Nerve growth factor modulates the tumor cells migration in ovarian cancer through the WNT/β-catenin pathway

Abstract

Nerve growth factor (NGF)/nerve growth factor receptors (NGFRs) axis and canonical WNT/β-catenin pathway have shown to play crucial roles in tumor initiation, progression and prognosis. But little did we know the relationship between them in modulation of tumor progress. In this report, we found that NGF/NGFRs and β-catenin were coexpression in ovarian cancer cell lines, and NGF can decrease the expression level of β-catenin and affect its activities, which may be related to the NGF-induced down-regulation of B-cell CLL/lymphoma 9-like (BCL9L, BCL9-2). Furthermore, NGF can also increase or decrease the downstream target gene expression levels of WNT/β-catenin depending on the cell types. Especially, we created a novel in vitro cell growth model based on a microfluidic device to intuitively observe the effects of NGF/NGFRs on the motility behaviors of ovarian cancer cells. The results showed that the migration area and maximum distance into three dimensional (3D) matrigel were decreased in CAOV3 and OVCAR3 cells, but increased in SKOV3 cells following the stimulation with NGF. In addition, we found that the cell colony area was down-regulated in CAOV3 cells, however, it was augmented in OVCAR3 cells after treatment with NGF. The inhibitors of NGF/NGFRs, such as Ro 08-2750, K252a and LM11A-31,can all block NGF-stimulated changes of gene expression or migratory behavior on ovarian cancer cells. The different results among ovarian cancer cells illustrated the heterogeneity and complexity of ovarian cancer. Collectively, our results suggested for the first time that NGF is functionally linked to β-catenin in the migration of human ovarian cancer cells, which may be a novel therapeutic perspective to prevent the spread of ovarian carcinomas by studying the interaction between NGF/NGFRs and canonical WNT/β-catenin signaling.

Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells

“…On the other hand, Pro-NGF levels are higher in SKOV3 cells. These results are in agreement with a previous study [ 74 ], which described that SKOV3 cells express less NGF and TRKA receptor, but elevated protein levels of the P75 receptor compared with A2780 cells. These findings could explain why SKOV3 cells required higher concentrations of NGF (150 ng/mL vs. 100 ng/mL used in A2780 cells) to increase proliferation/migration, given that SKOV3 cells express fewer TRKA receptors.…”

Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion

“…This corroborates numerous published reports on the requisite of Wnt signaling in endochondral bone formation during development, and specifically for chondrocyte-derived osteoblastogenesis 25,28,29 . NGF signaling has also been shown to modulate Wnt activation in several non-skeletal cell types 58,59 . However, this is the first study in which this relationship has been noted in cartilage after in vitro stimulation with β-NGF.…”

Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis

“…Furthermore, death receptor signaling can contrariwise regulate Wnt signaling. Several inhibitors of NGF and NGF receptors, such as Ro 08-2750 (targets NGF), K252a (targets TrkA) and LM11A-31 (targets P75), have been shown to increase β-catenin expression and cell migration in ovarian cancer cells [ 89 ]. Thus, we believe that the relationship between Nradd and Wnt signaling in the regulation of apoptosis mechanisms is context dependent.…”