Dual-functionality of RASSF1A overexpression in A375 cells is mediated by activation of IL-6/STAT3 regulatory loop.
Dual-functionality of RASSF1A overexpression in A375 cells is mediated by activation of IL-6/STAT3 regulatory loop.
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A375 细胞中 RASSF1A 过表达的双重功能是通过 IL-6/STAT3 调节环的激活介导的。
DOI：
10.1007/s11033-018-4288-3
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发表时间：
2018
影响因子：
2.8
通讯作者：
Xiang Bo
中科院分区：
文献类型：
--
作者：
Yi Mei;Wang Wei;Chen Shengnan;Peng Ya;Li Junjun;Cai Jing;Zhou Ying;Peng Qian;Ban Yuanyuan;Zeng Zhaoyang;Li Xiaoling;Xiong Wei;Li Guiyuan;Xiang Bo
RASSF1A是一种微管相关蛋白，是一种已知的肿瘤抑制因子，通过启动子高甲基化在多种癌症中沉默。RASSF1A参与细胞增殖和凋亡的调控。然而，其在黑色素瘤A375细胞侵袭和转移中的作用尚不清楚。在这里，我们报告了异位RASSF1A在A375细胞中的一个不寻常的双重功能角色。RASSF1A在体内抑制A375细胞的增殖，增强细胞的迁移、侵袭和转移潜能。我们发现RASSF1A同时上调了A375细胞中p21和波形蛋白的表达。波形蛋白表达的增加有助于RASSF1A介导的细胞迁移和侵袭能力的增强。转录组分析发现，RASSF1A促进了A375细胞IL-6的表达，进而激活了JAK2/STAT3信号转导。经重组IL-6处理后，空载体转染组A375细胞中p21和Vimentin蛋白的表达水平均升高至与RASSF1A表达细胞相似的水平。相反，siRNAs抑制IL-6的表达降低了表达RASSF1A的细胞中p21和波形蛋白的水平。用JAK2抑制剂WP1066阻断JAK2/STAT3信号转导通路，可降低RASSF1A表达细胞中IL-6、p21和波形蛋白的表达。我们的发现揭示了通过调节IL-6/STAT3调控环在A375细胞中异位过度表达RASSF1A的不寻常的双重功能，表明它应该对基于RASSF1A的基因治疗的安全性持谨慎态度。
The RASSF1A, a microtubule associated protein, is a well-known tumor suppressor silenced in various cancer via promoter hypermethylation. RASSF1A is implicated in the regulation of cellular proliferation and apoptosis. However, its role in melanoma A375 cells invasion and metastasis remain unclear. Here, we report an unusual dual function role of ectopic RASSF1A in A375 cells. RASSF1A suppressed A375 cells proliferation but enhanced cells migration, invasiveness and metastatic potential in vivo. We demonstrated RASSF1A simultaneously up-regulated p21 and vimentin expression in A375 cells. Increase of vimentin expression contributes to RASSF1A mediated enhancement of cells mobility and invasion. Transcriptome assay unclosed that RASSF1A promoted IL-6 expression in A375 cells, which in turn activate JAK2/STAT3 signaling. Treatment with recombinant IL-6 enhanced both p21 and vimentin protein level in the empty vector transfected A375 cells to similar level as RASSF1A expressing cells. In contrast, knockdown IL-6 expression by siRNAs decreased p21 and vimentin level in RASSF1A expressing cells. Blockade of JAK2/STAT3 signaling by use of JAK2 inhibitor WP1066 led to decrease of IL-6, p21 and vimentin protein in RASSF1A expressing cells. Our findings unclosed a unusual dual functionality of ectopic RASSF1A overexpression in A375 cells by regulating IL-6/STAT3 regulatory loop, suggesting it should be cautious about the safety of RASSF1A-based gene therapy.