Paracrine Induction of Epithelial-Mesenchymal Transition Between Colorectal Cancer Cells and its Suppression by a p53/miR-192/215/NID1 Axis
Paracrine Induction of Epithelial-Mesenchymal Transition Between Colorectal Cancer Cells and its Suppression by a p53/miR-192/215/NID1 Axis
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DOI：
10.1016/j.jcmgh.2019.02.003
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发表时间：
2019-01-01
影响因子：
7.2
通讯作者：
Hermeking, Heiko
中科院分区：
文献类型：
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作者：
Rokavec, Matjaz;Bouznad, Nassim;Hermeking, Heiko
背景与目的：肿瘤内异质性是结直肠癌的一个共同特征。在这里，我们分析了间充质样CRC细胞是否促进上皮样CRC细胞通过旁分泌mechanism.METHODS的进展：6 CRC细胞系，显示上皮表型与条件培养基（CM）从CRC细胞系，显示间充质表型，上皮-间充质转化（EMT），迁移，侵袭和化疗耐药性的影响进行了测定。通过使用细胞因子阵列鉴定了可能介导这些效应的分泌因子。这些因素与肿瘤进展和患者生存率的关联determined.RESULTS：CM获得间充质样CRC细胞诱导EMT与增加的迁移，侵袭，和耐药性的上皮样CRC细胞系。值得注意的是，间充质样CRC细胞中p53的激活阻止了CM的这些作用。在来自间充质样CRC细胞系的CM中鉴定出几种细胞因子的浓度增加，并且这些细胞因子的子集显示出p53的抑制。巢蛋白-1（NID 1）的下调特别显著，这是由于p53介导的microRNA-192和microRNA-215的诱导，它们直接靶向NID 1信使RNA。发现NID 1是诱导上皮样CRC细胞中的EMT、侵袭和迁移所必需的并且是足够的。在原发性CRC中，NID 1表达增加与p53突变和microRNA-192/215下调相关。重要的是，NID 1在CRC中的表达增加与肿瘤进展增强和患者生存率低相关。结论：综上所述，我们的研究结果表明，CRC细胞通过分泌NID 1促进肿瘤进展，NID 1诱导邻近肿瘤细胞的EMT。重要的是，p53对肿瘤细胞之间的这种旁分泌信号传导的干扰可能对肿瘤抑制起关键作用。
BACKGROUND & AIMS: Intratumor heterogeneity is a common feature of colorectal cancer (CRC). Here, we analyzed whether mesenchymal-like CRC cells promote the progression of epithelial-like CRC cells via paracrine mechanisms.METHODS: Six CRC cell lines that show an epithelial phenotype were treated with conditioned media (CM) from CRC cell lines that show a mesenchymal phenotype, and effects on epithelial-mesenchymal transition (EMT), migration, invasion, and chemoresistance were determined. Secreted factors potentially mediating these effects were identified by using cytokine arrays. Associations of these factors with tumor progression and patient survival were determined.RESULTS: CM obtained from mesenchymal-like CRC cells induced EMT associated with increased migration, invasion, and chemoresistance in epithelial-like CRC cell lines. Notably, activation of p53 in mesenchymal-like CRC cells prevented these effects of CM. Increased concentrations of several cytokines were identified in CM from mesenchymal-like CRC cell lines and a subset of these cytokines showed repression by p53. The down-regulation of nidogen-1 (NID1) was particularly significant and was owing to p53-mediated induction of microRNA-192 and microRNA-215, which directly target the NID1 messenger RNA. NID1 was found to be required and sufficient for inducing EMT, invasion, and migration in epithelial-like CRC cells. In primary CRCs, increased NID1 expression was associated with p53 mutation and microRNA-192/215 down-regulation. Importantly, increased NID1 expression in CRCs correlated with enhanced tumor progression and poor patient survival.CONCLUSIONS: Taken together, our results show that CRC cells promote tumor progression via secreting NID1, which induces EMT in neighboring tumor cells. Importantly, the interference of p53 with this paracrine signaling between tumor cells may critically contribute to tumor suppression.