TFAP2A Regulates Nasopharyngeal Carcinoma Growth and Survival by Targeting HIF-1α Signaling Pathway

Dingbo Shi,Tiebang Kang,Yun Zhang,Lingyi Fu,Wangbing Chen,Jingshu Wang,Wei Guo,Wuguo Deng,Wenlin Huang,Fangyun Xie,Yun Tian

doi:10.1158/1940-6207.capr-13-0271

Abstract

TFAP2A is a transcription factor that orchestrates a variety of cell processes, including cell growth and tissue differentiation. However, the regulation of TFAP2A in human nasopharyngeal carcinoma tumorigenesis and its precise mechanism of action remain largely unknown. In this study, we investigated the biologic role and clinical significance of TFAP2A in nasopharyngeal carcinoma growth and progression and identified the underlying molecular mechanisms. We found that TFAP2A was highly expressed in various nasopharyngeal carcinoma cell lines and tumor tissue specimens and was significantly correlated with hypoxia-inducible factor-1α (HIF-1α) expression. A positive correlation of TFAP2A overexpression with advanced tumor stage, local invasion, clinical progression, and poor prognosis of patients with nasopharyngeal carcinomas were also observed. Moreover, we found that knockdown of TFAP2A expression by siRNA significantly inhibited tumor cell growth in nasopharyngeal carcinoma cell lines and in a subcutaneous xenograft mouse model by targeting the HIF-1α-mediated VEGF/pigment epithelium-derived factor (PEDF) signaling pathway. Treatment of nasopharyngeal carcinoma cells with TFAP2A siRNA dramatically inhibited the expression and the release of VEGF protein but did not change the level of PEDF protein, resulting in a significant reduction of the ratio of VEGF/PEDF. Pretreatment with a HIF-1α siRNA did not significantly change the TFAP2A siRNA-mediated inhibition in cell viability. Our results indicate that TFAP2A regulates nasopharyngeal carcinoma growth and survival through the modulation of the HIF-1α-mediated VEGF/PEDF signaling pathway, and suggest that TFAP2A could be a potential prognostic biomarker and therapeutic target for nasopharyngeal carcinoma treatment.

Highlights

Nasopharyngeal carcinoma is a squamous epithelial cancer arising from the lateral wall surface of nasopharynx [1]
Transfection with a hypoxia-inducible factor-1a (HIF-1a) siRNA or TFAP2A siRNA alone considerably inhibited cell viability and VEGF expression (Fig. 4C and D); pretreatment with a HIF-1a siRNA did not significantly enhance the TFAP2A-mediated inhibitions in cell viability (Fig. 4D). These results indicate that the TFAP2A knockdown-mediated inhibition of cell growth may be partially through inhibition of the HIF-1a/ VEGF signaling in nasopharyngeal carcinoma cells
We detected the high expression of TFAP2A in nasopharyngeal carcinoma tumor tissues and cell lines, which is correlated with nasopharyngeal carcinoma growth, survival, and HIF-1a expression

Summary

Introduction

Nasopharyngeal carcinoma is a squamous epithelial cancer arising from the lateral wall surface of nasopharynx [1]. The incidence rate of nasopharyngeal carcinoma is very high in China, Japan, and other Southeast Asian countries. Nasopharyngeal carcinoma in the world [2]. Treatment of nasopharyngeal carcinoma is usually via radiotherapy. Nasopharyngeal carcinoma is more sensitive to ionizing radiation than other cancers [4]. Nasopharyngeal carcinoma has a poor prognosis because of late presentation of lesions, poor understanding of the molecular mechanisms, no suitable markers for early detection, and poor response to available therapies [7, 8]. There is an urgent need for further understanding the molecular mechanisms in nasopharyngeal carcinoma tumorigenesis and for identifying effective prognostic and diagnostic biomarkers and new therapeutic targets to improve the prognosis of patients

Methods

Results

Conclusion