Muscella Antonella, Vetrugno Carla, Marsigliante Santo
Dipartimento di Scienze e Tecnologie Biologiche e Ambientali (Di.S.Te.B.A.), Università del Salento, Lecce, Italy.
Mol Carcinog. 2017 Nov;56(11):2461-2473. doi: 10.1002/mc.22693. Epub 2017 Jul 4.
The relation between the tumor and its microenvironment is one of the most interesting and less understood issues. Recently, we showed a role of CCL20 chemokine in proning the healthy tissue neighboring the tumor to carcinogenesis. Besides, tumor-secreted CCL20 induced proliferation, migration, and EMT of healthy cells. In this context, we have studied here if CCL20 had effects on the migration of cancer cells and the intracellular pathways used in breast epithelial cells in primary culture. Using molecular (siRNA) and pharmacological (inhibitors) techniques, we found multiple signaling kinases to be activated and involved in CCL20-induced tumor breast cell migration. CCL20 provoked a 2.5-fold increase of cell migration and invasion; CCL20 also enhanced MMP- 2 and MMP-9 mRNAs/protein expression and activities. Cell migration and invasiveness due to CCL20 significantly decreased when MMP-2 and MMP-9 were inhibited in CCL20-stimulated cells. CCL20 controlled MMP-2 expression through the JAK2/STAT3 pathway, while the expression of MMP-9 occurred by PKC-α that activated, consequently, c-Src, Akt, and finally NF-kB. These results reveal a role for CCL20 also in tumor breast cell and point to CCL20 as a novel therapeutic target in cancer.
肿瘤与其微环境之间的关系是最有趣但又了解较少的问题之一。最近，我们发现CCL20趋化因子在促使肿瘤邻近的健康组织发生癌变方面发挥作用。此外，肿瘤分泌的CCL20可诱导健康细胞增殖、迁移并发生上皮-间质转化。在此背景下，我们研究了CCL20对癌细胞迁移以及原代培养的乳腺上皮细胞中所使用的细胞内信号通路是否有影响。运用分子（小干扰RNA）和药理学（抑制剂）技术，我们发现多种信号激酶被激活并参与CCL20诱导的乳腺肿瘤细胞迁移。CCL20使细胞迁移和侵袭增加了2.5倍；CCL20还增强了基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的信使核糖核酸/蛋白表达及活性。当在CCL20刺激的细胞中抑制MMP-2和MMP-9时，CCL20所致的细胞迁移和侵袭能力显著降低。CCL20通过JAK2/STAT3信号通路控制MMP-2的表达，而MMP-9的表达则通过蛋白激酶C-α（PKC-α）发生，PKC-α继而激活c-Src、Akt，最终激活核因子-κB（NF-κB）。这些结果揭示了CCL20在乳腺肿瘤细胞中也发挥作用，并指出CCL20是癌症治疗的一个新靶点。
