骨形成蛋白-2促人肺癌A549细胞株基质金属蛋白酶合成分泌的机制研究(4)
本研究进一步发现,用PI-3激酶抑制剂LY294002或ERK抑制剂U0126预处理A549细胞可抑制BMP-2促MMP-2分泌作用,但p38抑制剂无此作用,提示PI-3激酶和ERK介导了BMP-2促MMP-2分泌作用。用p38抑制剂SB203580和ERK抑制剂U0126预处理A549细胞可抑制BMP-2促MMP-9分泌作用,但PI-3抑制剂无此作用,提示p38和ERK介导了BMP-2促MMP-9分泌作用。本研究结果提示PI3、ERK和p38通过BMP受体介导参与BMP-2对人肺癌A549细胞MMP-2和MMP-9的调节。
BMP-2属于BMP-TGF-β-活化素(activin)-抑制素(inhibin)-抗苗勒管激素(AMH)超家族中的成员,能诱导骨与软骨的生成,对肺组织的发育与生长有促进作用。有研究报道BMP-2蛋白在非小细胞肺癌中表达上调,并且BMP-2蛋白可促进肺癌的生长、转移及血管的形成。但没有关于BMP-2对肺癌细胞MMP的作用及其机制的研究。此为首次关于BMP-2对人肺癌细胞MMP作用机制的研究。
, http://www.100md.com
综上所述,本研究证实 BMP-2可促进人肺癌A549细胞MMP-2和MMP-9分泌;BMPs的天然抑制剂noggin显著拮抗BMP-2促A549细胞MMP-2和MMP-9分泌的作用;PI-3和ERK参与介导BMP-2/BMPR对A549细胞MMP-2调节的信号转导,ERK和P38参与介导BMP-2/BMPR对A549细胞MMP-9调节的信号转导,Smad也可能参与介导BMP-2对A549细胞MMP的调节。本研究结果提示:Noggin可能对防止肺癌的侵袭转移有作用;BMPR-Ⅱ的小分子RNA干扰技术有可能成为新的肺癌分子治疗手段;通过阻断以上信号传导途径从而抑制BMP-2对肺癌细胞MMP-2和MMP-9的促分泌作用可能会成为降低肺癌危害的新方法。
参考文献
[1] Langenfeld EM,Calvano SE,Abou-Nukta F,et al. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis,2003,24(9):1445-1454
, 百拇医药
[2] Langenfeld EM,Langenfeld J. Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res,2004 2(3):141-149
[3] Hogan BL. Bone morphogenetic proteins:multifunctional regulators of vertebrate development. Genes Dev,1996,10:1580-1594
[4] Mehler MF,Mabie PC,Zhang D,et al. Bone morphogenetic proteins in the nervous system. Trends Neurosci,1997,20:309-317
[5] Massague J . TGF-beta signal transduction. Annu Rev Biochem,1998,67:753-791
, 百拇医药
[6] Fire A. Potent and specific genetic interference by double-strand RNA in caenorhabdiris elegans. Nature,1998,391:806-811
[7] Elbashir SM. Duplexes of 21-nucleotide RNAs mediate RNA intenference in culture mammalian cells. Nature,2001,411:494-498
[8] Hong IK,Kim YM,Jeoung DI,et al. Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK,JNK and c-Jun pathways in human melanoma cells. Exp Mol Med,2005,37(3):230-239
, 百拇医药
[9] Kim HS,Luo L,Pflugfelder SC,et al.Doxycycline inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci,2005,46(3):840-848
[10] Luo L,Li DQ,Doshi A,et al.Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci,2004,45(12):4293-4301
[11] Boyd PJ,Doyle J,Gee E,et al. MAPK signaling regulates endothelial cell assembly into networks and expression of MT1-MMP and MMP-2. Am J Physiol Cell Physiol,2005,288(3):C659-668
, 百拇医药
[12] Kim ES,Kim MS,Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK,but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol,2004,25(5):1375-1382
[13] Qiu Q,Yang M,Tsang BK,et al. EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways. Reproduction,2004,128(3):355-363
[14] Kim HS,Kim MH,Jeong M,et al. EGCG blocks tumor promoter-induced MMP-9 expression via suppression of MAPK and AP-1 activation in human gastric AGS cells. Anticancer Res,2004,24(2B):747-753, 百拇医药(唐四元 谢 辉 罗自强)
BMP-2属于BMP-TGF-β-活化素(activin)-抑制素(inhibin)-抗苗勒管激素(AMH)超家族中的成员,能诱导骨与软骨的生成,对肺组织的发育与生长有促进作用。有研究报道BMP-2蛋白在非小细胞肺癌中表达上调,并且BMP-2蛋白可促进肺癌的生长、转移及血管的形成。但没有关于BMP-2对肺癌细胞MMP的作用及其机制的研究。此为首次关于BMP-2对人肺癌细胞MMP作用机制的研究。
, http://www.100md.com
综上所述,本研究证实 BMP-2可促进人肺癌A549细胞MMP-2和MMP-9分泌;BMPs的天然抑制剂noggin显著拮抗BMP-2促A549细胞MMP-2和MMP-9分泌的作用;PI-3和ERK参与介导BMP-2/BMPR对A549细胞MMP-2调节的信号转导,ERK和P38参与介导BMP-2/BMPR对A549细胞MMP-9调节的信号转导,Smad也可能参与介导BMP-2对A549细胞MMP的调节。本研究结果提示:Noggin可能对防止肺癌的侵袭转移有作用;BMPR-Ⅱ的小分子RNA干扰技术有可能成为新的肺癌分子治疗手段;通过阻断以上信号传导途径从而抑制BMP-2对肺癌细胞MMP-2和MMP-9的促分泌作用可能会成为降低肺癌危害的新方法。
参考文献
[1] Langenfeld EM,Calvano SE,Abou-Nukta F,et al. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis,2003,24(9):1445-1454
, 百拇医药
[2] Langenfeld EM,Langenfeld J. Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res,2004 2(3):141-149
[3] Hogan BL. Bone morphogenetic proteins:multifunctional regulators of vertebrate development. Genes Dev,1996,10:1580-1594
[4] Mehler MF,Mabie PC,Zhang D,et al. Bone morphogenetic proteins in the nervous system. Trends Neurosci,1997,20:309-317
[5] Massague J . TGF-beta signal transduction. Annu Rev Biochem,1998,67:753-791
, 百拇医药
[6] Fire A. Potent and specific genetic interference by double-strand RNA in caenorhabdiris elegans. Nature,1998,391:806-811
[7] Elbashir SM. Duplexes of 21-nucleotide RNAs mediate RNA intenference in culture mammalian cells. Nature,2001,411:494-498
[8] Hong IK,Kim YM,Jeoung DI,et al. Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK,JNK and c-Jun pathways in human melanoma cells. Exp Mol Med,2005,37(3):230-239
, 百拇医药
[9] Kim HS,Luo L,Pflugfelder SC,et al.Doxycycline inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci,2005,46(3):840-848
[10] Luo L,Li DQ,Doshi A,et al.Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci,2004,45(12):4293-4301
[11] Boyd PJ,Doyle J,Gee E,et al. MAPK signaling regulates endothelial cell assembly into networks and expression of MT1-MMP and MMP-2. Am J Physiol Cell Physiol,2005,288(3):C659-668
, 百拇医药
[12] Kim ES,Kim MS,Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK,but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol,2004,25(5):1375-1382
[13] Qiu Q,Yang M,Tsang BK,et al. EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways. Reproduction,2004,128(3):355-363
[14] Kim HS,Kim MH,Jeong M,et al. EGCG blocks tumor promoter-induced MMP-9 expression via suppression of MAPK and AP-1 activation in human gastric AGS cells. Anticancer Res,2004,24(2B):747-753, 百拇医药(唐四元 谢 辉 罗自强)