Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition.

Si-Rui Ma,Wei-Ming Wang,Cong-Fa Huang,Wen-Feng Zhang,Zhi-Jun Sun

doi:10.18632/oncotarget.3556

Abstract

Anterior gradient protein 2 (AGR2) is a novel biomarker with potential oncogenic role. We sought to investigate the diagnostic and prognostic role of AGR2 on head and neck squamous cell carcinoma (HNSCC) with an emphasis on its correlation of cancer stemloid cells (CSC) and epithelial mesenchymal transition (EMT). We found that AGR2 protein levels were higher in HNSCC than in normal oral mucosa. High levels of AGR2 were associated with the T category, pathological grade and lymph node metastasis of HNSCC. Expression of AGR2 increased in recurring HNSCC after radiotherapy and in post cisplatin-based chemotherapeutic tissues. In HNSCC cell lines, knock-down of AGR2 induced apoptosis, reduced sphere formation, and down-regulated Survivin, Cyclin D1, Bcl2, Bcl2l1, Slug, Snail, Nanog and Oct4. In addition, over-expressed AGR2 in transgenic mice with spontaneous HNSCC was associated with lost function of Tgfbr1 and/ or lost function of Pten. In vitro knockdown TGFBR1 in HNSCC cell lines increased AGR2 expression. These results suggest that AGR2 is involved in EMT and self-renewal of CSC and may present a potential therapeutic target (oncotarget) for HNSCC.

Highlights

Cancer stem cells (CSC) or cancer initiating cell are thought to be responsible for tumor metastasis, chemoresistance, radioresistance and recurrence [1]
To determine whether Anterior gradient protein 2 (AGR2) expression was associated with head and neck squamous cell carcinoma (HNSCC) in humans, we interrogated the Tissue Cancer Genome Atlas dataset [23] and Oncomine database [24]
In a meta-analysis of gene expression profiling, increased AGR2 DNA copy number of mRNA expression was significantly increased in many cancers compared with the normal counterpart (P < 0.001, Supplementary Fig. 1), thereby suggesting that AGR2 may act as an oncogene in human cancer cells

Summary

Introduction

Cancer stem cells (CSC) or cancer initiating cell are thought to be responsible for tumor metastasis, chemoresistance, radioresistance and recurrence [1]. The CSC theory suggests that a part of cancer cells with self-renewal and multi-potential differentiation abilities are responsible for the maintenance and progression of tumors [2, 3]. Over expressions of Sox and Oct 4 in numerous malignancies were reportedly related to the pluripotency, proliferation, and self-renewal properties of embryonic stem cells (ESCs) and germ cells [5]. Accumulated studies demonstrated that EMT is a common event in malignancies, and contributes to the invasion process and cancer stem cell development. Previous studies showed that metastasis cancer cells, which probably underwent EMT, could exhibit CSC phenotype [2]. Snail and Slug effectively mediate cell survival and are involved in the acquisition of a self-renewal CSC-like trait (e.g., NANOG, HDAC1, DHAC3, TCF4, KLF4, and GPC3) [8]

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