HPV16 E6-E7 induces cancer stem-like cells phenotypes in esophageal squamous cell carcinoma through the activation of PI3K/Akt signaling pathway in vitro and in vivo.

Ruxing Xi,Tuotuo Gong,Beina Hui,Shenbo Fu,Xuanwei Zhang,Xin Chen,Shaomin Che,Shupei Pan,Xiaozhi Zhang,Li Zhang,Xiaolong Li,Jia Guo

doi:10.18632/oncotarget.10959

Abstract

High-risk human papillomavirus (HPV), especially HPV16, correlates with cancerogenesis of human esophageal squamous cell carcinoma (ESCC) and we have reported that HPV16 related with a poor prognosis of ESCC patients in China. We aim to investigate the potential role and mechanism of HPV16 in ESCC development and progress. Our following researches demonstrated that ESCC cells which were stably transfected by HPV16 E6-E7 lentiviral vector showed a remarkable cancer stem-like cells (CSCs) phenotype, such as: migration, invasion, spherogenesis, high expression of CSCs marker in ESCC---p75NTR, chemoresistance, radioresistance, anti-apoptosis ability in vitro and cancerogenesis in vivo. HPV16 E6-E7 induced PI3K/Akt signaling pathway activation and this affect could be effectively inhibited by LY294002, a specific PI3K inhibitor. It was also indicated that the inhibition of PI3K/Akt signaling pathway by PI3K and Akt siRNA reverse the effect which induced by HPV16 E6-E7 in ESCC cells. Taken together, the present study demonstrates that HPV16 E6-E7 promotes CSCs phenotype in ESCC cells through the activation of PI3K/Akt signaling pathway. Targeting the PI3K/Akt signaling pathway in HPV16 positive tissues is an available therapeutic for ESCC patients.

Highlights

Esophageal carcinoma was the sixth and ninth lethal malignancy worldwide in men and women in 2012 [1], respectively
HPV16 E6-E7 protein was stably expressed in HPV16 E6-E7 lentiviral vector transfected esophageal squamous cell carcinoma (ESCC) cells, which were labeled as Eca109-psb and TE-1-psb cells, while no expression of HPV16 E6-E7 protein was observed in control vector transfected ESCC cells, which were labeled as Eca109-control and TE-1-control cells
The present study firstly aims at finding the influence on cell behavior and potential mechanism after HPV16 E6-E7 infecting the ESCC cells

Summary

Introduction

Esophageal carcinoma was the sixth and ninth lethal malignancy worldwide in men and women in 2012 [1], respectively. The advanced treatment such as radical surgical resection, chemotherapy and radiotherapy are extensively applied, the 5-year survival rate of esophageal squamous cell carcinoma (ESCC) patients remained less than 30%, resulting in 400,200 deaths in 2012 worldwide [2]. High-risk HPV, including HPV16 and HPV18, expresses oncogenes E6 and E7 which can be bound to the p53 and Rb tumor suppressor, respectively, leading the rapid p53 degradation and the loss of Rb products. This might suggest the etiological involvement of high-risk HPV in ESCC [7,8,9,10]

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