Overexpression of HMGA2 promotes tongue cancer metastasis through EMT pathway.

Xiao-Peng Zhao,Dong-Xiao Tang,Hong Zhang,Yu-Ling Wu,Chao-Bin Pan,Jiu-Yang Jiao

doi:10.1186/s12967-016-0777-0

Abstract

BackgroundMetastasis to long distance organs is the main reason leading to morality of tongue squamous cell carcinoma (TSCC); however, the molecular mechanisms are still unknown. High mobility group AT-hook 2 (HMGA2) is highly expressed in multiple metastatic carcinomas, in which it contributes to cancer progression, metastasis and poor prognosis by upregulating Snail expression and inducing epithelial mesenchymal transition (EMT). This study focuses on investigating the role and mechanism of regulation of HMGA2 in the metastasis of TSCC.MethodsHMGA2 mRNA and protein expression were examined in TSCC specimens by quantitative real-time polymerase chain reaction, western blotting and immunohistochemistry (IHC). Western blotting, IHC and immunofluorescence were also used to measure the expression and localization of EMT marker E-Cadherin and Vimentin both in TSCC cells and tissues. Knockdown assay was performed in vitro in TSCC cell lines using small interfering RNAs and the functional assay was carried out to determine the role of HMGA2 in TSCC cell migration and invasion.ResultsTSCC mRNA and protein expression were significantly up-regulated in tumor tissues when compared to adjacent non-tumor tissues, and the overexpression of HMGA2 was closely correlated with lymph nodes metastasis. Clinicopathological analysis indicated that HMGA2 expression was associated with clinical stage (P = 0.001), lymph node metastasis (P = 0.000), histological differentiation (P = 0.002) and survival (P = 0.000). Silencing the HMGA2 expression in Cal27 and UM1 resulted in the inhibition of cell migration and invasion, meanwhile down-regulation of HMGA2 impaired the phenotype of EMT in TSCC cell lines and tissues. The Multivariate survival analysis indicates that HMGA2 can be an independent prognosis biomarker in TSCC.ConclusionOur findings demonstrate that HMGA2 promotes TSCC invasion and metastasis; additionally, HMGA2 is an independent prognostic factor which implied that HMGA2 can be a biomarker both for prognosis and therapeutic target of TSCC.

Highlights

Metastasis to long distance organs is the main reason leading to morality of tongue squamous cell carcinoma (TSCC); the molecular mechanisms are still unknown
We demonstrate that overexpression of HMGA2 is closely associated with progression and poorer overall survival in human TSCC, and provide evidence that the expression of HMGA2 can promote the progression of TSCC by upregulating Snail and inducing the epithelial mesenchymal transition (EMT)
HMGA2 expression is up‐regulated in TSCC cells lines Overexpression of HMGA2 has been reported in many kinds of human cancers

Summary

Introduction

Metastasis to long distance organs is the main reason leading to morality of tongue squamous cell carcinoma (TSCC); the molecular mechanisms are still unknown. High mobility group AT-hook 2 (HMGA2) is highly expressed in multiple metastatic carcinomas, in which it contributes to cancer progression, metastasis and poor prognosis by upregulating Snail expression and inducing epithelial mesenchymal transition (EMT). More and more studies demonstrated that epithelial mesenchymal transition (EMT) is a key process which has been shown to be of critical biological function and significance during embryogenesis and carcinogenesis [5,6,7]. Increasing evidences have recognized that the epithelial to mesenchymal transition (EMT), a driver of invasion and metastasis of cancer, may play a pivotal role in multiple types of tumor cell metastatic dissemination by endowing cells with a more motile, invasive potential [8,9,10,11]. HMGA2 overexpression in transgenic mice causes tumorigenesis; HMGA2-knockout in mice can severely impair the mice growth and development, leading a nanous shape [25]

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Conclusion