IRE1α-XBP1 pathway promotes melanoma progression by regulating IL-6/STAT3 signaling.
IRE1α-XBP1 pathway promotes melanoma progression by regulating IL-6/STAT3 signaling.
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DOI：
10.1186/s12967-017-1147-2
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发表时间：
2017-02-21
影响因子：
7.4
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Chen C;Zhang X
IRE 1 α-XBP 1通路是未折叠蛋白应答通路中最保守的分支，在内质网（endoplasmic reticulum，ER）应激时被激活，这是由于未折叠/错误折叠蛋白在内质网腔中的积累所致。IRE 1 α-XBP 1途径在各种癌症中发挥着关键作用。然而，这一途径在黑色素瘤细胞生长中的作用仍不清楚。61对黑色素瘤标本和相应的正常组织的患者进行了染色与XBP 1。然后，在mRNA水平上检测人体组织和细胞系中的XBP 1剪接水平。在过表达剪接形式的XBP 1（XBP 1 s）的黑素细胞（HEMn-MP）和黑素瘤细胞（Mel-RMu）中测定IL-6表达水平。在4μ 8 C处理的HEMn-MP和过表达IRE 1 α的Mel-RMu细胞中也检测了IL-6表达。接下来，我们分析了IL-6启动子内潜在的XBP 1 s结合位点，并进行了ChIP实验。通过蛋白质印迹法检测IL-6/STAT 3信号转导。CCK 8和BrdU检测黑色素瘤细胞增殖。与正常组织或黑素细胞相比，在人黑色素瘤组织和细胞系中，XBP 1 s的mRNA和蛋白表达水平显著升高，表明黑色素瘤中IRE 1 α-XBP 1分支被激活。在HEMn-MP和Mel-RMu细胞中，IRE 1 α或XBP 1 s的异位表达强烈地增强了IL-6的表达。抑制IRE 1 α的RNase活性也可使IRE 1 α促进IL-6表达的作用消失。在机制上，XBP 1结合IL-6启动子并激活其表达。此外，分泌的IL-6以自分泌/旁分泌方式发挥作用，激活细胞内JAK/STAT 3途径并促进黑素瘤细胞的增殖。我们的研究结果表明，IRE 1 α-XBP 1通路通过激活IL-6/STAT 3信号转导调节Mel-RMu细胞的增殖和进展。
The IRE1α-XBP1 pathway is the most conserved branch of the unfolded protein response pathways, which are activated during endoplasmic reticulum (ER) stress caused by the accumulation of unfolded/misfolded proteins in the ER lumen. The IRE1α-XBP1 pathway plays a critical role in various cancers. However, the role of this pathway in melanoma cell growth remains unclear. Sixty-one pairs of melanoma specimens and corresponding normal tissues from patients were stained with XBP1. Then, XBP1 splicing levels were detected in human tissues and cell lines at the mRNA level. IL-6 expression levels were determined in both melanocytes (HEMn-MP) and melanoma cells (Mel-RMu) overexpressing the spliced form of XBP1 (XBP1s). IL-6 expression was also examined in 4μ8C-treated HEMn-MP and Mel-RMu cells overexpressing IRE1α. Next, we analyzed potential XBP1s binding sites within the IL-6 promoter and conducted ChIP experiments. IL-6/STAT3 signaling was detected by western blotting. Melanoma cell proliferation was examined by CCK8 and BrdU assays. The mRNA and protein expression levels of XBP1s were significantly elevated in human melanoma tissues and cell lines compared with normal tissues or melanocytes, thus indicating the activation of the IRE1α-XBP1 branch in melanoma. Ectopic expression of IRE1α or XBP1s robustly enhanced IL-6 expression in HEMn-MP and Mel-RMu cells. Moreover, the inhibition of the RNase activity of IRE1α also abolished the effect of IRE1α in promoting IL-6 expression. Mechanistically, XBP1 binds the IL-6 promoter and activates its expression. Furthermore, secreted IL-6 functions in an autocrine/paracrine manner, activates the intracellular JAK/STAT3 pathway and promotes the proliferation of melanoma cells. Our results reveal that the IRE1α-XBP1 pathway regulates Mel-RMu cell proliferation and progression by activating IL-6/STAT3 signaling.