SDF-1/CXCR4轴激活ERK1/2信号通路在卵巢癌转移中的作用
摘要
目的探讨SDF-1/CXCR4轴通过激活ERK1/2信号通路对卵巢癌转移的影响。
方法采用激光共聚焦显微镜检测加SDF-1α前后细胞内钙离子的波动,Western blot法分析SDF-1α对SKOV3细胞ERK1/2磷酸化的影响,分别通过黏附实验和明胶酶谱法检测SDF-1/CXCR4对卵巢癌细胞SKOV3黏附能力和基质金属蛋白酶(MMP)的分泌的影响。
结果SDF-1α诱导了卵巢癌细胞胞内钙的迅速动员,钙波测定表明加入SDF-1α20秒钙离子开始升高,200秒达高峰;SDF-1α也诱导了ERK1/2的快速磷酸化,western blot实验表明加入SDF-1α5min ERK1/2开始出现磷酸化,5min至30min磷酸化程度逐渐增强,表明SDF-1α与卵巢癌细胞表面CXCR4的相互作用可以活化对肿瘤细胞增殖和转移有重要作用的ERK1/2信号通路,SDF-1α增加了卵巢癌细胞黏附于纤维连接蛋白(FN)和Ⅳ型胶原(COL)的能力,加入ERK1/2信号通路的抑制剂PD98059后,降低了SDF-1α促进卵巢癌细胞黏附于细胞外基质蛋白(ECM)的作用, SDF-1α也促进了卵巢癌细胞分泌活性的MMP-2和MMP-9。
结论卵巢癌侵袭和转移在一定程度上依赖于SDF-1/CXCR4的相互作用,SDF-1增加卵巢癌细胞株SKOV3的侵袭力和转移力,这些作用至少部分是通过激活ERK1/2信号通路使细胞的黏附能力增加和促进MMP-2、MMP-9的分泌实现的。提示通过对MAPK信号通路的降调节可能发挥抑制卵巢癌的转移的作用。
Objective: To explore the role of SDF-1/CXCR4 in mediating the Metastasis of ovarian cancer cell through activation of ERK1/2 signal pathway.
Methods:Intracellular calcium mobilization was detected with a Laser Scanning Confocal Fluorescence Microscopy. Western blotting was used to detect the phospharylation of ERK1/2 in SKOV3 cells after exposure to SDF-1α. Adhesion capability and matrix metalloproteinase(MMP) activity of ovarian cancer cells after exposure to SDF-1αwere mesured by adhesion assay and gelatin zymography.
Results:SDF-1αinduced rapid intracellular calcium mobilization in a metastatic ovarian cancer cell line SKOV3. Calcium mobilization assay show that Calcium flux rapidly increased after 20 second of exposure to SDF-1αand the peak time of Calcium flux was 200 second. SDF-1αalso induced rapid phosphorylation of ERK-1/2. Western blotting showed that ERK-1/2 was phosphorylated in SKOV3 cells after 5 minutes of exposure to SDF-1α. There was gradually increase in the ratio of phospho-ERK at 0 minute to at 30 minutes.SDF-1/CXCR4 interaction can activate ERK signal pathway that plays an important role in regulating cell proliferation and migration. Ovarian cancer cell adhesion to fibronectin and collagen IV, increased after SDF-1αtreatment, while the addition of an inhibitor of ERK-1/2 signaling, PD98059, reduced the effects of SDF-1αSDF-1αalso increased the active MMP-2 and MMP-9 secreted.
Conclusion:The SDF-1/CXCR4 axis plays a critical role in the migration and metastasis of human ovarian cancer by regulating the adhesion capability and MMP-2 and MMP-9 activity through ERK1/2 signal pathway.Together, these studies reveal important cellular and molecular mechanisms of SDF-1/CXCR4-mediated ovarian cancer migration and invasion and investigate the ways to block this process by inhabiting the MAPK signaling transduction pathway.
方法采用激光共聚焦显微镜检测加SDF-1α前后细胞内钙离子的波动,Western blot法分析SDF-1α对SKOV3细胞ERK1/2磷酸化的影响,分别通过黏附实验和明胶酶谱法检测SDF-1/CXCR4对卵巢癌细胞SKOV3黏附能力和基质金属蛋白酶(MMP)的分泌的影响。
结果SDF-1α诱导了卵巢癌细胞胞内钙的迅速动员,钙波测定表明加入SDF-1α20秒钙离子开始升高,200秒达高峰;SDF-1α也诱导了ERK1/2的快速磷酸化,western blot实验表明加入SDF-1α5min ERK1/2开始出现磷酸化,5min至30min磷酸化程度逐渐增强,表明SDF-1α与卵巢癌细胞表面CXCR4的相互作用可以活化对肿瘤细胞增殖和转移有重要作用的ERK1/2信号通路,SDF-1α增加了卵巢癌细胞黏附于纤维连接蛋白(FN)和Ⅳ型胶原(COL)的能力,加入ERK1/2信号通路的抑制剂PD98059后,降低了SDF-1α促进卵巢癌细胞黏附于细胞外基质蛋白(ECM)的作用, SDF-1α也促进了卵巢癌细胞分泌活性的MMP-2和MMP-9。
结论卵巢癌侵袭和转移在一定程度上依赖于SDF-1/CXCR4的相互作用,SDF-1增加卵巢癌细胞株SKOV3的侵袭力和转移力,这些作用至少部分是通过激活ERK1/2信号通路使细胞的黏附能力增加和促进MMP-2、MMP-9的分泌实现的。提示通过对MAPK信号通路的降调节可能发挥抑制卵巢癌的转移的作用。
Objective: To explore the role of SDF-1/CXCR4 in mediating the Metastasis of ovarian cancer cell through activation of ERK1/2 signal pathway.
Methods:Intracellular calcium mobilization was detected with a Laser Scanning Confocal Fluorescence Microscopy. Western blotting was used to detect the phospharylation of ERK1/2 in SKOV3 cells after exposure to SDF-1α. Adhesion capability and matrix metalloproteinase(MMP) activity of ovarian cancer cells after exposure to SDF-1αwere mesured by adhesion assay and gelatin zymography.
Results:SDF-1αinduced rapid intracellular calcium mobilization in a metastatic ovarian cancer cell line SKOV3. Calcium mobilization assay show that Calcium flux rapidly increased after 20 second of exposure to SDF-1αand the peak time of Calcium flux was 200 second. SDF-1αalso induced rapid phosphorylation of ERK-1/2. Western blotting showed that ERK-1/2 was phosphorylated in SKOV3 cells after 5 minutes of exposure to SDF-1α. There was gradually increase in the ratio of phospho-ERK at 0 minute to at 30 minutes.SDF-1/CXCR4 interaction can activate ERK signal pathway that plays an important role in regulating cell proliferation and migration. Ovarian cancer cell adhesion to fibronectin and collagen IV, increased after SDF-1αtreatment, while the addition of an inhibitor of ERK-1/2 signaling, PD98059, reduced the effects of SDF-1αSDF-1αalso increased the active MMP-2 and MMP-9 secreted.
Conclusion:The SDF-1/CXCR4 axis plays a critical role in the migration and metastasis of human ovarian cancer by regulating the adhesion capability and MMP-2 and MMP-9 activity through ERK1/2 signal pathway.Together, these studies reveal important cellular and molecular mechanisms of SDF-1/CXCR4-mediated ovarian cancer migration and invasion and investigate the ways to block this process by inhabiting the MAPK signaling transduction pathway.
引文
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3 Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N,Imamura M. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res, 2000, 6:3530-5.
4 Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP,Ben-Baruch A. A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol, 2001, 167:4747-57.
5 Wehler T, Wolfert F, Schimanski CC, Gockel I, Herr W, Biesterfeld S, Seifert JK, Adwan H, Berger MR, Junginger T, Galle PR,Moehler M. Strong expression of chemokine receptor CXCR4 by pancreatic cancer correlates with advanced disease. Oncol Rep, 2006, 16:1159-64.
6 Crump MP, Gong JH, Loetscher P, Rajarathnam K, Amara A, Arenzana-Seisdedos F, Virelizier JL, Baggiolini M, Sykes BD,Clark-Lewis I. Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J, 1997, 16:6996-7007.
7 Balkwill F. Chemokine biology in cancer. Semin Immunol, 2003, 15:49-55.
8 Nicolson GL. Paracrine and autocrine growth mechanisms in tumor metastasis tospecific sites with particular emphasis on brain and lung metastasis. Cancer Metastasis Rev, 1993, 12:325-43.
9李芳,朱怀仕,马丁.趋化因子受体及配体在卵巢癌细胞迁移中的作用.癌症, 2005, 24:23-27.
10 Russell S. Taichman, Carlton Cooper, Evan T. Keller, Kenneth J. Pienta, Norton S. Taichman, and Laurie K. McCauley. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res, 2002, 62:1832–37.
11 Engl T, Relja B, Marian D, Blumenberg C, Muller I, Beecken WD, Jones J, Ringel EM, Bereiter-Hahn J, Jonas D,Blaheta RA. CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia, 2006, 8:290-301.
12 Scotton CJ, Wilson JL, Milliken D, Stamp G,Balkwill FR. Epithelial cancer cell migration: a role for chemokine receptors?. Cancer Res, 2001, 61:4961-5.
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