Overexpression of ZEB2-AS1 promotes epithelial-to-mesenchymal transition and metastasis by stabilizing ZEB2 mRNA in head neck squamous cell carcinoma.

Pengfei Diao,Zhongwu Li,Jie Cheng,Han Ge,Yaping Wu,Yanling Wang,Jianrong Yang,Yue Song,Jin Li

doi:10.1111/jcmm.14318

Abstract

The long noncoding RNAs (lncRNAs) have been increasingly appreciated as key players underlying tumourigenesis and hold great potentials as prognostic biomarkers and therapeutic targets. However, their roles in head neck squamous cell carcinoma (HNSCC) have remained incompletely known. Here, we sought to reveal the oncogenic roles and clinical significance of a tumour‐associated lncRNA, zinc finger E‐box binding homeobox 2 antisense RNA 1 (ZEB2‐AS1), in HNSCC. ZEB2‐AS1 was aberrantly overexpressed in a fraction of HNSCC samples. Its overexpression significantly associated with large tumour size, cervical node metastasis and reduced overall and disease‐free survival. Antisense oligonucleotides (ASO)‐mediated ZEB2‐AS1 depletion markedly inhibited cell proliferation, migration and invasion while triggered apoptosis in HNSCC cells in part via modulating ZEB2 mRNA stability. Enforced overexpression of ZEB2 largely attenuated the phenotypic changes resulted from ZEB2‐AS1 inhibition except the impaired cell proliferation. In addition, ZEB2‐AS1 was required for TGF‐β1‐induced epithelial‐mesenchymal transition (EMT) in vitro. Significantly reduced tumour growth and lung metastasis were observed in ZEB2‐AS1‐depleted cells in HNSCC xenograft animal models. Taken together, our findings reveal that overexpression of ZEB2‐AS1 associates with tumour aggressiveness and unfavourable prognosis by serving as a putative oncogenic lncRNA and a novel prognostic biomarker in HNSCC.

Highlights

Head neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with about 500 000 new cases diagnosed each year and remains as one leading cause of cancer‐related death.[1]
Several oncogenic long noncoding RNAs (lncRNAs) have been demonstrated with potent anti‐cancer effects when they were therapeutically inhibited in vivo.[4,27]
Our results reveal that lncRNA ZEB2‐AS1 probably serves as pro‐oncogenic noncoding RNA by stabilizing ZEB2 mRNA and hold potentials as a novel prognostic biomarker and therapeutic target in HNSCC with its aberrant overexpression

Summary

| INTRODUCTION

Head neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with about 500 000 new cases diagnosed each year and remains as one leading cause of cancer‐related death.[1]. Several prognostic factors like clinical stage, invasive depth, status of surgical margins as well as cervical node involvement have been identified to be significantly associated with local recurrence, distant metastasis and patient survival.[3] these prognostic biomarkers for HNSCC are still far from optimal. The lncRNA zinc finger E‐box binding homeobox 2 antisense RNA1 (ZEB2‐AS1) has attracted our attentions as it was highly expressed in several solid cancers like hepatocellular carcinoma, lung cancer and pancreatic cancer It usually promoted cell proliferation, invasion and EMT while inhibited apoptosis in diverse cancer contexts.[14,15,16,17] These findings suggested that ZEB2‐AS1 was an oncogenic NAT with incompletely delineated roles in human cancer. We sought to determine the expression pattern of ZEB2‐AS1 in primary HNSCC and uncover its roles during HNSCC tumourigenesis by loss‐of‐function assay and xenograft animal model

| MATERIALS AND METHODS

Findings

| DISCUSSION