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

Min Zheng; Ya-ping Jiang; Wei Chen; Kai-de Li; Xin Liu; Shi-yu Gao; Hao Feng; Sha-sha Wang; Jian Jiang; Xiang-rui Ma; Xiao Cen; Ya-jie Tang; Yu Chen; Yun-feng Lin; Ya-ling Tang; Xin-hua Liang

doi:10.18632/oncotarget.3180

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

Oncotarget. 2015 Mar 30;6(9):6797-810. doi: 10.18632/oncotarget.3180.

Authors

Min Zheng^{1

2}, Ya-ping Jiang¹, Wei Chen^{1

3}, Kai-de Li¹, Xin Liu¹, Shi-yu Gao¹, Hao Feng¹, Sha-sha Wang¹, Jian Jiang¹, Xiang-rui Ma¹, Xiao Cen¹, Ya-jie Tang⁴, Yu Chen¹, Yun-feng Lin¹, Ya-ling Tang^{1

5}, Xin-hua Liang^{1

6}

Affiliations

¹ State Key Laboratory of Oral Diseases West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China.
² Department of Stomatology, Zhoushan Hospital, Zhoushan, Zhejiang 316000, People's Republic of China.
³ Department of Oral and Maxillofacial Surgery, Tianjin Stomatological Hospital, Tianjin 300041, People's Republic of China.
⁴ Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, People's Republic of China.
⁵ Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China.
⁶ Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China.

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.

Keywords: Slug; Snail; epithelial-mesenchymal transition (EMT); miR-101; oral tongue squamous cell carcinoma (OTSCC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Squamous Cell / enzymology*
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / mortality
Carcinoma, Squamous Cell / secondary
Cell Line, Tumor
Cell Movement*
Enhancer of Zeste Homolog 2 Protein
Epithelial-Mesenchymal Transition*
Female
Gene Expression Regulation, Neoplastic
Head and Neck Neoplasms / enzymology*
Head and Neck Neoplasms / genetics
Head and Neck Neoplasms / mortality
Head and Neck Neoplasms / pathology
Humans
Kaplan-Meier Estimate
Lymphatic Metastasis
Male
MicroRNAs / genetics
MicroRNAs / metabolism*
Middle Aged
Neoplasm Invasiveness
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism*
Prognosis
Proportional Hazards Models
RNA Interference
Signal Transduction
Snail Family Transcription Factors
Squamous Cell Carcinoma of Head and Neck
Time Factors
Tongue Neoplasms / enzymology*
Tongue Neoplasms / genetics
Tongue Neoplasms / mortality
Tongue Neoplasms / pathology
Transcription Factors / genetics
Transcription Factors / metabolism*
Transfection

Substances

MIRN101 microRNA, human
MicroRNAs
SNAI1 protein, human
Snail Family Transcription Factors
Transcription Factors
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2