Invasiveness-triggered state transition in malignant melanoma cells
Invasiveness-triggered state transition in malignant melanoma cells
复制标题
恶性黑色素瘤细胞侵袭触发的状态转换
DOI：
10.1002/jcp.27405
复制
发表时间：
2018
影响因子：
5.6
通讯作者：
Yao-Qing Yu
中科院分区：
文献类型：
--
作者：
Huan Wang;Yan-Guo Zhang;Jing Ma;Jun-Chang Li;Jian Zhang;Yao-Qing Yu
认为癌细胞在人黑素瘤组织中具有高度形态异质性。在这里，我们报告说，上皮癌细胞是占主导地位的不同发展阶段的人类黑色素瘤组织。在A2058细胞系中进一步研究了维持黑素瘤细胞处于上皮状态的细胞和分子机制。我们发现，在划痕试验中，8 μm的transwell浸润，而不是表面迁移，可以在4天内诱导上皮和间充质黑色素瘤细胞之间的显著形态学变化。形态转换与上皮-间质转化（EMT）标志物E-钙粘蛋白和波形蛋白的动态变化相关。进一步的免疫荧光染色和免疫共沉淀试验显示，上皮黑色素瘤细胞中M3毒蕈碱乙酰胆碱受体（mAChR）和p75神经营养因子受体（p75 NTR）解偶联。通过小干扰RNA（siRNA）特异性敲低M3 mAChR，可显著消除梭形间充质细胞向上皮细胞的转化。总的来说，我们报告了一种侵袭性触发状态转换（ITST）的细胞模型，其中黑色素瘤细胞侵袭可以诱导上皮细胞和间充质细胞之间的形态学变化。ITST是维持转移性黑色素瘤细胞处于上皮状态的生物学基础之一。此外，M3 mAChR受体介导的ITST为抑制恶性黑色素瘤的发展提供了一种新的治疗策略。
Cancer cells are considered to have high morphological heterogeneity in human melanoma tissue. Here, we report that epithelial cancer cells are dominant in different development stages of human melanoma tissues. The cellular and molecular mechanisms that maintain melanoma cells in the epithelial state are further investigated in the A2058 cell line. We find that micropore (8 µm) transwell invasion, but not superficial migration in the scratch assay, can induce remarkable morphological changes between epithelial and mesenchymal melanoma cells within 4 days. The morphological switch is associated with dynamic changes of epithelial–mesenchymal transition (EMT) hallmarks E‐cadherin and vimentin. Further immunoflurencent staining and co‐immunoprecipitation assay showed the uncoupling of the M3 muscarinic acetylcholine receptor (mAChR) and the p75 neurotrophin receptor (p75NTR) in epithelial melanoma cells. Specific knockdown of M3 mAChR by small interfering RNA (siRNA) significantly abrogates the transition of spindle‐shaped mesenchymal cells to epithelial cells. Collectively, we report a cellular model of invasiveness‐triggered state transition (ITST) in which melanoma cell invasion can induce morphological changes between epithelial and mesenchymal cells. ITST is one of the biological basis for maintaining metastatic melanoma cells in the epithelial state. Furthermore, M3 mAChR receptor‐mediated ITST provides a novel therapeutic strategy to inhibit the development of malignant melanoma.