GLI1 orchestrates CXCR4/CXCR7 signaling to enhance migration and metastasis of breast cancer cells.
GLI1 orchestrates CXCR4/CXCR7 signaling to enhance migration and metastasis of breast cancer cells.
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DOI：
10.18632/oncotarget.5203
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发表时间：
2015-10-20
期刊：
影响因子：
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通讯作者：
Kasai K
中科院分区：
文献类型：
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作者：
Inaguma S;Riku M;Ito H;Tsunoda T;Ikeda H;Kasai K
趋化因子受体CXCR 4和CXCR 7的表达上调对乳腺癌的远处转移和预后有影响，但其表达调控机制的研究还很有限。同时，Hedgehog信号转导的GLI转录因子在多种人类癌症的发生和发展中起着关键作用。在乳腺癌中，GLI 1的表达增加与转移和不利的总体预后相关，尽管其分子机制还不完全清楚。基于我们在小鼠模型系统中GLI 1增强乳腺癌细胞肺转移的发现，我们全面筛选了乳腺癌细胞中GLI 1上调的基因，并因此鉴定了CXCR 4，CXCR 7/ACKR 3和肌动蛋白结合蛋白LCP 1/L-PLASTIN，所有这些都被报道参与了CXCL 12刺激信号传导。在乳腺癌细胞中，我们发现GLI 1和GLI 2上调了这些表达，而GLI特异性抑制剂GANT 61的治疗降低了这些表达。至于CXCR 4，我们通过报告基因测定和染色质免疫沉淀测定证实其为GLI 1的直接靶点。我们还发现GLI 1增强了CXCL 12诱导的ERK磷酸化和细胞迁移，这两者都被CXCR 4特异性抑制剂或CXCR 7或LCP 1的敲低所阻断。这些证据表明GLI 1通过增强CXCL 12/CXCR 4信号传导在乳腺癌细胞的迁移和转移中起不可或缺的作用。
The up-regulation of chemokine receptors CXCR4 and CXCR7 impacts on the distant metastasis and prognosis of breast cancer, though knowledge about the regulatory mechanism of their expressions is limited. Meanwhile, the GLI transcription factors of Hedgehog signaling have been reported to play a pivotal role in the development and progression of many types of human cancer. In breast cancer, the increased expression of GLI1 correlated with metastasis and unfavorable overall prognosis, though its molecular mechanism is also not fully understood. Based on our findings that GLI1 enhanced the lung metastasis of breast cancer cells in a mouse model system, we comprehensively screened for genes up-regulated by GLI1 in breast cancer cells, and as such identified CXCR4, CXCR7/ACKR3, and actin-binding protein LCP1/L-PLASTIN, all of which have been reported to be involved in CXCL12-stimulating signaling. In breast cancer cells, we found that GLI1 and GLI2 up-regulated these expressions, while treatment with GLI-specific inhibitor GANT61 reduced the expressions. As for CXCR4, we confirmed it as a direct target of GLI1 through the reporter assay and the chromatin immunoprecipitation assay. We also found that GLI1 enhanced CXCL12-induced ERK phosphorylation and cell migration, both of which were blocked by either CXCR4-specific inhibitor or knockdown of CXCR7 or LCP1. These evidences suggest an indispensable role of GLI1 in the migration and metastasis of breast cancer cells through CXCL12/CXCR4 signaling enhancement.