Effect of the Mutual Interaction of GPNMB and LPAR1 on Cellular Motility and Tumorigenicity in Mammary Epithelial Cells.

Abstract

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a poor prognostic factor, which is highly expressed in many types of malignant tumors, including breast cancer. Previously, the overexpression of GPNMB was shown to confer tumorigenic potential like tumor formation and cellular motility to non-tumorigenic mammary gland epithelial cells through the induction of the epithelial-mesenchymal transition (EMT). However, the detailed mechanism by which GPNMB activates cellular motility remains unclear. To address this issue, we focused on the actin reorganization-like elevated stress fiber formation in GPNMB-expressing cells and found that GPNMB enhanced Ras homology family member A (RhoA) activation upon lysophosphatidic acid (LPA) stimulation probably because of the high expression level of LPA receptor (LPAR) 1. We also showed that LPA ligand stimulates cellular motility via the RhoA-ROCK pathway in GPNMB-expressing cells. Moreover, we found that LPAR1 overexpression increases the expression level of GPNMB in NMuMG cells, and that LPA-LPAR1-RhoA signaling could activate GPNMB transcription. In addition, LPAR1-induced sphere-forming ability was impaired by GPNMB knockdown. Collectively, we showed the mutual induction and function of GPNMB and LPAR1 for the activation of cellular motility and the tumorigenic ability of mammary gland epithelial cells.