Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2

Abstract

Nm23-H1 transcriptionally down-regulates expression of the lysophosphatidic acid receptor EDG2 and this down-regulation is critical for Nm23-H1-mediated motility suppression in vitro. We investigated the effect of altered EDG2 expression on Nm23-H1-mediated metastasis suppression in vivo. Clonal MDA-MB-435-derived tumor cell lines transfected with Nm23-H1 together with either a vector control or EDG2 had similar anchorage-dependent and anchorage-independent growth rates in vitro. However, a 45-and 300-fold inhibition of motility and invasion (P < 0.0001), respectively, was observed in Nm23-H1/vector lines, whereas coexpression of EDG2 restored activity to levels observed in the parental line. Using fluorescently labeled cells and ex vivo microscopy, the capacity of these cells to adhere, arrest, extravasate, and survive in the murine lung over a 24-h time course was measured. Only 5% of Nm23-H1/vector-transfected cells were retained in the murine lung 6 h following tail vein injection; coexpression of EDG2 enhanced retention 8-to 13-fold (P < 0.01). In a spontaneous metastasis assay, the primary tumor size of Nm23-H1/vector and Nm23-H1/EDG2 clones was not significantly different. However, restoration of EDG2 expression augmented the incidence of pulmonary metastasis from 51.9% to 90.4% (P = 2.4 Â 10 À5 ), comparable with parental MDA-MB-435 cells. To determine the relevance of this model system to human breast cancer, a cohort of breast carcinomas was stained for Nm23-H1 and EDG2 and a statistically significant inverse correlation between these two proteins was revealed (r = À0.73; P = 0.004).

GPCRs and cancer

“…Aberrant expressions and mutations of LPA receptors have been found in several types of tumors, suggesting their involvement in the growth advantage of cancer cells [3,14,15] . For instance, LPA1 was inversely correlated in breast cancer tissues with the Nm23 metastases regulator [16] and contributed to bone metastasis in breast cancer xenografts [17] . Furthermore, LPA induced migration in breast cancer cells by activating LPA1, which promoted the phosphorylation of nonmuscle myosin II (NM II) light chain through the activation of ROCK and RhoA activity [18] .…”

NME1 at the human maternal–fetal interface downregulates titin expression and invasiveness of trophoblast cells via MAPK pathway in early pregnancy

“…For example, the NME1 gene may have an impact on the cell adhesion-related signaling pathway, through NDPKmediated GTP, significantly increase b-catenin, E-cadherin, and CD44 mRNA and protein expression to strengthen intercellular adhesion, further inhibiting tumor invasion and metastasis (Kim & Kim 2006). Also, NME1 can reduce the expression of matrix metalloproteinase 9 (MMP9) and MMP2, and increase tissue inhibitor of metalloproteinase (TIMP) through the RAS-RAF-MEK-extracellular signal-regulated kinase 1/2 (ERK)-ELK1 pathway, phosphatidylinositol 3-kinase-AKT-nuclear factor-kB/AP-1 pathway, and RAS-RAC-MKK3/6-p38 pathway, and promote the angiogenesis-related vascular endothelial growth factor (VEGF) expression, finally weakening the metastasis ability of tumor cells (Ohba et al 2005, Horak et al 2007). In addition, NME1 can activate P53 controlling cell cycle, differentiation, and apoptosis; the adoption of the P53 pathway is to downregulate growth and metastasis of tumors (Lombardi 2006).…”

Cancer Dormancy: A Model of Early Dissemination and Late Cancer Recurrence

“…Although the molecular mechanism of Nm23-1 H-mediated dormancy has not been fully elucidated, it is believed that Nm23-1 H suppresses multiple aspects of metastasis, including invasion, tumor cell survival, and metastatic colonization. In an in vivo model, Nm23-1 H appeared to interact with EDG2 lysophosphatidic acid receptor 1, a strong activator of ERK1/2, to reduce MAPK ERK1/2 activation and balance the p38:ERK1/2 signaling ratio, thus favoring dormancy (52).…”