Palmieri D, Astigiano S, Barbieri O, Ferrari N, Marchisio S, Ulivi V, Volta C, Manduca P
Laboratorio di Genetica, Dip. Biologia, Università di Genova, Italy.
Exp Cell Res. 2008 Jul 1;314(11-12):2289-98. doi: 10.1016/j.yexcr.2008.04.016. Epub 2008 May 10.
The COOH-terminal fragment of procollagen type I (C3) is produced in tissues with high synthesis of collagen I, such as in breast cancer stroma and in bone. We previously demonstrated that C3 is chemoattractant for breast carcinoma and endothelial cells, and that in tumor cells it induces expression and activation of metalloproteinases (MMP) -2 and -9. Here we demonstrate that C3 induces expression of vascular-endothelial growth factor (VEGF) and of CXCR4, the receptor of the CXCL12/SDF-1 chemokine, in MDA MB 231 breast cancer cells. We show that the changes in gene expression and motility induced by C3 occur in a timely succession and are mediated by multiple and different signaling pathways. C3 induces early phosphorylation of p38/MAPK. Induction of VEGF expression requires continual activity of p38/MAPK and of Protein Kinase C (PKC). Pro-MMP-2 and -9 are induced through a signaling pathway involving G0alpha.i protein, and cell migration requires the activity of a combination of these signaling pathways. Our results suggest that C3 acts as a stromal-derived, cancer-promoting agent active in inducing the migratory phenotype and the survival of cancer cells and determining timely changes in their gene expression that establish conditions promoting tumor angiogenesis and invasion.
I型前胶原的羧基末端片段（C3）在I型胶原合成旺盛的组织中产生，如乳腺癌基质和骨骼中。我们之前证明C3对乳腺癌细胞和内皮细胞具有趋化作用，并且在肿瘤细胞中它能诱导金属蛋白酶（MMP）-2和-9的表达及激活。在此我们证明C3能诱导MDA MB 231乳腺癌细胞中血管内皮生长因子（VEGF）以及CXCL12/SDF-1趋化因子的受体CXCR4的表达。我们发现C3诱导的基因表达和迁移变化是按时间顺序相继发生的，且由多种不同的信号通路介导。C3诱导p38/丝裂原活化蛋白激酶（MAPK）的早期磷酸化。VEGF表达的诱导需要p38/MAPK和蛋白激酶C（PKC）的持续活性。前MMP-2和-9是通过涉及G0α.i蛋白的信号通路诱导产生的，细胞迁移需要这些信号通路组合的活性。我们的结果表明，C3作为一种源自基质的促癌因子，在诱导癌细胞的迁移表型和存活以及决定其基因表达的适时变化从而建立促进肿瘤血管生成和侵袭的条件方面具有活性。
