2576–2578．
[125]Premkumar DR，Arnold B，Jane E P，et al．Synergistic interaction between 17-AAG andphosphatidylinositol 3-kinase inhibition in human malignant glioma cells[ J ]．MolCarcinog，2006，45(1)：47-59．
[126]Eustace BK，Sakurai T，Stewart JK，et al．Functional proteomic screens reveal anessential extracellular role forhsp90 in cancer cell invasiveness[ J ]．Nat Cell Biol，2004，6：507–514．
[127]Elizabeth W，Newcomba，Yevgeniy Lukyanova，et al．The geldanamycin analogue17-allylamino-17-demethoxygeldanamycin inhibits the growth of GL261 glioma cells invitro and in vivo[ J ]．Anticancer Drugs，2007，18(8)：875-882．
[128]Xie Q，Gao CF，Shinomiya N．Geldanamycins exquisitely inhibit HGF/SF mediated tumor cell invasion[J ]．Oncogene，2005，24：3697 707．
[129]Zhang H，Chung D，Yang Y-C，et al．Identification of new biomarkers for clinical trialsof Hsp90 inhibitors．Mol Cancer Ther，2006，5：1256–1264．
[130]Yung WK，Prados MD，Yaya-Tur R，et al．Multicenter phase trial of temozolomideⅡde inpatient s with anaplastic astrocytoma or anaplastic oligoast rectum at first relapse：Temporal Brain Tumor Group〔J〕．J Clint Once，1999，17 (9)：2762-2771．
[131]Laterra J，Rosen E，Nam M，et al．Scatter factor/hepatocyte growth factor expressionenhances human glioblastoma tumorigenicity and growth[J]．1997，235(3)：743-7．
[132]Laterra J．Scatter factor/hepatocyte growth factor gene transfer enhances glioma growthand angiogenesis in vivo[J]．Lab Invest，1997，76(4)：565-77．
[133]Martens T，Schmidt N O，Eckerich C，et al．A novel one-armed anti-c-Met antibodyinhibits glioblastoma growth in vivo [J]．Clint Caceres，2006，12(20)：6144-6152．
[134]Kamala A，Thai L，Sensintaffar J，et al．A high-affinity conformation of Hsp90 conferstumour selectivity on Hsp90 inhibitors [J]．Nature，2003，425(6956)：407-10．
[135]Hollingshead M，Alley M，Burger A M，et al．In vivo antitumor efficacy of17-DMAG(17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride),a water-soluble geldanamycin derivative Cancer Chemother Pharmacol [J].2005,56(2):115-25.
[136]Hermisson M,Strik H,Rieger J,et al. Expression and functional activity of heat shock proteins in human glioblastoma multiforme[J].Neurology,2000,54:1357–65.
[137]Strik HM,Weller M,Frank B,et al.Heat shock protein expression in human gliomas[J].Anticancer Res,2000,20:4457–62.
[138]Tokunou M,Niki T,Eguchi K,et al.c - MET exp ression in myofibro-blasts: Role in autocrine activation and p rognostic significance in lung adenocarcinoma[ J ].Am J Pathol,2001,158 (4):1451– 1463.
[139]楚胜华,袁先厚.肝细胞因子及其受体mRNA在星形细胞瘤中的表达[ J ].肿瘤,2005,3 (25):173-176.
[140]Schmidt NO,Westphal M,Hagel C,et al.Levels of vascular endothelial growth factor,hepatocyte growth factor/scatter factor,and basic fibroblast growth factor in human gliomas and their relation to angiogenesis[J].Int J Cancer,1999,84(1):10-8.
[141]Lamszus K,Schmidt NO,Jin L,et al.Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells[J].Int J Cancer ,1998,75:19- 28.
[142]Lee HS,Huang AM,Huang GT,et al.Hepaticyte growth factor stimulates the growth and activates mitogen - activated protein kinase in human heptoma cells[J ].J Biomed Sci,1998,5 (3):180 -184.
[143]Hoffmann KM,Tapia JA,Jensen RT.Activation of Gab1 in pancreatic acinar cells: effects ofgastrointestinalgrowth factors/hormones on stimulation, phosphospecific phosphorylation,translocation and interactionwith downstream signalingmolecules[J]. CellSignal,2006, 18(7):942-954.
[144]Park J W,Yeh MW,Wong M G.The heat shock protein 90-binding geldanamycin inhibits cancer cell proliferation, down-regulates oncoproteins, and inhibits epidermal growth factor-induced invasion in thyroid cancer cell lines [J ].J Clin Endocrinol Metab.2003,88(7):3346-53.
[145]Ewa Leskoa,Jolanta Gozdzika,Jacek Kijowskia.HSP90 antagonist, geldanamycin, inhibits proliferation,induces apoptosis and blocks migration of rhabdomyosarcomacells in vitro and seeding into bone marrow in vivo[J].Anti-Cancer Drugs. 2007,18:1173–1181.
[146]Walter K.A,Hossain, M.A,Luddy C.Scatter factor/hepatocyte growth factor stimulation of glio-blastoma cell cycle progression through G(1) is c-Myc dependent, and independent of p27 suppression, cdk2 activation, or E2F1-dependent transcription.Mol. Cell. Biol,2002,22:2703–2715.
[147]Bedin M,Gaben AM,Saucier C,et al.Geldanamycin,an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest[J].Int J Cancer 2004,109:643–652.
[148]Megumi Senju.Naoko.Sueoka.Akemi Sato.Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines[J].J Cancer Res Clin Oncol,2006,132:150–158.
[149]Savill J.Apoptosis in disease[J].Eru J Clin Invest,1994,24:715-719.
[150]Abounader R,Lal B,Luddy C,et al.In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis[J].FASEB J,2002,16:108-10.
[151]Bowers DC,Fan S,Walter KA,et al.Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways[J].Cancer Res,2000,60;4277-83.
[152]Fan S,MaYX,Wang JA,et al.The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′kinase[J].Oncogene ,2000,19:2212-23.
[153]Bowers DC,Fan S,Walter KA,et al.Scatter factor/ hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase-and AKT-de-pendent pathways[J ].Cancer Res,2000,60(15):4277 -4283.
[154]Stetler-StevensonW G,Hew itt R,Corcoran M.Matrix metallo-proteinases and tumo r invasion:F rom co rrelation and causality to clinic [J ].Sem in Cancer Biol, 1996,7:147- 154.
[155]Tonn JC,Kerkau S,Hanke A,et al.Effect of synthetic matrix-metallo-proteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in v itro[J ].Int J Cancer,1999,80:764- 772.
[156]Sun YN,Yang BF,Liu M,et al.The experimental investigation of the invasion and growth of laryngeal cancer by matrix metalloproteinase-2 andmatrix metalloproteinase-9 gene silence together[J].Zhong hua Yi Xue Za Zhi,2008,88(1):36-9.
[157]Tryggvason K,Hoyhtya M,Salo T.P reteolytic degration of extracellulor matrix in tumo r invasion [J ].Biochim Biophys Acta,1987,907:191- 217.
[158]Adair JC,Baldwin N,Kornfeld M ,et al.Radiation-induced blood-brain barrier damage in astrocytoma:Relation to elevated gelatinase B and urok inase [ J ].J Neu rooncol,1999,44:283- 289.
[159]Yano H,Hara A,Murase S,et al.Expression of hepatocyte growth factor and matrix metalloproteinase-2 in human glioma [J ].Brain Tumor Pathol,2001,18(1):7-12.
[160]Kondraganati S,Mohnama S,Chintala SK,etal.Selective suppression of Matrix metalloproteinase-9 in human glioblastoma cells by antisense gene transfer impairs glioblastom cell invasion [J ].Cancer Res,2000 ,15:60(26):6851-6855.
[161]Radotra B,McCormick D,Crockard A.CD44 plays a role in adhesiveinteractions between glioma cells and extracellular matrix components[J] . Neuropathol Appl Neurobiol,1994,20(4):399-405.
[162]廖志勇,甄永苏.热休克蛋白90抑制剂geldanamycin的抗肿瘤作用研究进展[J ].药学学报,2001,36 (9):569.
[163]廖志勇,张胜华,甄永苏.Geldanamycin增强顺铂的抗肿瘤作用[J ].癌症,2000,19 (8):731.
[164]Seiki M.Membrane-type matrix metalloproteinases [J ].APMIS,1999, 107(1):137.
[165]Hamasuna R,Kataoka H,Moriyama T.Regulation of matrix metalloproteinase-2 (MMP-2) by hepatocyte growth factor/scatter factor (HGF/SF) in human glioma cells: HGF/SF enhances MMP-2 expression and activation accompanying up-regulation of membrane type-1 MMP [J ].Int J Cancer,1999,82(2):274-81.
[166]Murphy G,Gavrilovic J.Proteolysis and cell migration:creating a path [J ] ?Curl Opin Cell Biol,1999,11:614-621.
[167]Yamamoto M,Sawaya R,Mohanam S,et al.Expression and localization ofurokinase-type plasminogen activator in human astrocytomas in vivo [J ].Cancer Res,1994,54:3656-3661.
[168]Landau B,Kwaan H,Verrusio E,et al.Elevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 in malignant human brain tumors[J ].Cancer Res,1994,54:1105.
[169]Naldini L,Vigna E,Bardelli A,et al.Biological activation of pr o-HGF(hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction[J ].J Biol Chem,1995,270:603-11.