CCL20 induces migration and proliferation on breast epithelial cells
CCL20 induces migration and proliferation on breast epithelial cells
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DOI：
10.1002/jcp.24349
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发表时间：
2013-09-01
影响因子：
5.6
通讯作者：
Muscella, Antonella
中科院分区：
文献类型：
--
作者：
Marsigliante, Santo;Vetrugno, Carla;Muscella, Antonella
肿瘤细胞与周围细胞之间的交流有助于推动肿瘤进展的过程。由于乳腺癌的微环境包括CCL 20趋化因子，本研究的目的是确定CCL 20是否调节肿瘤附近区域健康乳腺上皮细胞的生理学。因此，使用取自正常瘤周区域的乳腺细胞原代培养物。我们评估了乳腺细胞表达CCR 6 CCL 20受体。利用分子（siRNA）和药理学（抑制剂）技术，我们发现多种信号激酶被CCR 6激活，并参与CCL 20诱导的乳腺细胞增殖和迁移。10 ng/ml的CCL 20与CCR 6的结合诱导细胞迁移，而更高浓度（15 - 25 ng/ml）导致细胞增殖。CCL 20通过激活Src的PKC-α控制细胞迁移和MMP-9表达，Src导致下游Akt、JNK和NF-kB通路的激活。此外，更高的CCL 20浓度增加cycE和降低p27 Kip表达，最终增强细胞增殖。细胞增殖是通过PKC β激活EGFR和ERK 1/2/MAPK通路而发生的。尽管这些通路被不同浓度的CCL 20激活，但它们在一定程度上平行发挥作用并相互干扰，因为Akt激活负责ERK 1/2核转位并增强c-fos和c-myc的转录，参与细胞增殖。总之，肿瘤细胞与周围的健康细胞交换信号，通过酶分泌修饰细胞外基质;因此，CCL 20可能是乳腺癌个体发生中的一个因子。J.细胞。228：18731883，2013。(c)2013 Wiley Periodicals，Inc.
The communication between the tumor cells and the surrounding cells helps drive the process of tumor progression. Since the microenvironment of breast cancer includes CCL20 chemokine, the purpose of this study was to determine whether CCL20 modulates the physiology of healthy breast epithelial cells in areas adjacent to the tumor. Therefore, primary cultures of mammary cells taken from normal peritumoral areas were used. We assessed that breast cells expressed CCR6 CCL20 receptor. Using molecular (siRNA) and pharmacological (inhibitors) techniques, we found multiple signaling kinases to be activated by CCR6 and involved in CCL20-induced breast cell proliferation and migration. The binding of 10ng/ml CCL20 to CCR6 induced cell migration whilst higher concentrations (from 15 to 25ng/ml) led to cell proliferation. CCL20 controlled cell migration and MMP-9 expression by PKC-alpha that activated Src, which caused the activation of downstream Akt, JNK, and NF-kB pathways. Furthermore, higher CCL20 concentrations increased cycE and decreased p27Kip expression ending in enhanced cell proliferation. Cell proliferation occurred through PKC-epsilon activation that transactivated EGFR and ERK1/2/MAPK pathway. Although activated by different CCL20 concentrations, these pathways function in parallel and crosstalk to some extent, inasmuch as Akt activation was responsible for ERK1/2 nuclear translocation and enhanced the transcription of of c-fos and c-myc, involved in cell proliferation. In summary, tumor cells exchange signals with the surrounding healthy cells modifying the extracellular matrix through enzyme secretion; thus, CCL20 might be a factor involved in the ontogeny of breast carcinoma. J. Cell. Physiol. 228: 18731883, 2013. (c) 2013 Wiley Periodicals, Inc.