Distinct miRNA profiles in normal and gastric cancer myofibroblasts and significance in Wnt signaling.
Distinct miRNA profiles in normal and gastric cancer myofibroblasts and significance in Wnt signaling.
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DOI：
10.1152/ajpgi.00443.2015
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发表时间：
2016-05
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影响因子：
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通讯作者：
Liyi Wang;I. Steele;J. D. Kumar;R. Dimaline;P. Jithesh;L. Tiszlavicz;Z. Reisz;G. Dockray;A. Varró
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文献类型：
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作者：
Liyi Wang;I. Steele;J. D. Kumar;R. Dimaline;P. Jithesh;L. Tiszlavicz;Z. Reisz;G. Dockray;A. Varró
基质细胞影响健康和疾病中的上皮功能。肌成纤维细胞是丰富的基质细胞，其通过释放细胞外基质（ECM）蛋白、生长因子、蛋白酶、细胞因子和趋化因子来影响细胞微环境。癌症相关肌成纤维细胞（CAM）不同于邻近组织（ATM）和正常组织肌成纤维细胞（NTM），但其基础尚不完全清楚。我们现在报告的差异表达的miRNA在胃癌CAM。microRNA阵列鉴定了胃和食管NTM以及来自胃的CAM与NTM相比的miRNA谱的差异。miR-181 d在胃CAM中上调。差异调节的miRNA的分析表明参与Wnt信号传导。然后，微阵列数据集的检查将Wnt 5a鉴定为胃CAM中唯一一致上调的Wnt配体。Wnt 5a刺激miR-181 d表达，而miR-181 d的敲低抑制了Wnt 5a对CAM增殖和迁移的刺激。对miR-181 d靶点的分析表明其在趋化性中发挥作用。来自CAMs的条件培养基比来自ATM的条件培养基更能刺激胃癌细胞（AGS）迁移，并且miR-181 d敲低降低了CAM-CM对AGS细胞迁移的影响，但对AGS细胞对ATM条件培养基的反应没有影响。这些数据表明，胃CAM中的miRNA表达失调，继发于Wnt 5a信号传导，至少部分地解释了CAM在促进癌细胞迁移中的作用。
Stromal cells influence epithelial function in both health and disease. Myofibroblasts are abundant stromal cells that influence the cellular microenvironment by release of extracellular matrix (ECM) proteins, growth factors, proteases, cytokines, and chemokines. Cancer-associated myofibroblasts (CAMs) differ from adjacent tissue (ATMs) and normal tissue myofibroblasts (NTMs), but the basis of this is incompletely understood. We report now the differential expression of miRNAs in gastric cancer CAMs. MicroRNA arrays identified differences in the miRNA profile in gastric and esophageal NTMs and in CAMs from stomach compared with NTMs. miR-181d was upregulated in gastric CAMs. Analysis of differentially regulated miRNAs indicated an involvement in Wnt signaling. Examination of a microarray data set then identified Wnt5a as the only consistently upregulated Wnt ligand in gastric CAMs. Wnt5a stimulated miR-181d expression, and knockdown of miR-181d inhibited Wnt5a stimulation of CAM proliferation and migration. Analysis of miR-181d targets suggested a role in chemotaxis. Conditioned medium from CAMs stimulated gastric cancer cell (AGS) migration more than that from ATMs, and miR-181d knockdown reduced the effect of CAM-CM on AGS cell migration but had no effect on AGS cell responses to ATM conditioned media. The data suggest that dysregulation of miRNA expression in gastric CAMs, secondary to Wnt5a signaling, accounts at least in part for the effect of CAMs in promoting cancer cell migration.