The LPI/GPR55 axis enhances human breast cancer cell migration via HBXIP and p-MLC signaling

Xiao-lei ZHOU1, Xin GUO2, Yu-pin SONG3, Chong-yue ZHU1, Wei ZOU1
1 Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, Shijiazhuang 050018, China
2 Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
3 College of Chemical Engineering, Shijiazhuang University, Shijiazhuang 050035, China
Correspondence to: Xiao-lei ZHOU:,
DOI: 10.1038/aps.2017.157
Received: 6 April 2017
Accepted: 9 July 2017
Advance online: 30 November 2017


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 L-alysophosphatidylinositol (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.
Keywords: GPR55; LPI; CID16020046; HBXIP; breast cancer; cancer metastasis; cell migration; xenograft nude mouse model

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