Snail and Slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma.

Min Zheng,Xiang-Rui Ma,Xiao Cen,Xin Liu,Hao Feng,Kai-De Li,Ya-Jie Tang,Yun-Feng Lin,Ya-Ping Jiang,Yu Chen,Ya-Ling Tang,Sha-Sha Wang,Jian Jiang,Shi-Yu Gao,Xin-Hua Liang,Wei Chen

doi:10.18632/oncotarget.3180

Abstract

microRNAs(miRNAs) can regulate epithelial-mesenchymal transition (EMT) through transcription factors, however, little is known whether EMT transcription factors can modulate miRNAs and further induce EMT and cancer metastasis. Here we show that overexpression of Snail and Slug leads to a mesenchymal phenotype and morphology and enhances cell invasion along with stem cell properties in squamous cell carcinoma of oral tongue (OTSCC) cells. Repression of miR-101 expression by Snail and Slug is essential for Snail/Slug-induced malignant phenotypes. The suppression of miR-101 subsequently activates EZH2, the sole histone methyltransferase, inducing EMT, migration and invasion of OTSCC cells. Importantly, co-overexpression of Slug and Snail correlates with poor survival and elevated EZH2 expression in two independent patient cohorts of OTSCC specimens. These findings defined a Snail and Slug/miR-101/EZH2 pathway as a novel regulatory axis of EMT-mediated-microRNA signaling.

Highlights

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent cancer in the world [1]
We have investigated the interplay between Snail and Slug in tumor metastasis and prognosis in OTSCC clinical specimens and cell lines targeting each factor by stable RNAi, screened their miRNAs mediated by Snai1 and Slug using microRNA microarray, and analyzed their effect in the migration and invasion behavior
Snail or Slug or two protein co-expressions was significantly associated with T classification, pathological grade, and lymph node metastasis (Table 1)

Summary

Introduction

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent cancer in the world [1]. Despite its significance and the enormous knowledge accumulated in the past decades on the mechanisms of HNSCC generation and progression, very little is still known about the molecular mechanisms governing metastatic dissemination [2]. Epithelial-mesenchymal transitions (EMT), interconverting epithelial cell types into cells with mesenchymal attributes, has been shown to play a pivotal role in various steps of tumor metastatic cascades, including HNSCC [3, 4]. A comprehensive study demonstrating the interplay between Snail and Slug will provide essential information for the metastasis molecular and prognosis prediction in squamous cell carcinoma of oral tongue (OTSCC), which is one of the most common forms of HNSCC

Methods

Results

Conclusion