Role of miR-96/EVI1/miR-449a Axis in the Nasopharyngeal Carcinoma Cell Migration and Tumor Sphere Formation.

Lai-Sheung Chan,Sai Wah Tsao,Michael Kahn,Maria Li Lung,Rotraud Wieser,Roger Kai-Cheong Ngan,Nai-Ki Mak,Kwok-Wai Lo,Anne Wing-Mui Lee,Hong-Lok Lung

doi:10.3390/ijms21155495

Abstract

The Wnt signaling pathway is one of the major signaling pathways used by cancer stem cells (CSC). Ecotropic Viral Integration Site 1 (EVI1) has recently been shown to regulate oncogenic development of tumor cells by interacting with multiple signaling pathways, including the Wnt signaling. In the present study, we found that the Wnt modulator ICG-001 could inhibit the expression of EVI1 in nasopharyngeal carcinoma (NPC) cells. Results from loss-of-function and gain-of-function studies revealed that EVI1 expression positively regulated both NPC cell migration and growth of CSC-enriched tumor spheres. Subsequent studies indicated ICG-001 inhibited EVI1 expression via upregulated expression of miR-96. Results from EVI1 3′UTR luciferase reporter assay confirmed that EVI1 is a direct target of miR-96. Further mechanistic studies revealed that ICG-001, overexpression of miR-96, or knockdown of EVI1 expression could restore the expression of miR-449a. The suppressive effect of miR-449a on the cell migration and tumor sphere formation was confirmed in NPC cells. Taken together, the miR-96/EVI1/miR-449a axis is a novel pathway involved in ICG-001-mediated inhibition of NPC cell migration and growth of the tumor spheres.

Highlights

Nasopharyngeal carcinoma (NPC), a type of epithelial malignancy in the region of the nasopharynx, has a high frequency of occurrence in southern China
We found that the miR-96/Ecotropic Viral Integration Site 1 (EVI1)/miR-449a axis is involved in the inhibition of the growth and migration of nasopharyngeal carcinoma (NPC) cells
We sought to determine whether pharmacological intervention in the Wnt/β-catenin signal pathway with a selective CREB-binding protein (CBP)/β-catenin antagonist ICG-001 would have an effect on the expression of EVI1

Summary

Introduction

Nasopharyngeal carcinoma (NPC), a type of epithelial malignancy in the region of the nasopharynx, has a high frequency of occurrence in southern China. High EVI1 expression was found to correlate with the tumor size and distant metastasis, and with the shorter overall survival of the NPC patients [3]. EVI1 has been shown to be expressed in various developing tissues, such as the heart, respiratory system and nasal cavity [5]. It has been shown that dysregulated expression of EVI1 is involved in the oncogenic development of leukemia [8]. The role of EVI1 in the oncogenic development of epithelial cancers has been reported recently. A high expression level of EVI1 was found to correlate with a larger tumor size [13]. The contribution of EVI1 to the oncogenic development of NPC has not been fully studied

Methods

Results

Conclusion