The LPI/GPR55 axis enhances human breast cancer cell migration via HBXIP and p-MLC signaling
The LPI/GPR55 axis enhances human breast cancer cell migration via HBXIP and p-MLC signaling
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LPI/GPR55 轴通过 HBXIP 和 p-MLC 信号传导增强人乳腺癌细胞迁移
DOI：
10.1038/aps.2017.157
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发表时间：
2018-03-01
影响因子：
8.2
通讯作者：
Zou, Wei
中科院分区：
文献类型：
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作者：
Zhou, Xiao-lei;Guo, Xin;Zou, Wei
G蛋白偶联受体55 （GPR55）在多种组织中表达，并与癌症发病有关，但对其在癌细胞，特别是乳腺癌细胞的迁移行为中的作用知之甚少。在本研究中，我们首次发现GPR55在38例乳腺癌患者转移淋巴结中的表达水平显著升高，并与人乳腺癌细胞的迁移能力呈正相关。此外，与健康个体相比，乳腺癌患者血浆GPR55内源性激动剂la -溶血磷脂酰肌醇（LPI）水平显著升高。在人乳腺癌LM-MCF-7和MDA-MB-231细胞中，LPI （2.5 μmol/L）可显著增加丝状足形成并导致细胞迁移，这种迁移可被GPR55拮抗剂CID16020046或sirna介导的GPR55敲低阻断。此外，双荧光素酶报告基因分析显示，GPR55在启动子处上调HBXIP；在乳腺癌组织和8种乳腺癌细胞系中，GPR55表达水平与HBXIP表达水平呈正相关。我们还发现LPI/GPR55轴通过HBXIP/p-ERK1/2/Capn4和MLCK/MLC两条相互排斥的信号通路促进乳腺癌细胞的迁移。在异种移植裸鼠模型中，GPR55的缺失主要影响乳腺癌细胞的转移和转移灶的形成。因此，GPR55参与了人乳腺癌细胞的迁移行为，可作为预防转移的药理靶点。
The G protein-coupled receptor 55 (GPR55) is expressed in multiple tissues, and has been implicated in cancer pathogenesis, but little is known about its role in the migratory behavior of cancer cells, particularly breast cancer cells. In this study we first showed that GPR55 expression levels in 38 metastatic lymph nodes of breast cancer patients were profoundly elevated, and were positively associated in human breast cancer cells with their migratory ability. Moreover, the plasma levels of GPR55 endogenous agonist La-lysophosphatidylinositol (LPI) were significantly increased in breast cancer patients compared with healthy individuals. In human breast cancer LM-MCF-7 and MDA-MB-231 cells, treatment with LPI (2.5 μmol/L) significantly increased filopodia formation and resulted in cell migration, which could be blocked either by the GPR55 antagonist CID16020046 or by siRNA-mediated GPR55 knockdown. Furthermore, dual-luciferase report gene assays showed that GPR55 upregulated HBXIP at the promoter; GPR55 expression levels were positively correlated with HBXIP expression levels in breast cancer tissues and 8 breast cancer cell lines. We also showed that the LPI/GPR55 axis promoted the migration of breast cancer cells via two mutually exclusive pathways—the HBXIP/p-ERK1/2/Capn4 and MLCK/MLC signaling pathways. In xenograft nude mouse model, loss of GPR55 mainly affected breast cancer cell metastasis and the formation of metastatic foci. Thus, GPR55 is involved in the migratory behavior of human breast cancer cells and could serve as a pharmacological target for preventing metastasis.