Nerve growth factor modulates the tumor cells migration in ovarian cancer through the WNT/β-catenin pathway
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Bo Li1,2, Shaoxi Cai1, Yi Zhao1, Qiyi He3, Xiaodong Yu3, Longcong Cheng1, Yingfeng Zhang3, Xiancheng Hu4, Ming Ke1, Sijia Chen1, Misha Zou1
1Key laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
2School of Education, Chongqing Normal University, Chongqing, China
3College of Life Sciences, Chongqing Normal University, Chongqing, China
4College of Chemistry, Chongqing Normal University, Chongqing, China
Shaoxi Cai, email: [email protected]
Xiaodong Yu, email: [email protected]
Keywords: NGF, NGFRs, WNT/β-catenin pathway, 3D microfluidic device, migration
Received: April 13, 2016 Accepted: October 21, 2016 Published: November 07, 2016
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.
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