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

Abstract

// Ruxing Xi 1 , Shupei Pan 1 , Xin Chen 2 , Beina Hui 1 , Li Zhang 1 , Shenbo Fu 1 , Xiaolong Li 3 , Xuanwei Zhang 1 , Tuotuo Gong 1 , Jia Guo 1 , Xiaozhi Zhang 1 , Shaomin Che 1 1 Department of Radiotherapy, The First Hospital Affiliated of Xi&rsquo;an Jiao Tong University, Xi&rsquo;an, Shaan Xi, 710061, P.R.China 2 Department of Radiotherapy, People&rsquo;s Hospital of Shaanxi Province, Xi&rsquo;an, Shaan Xi, 710068, P.R.China 3 Department of Radiotherapy, The People&rsquo;s Liberation Army 323 Hospital, Xi&rsquo;an, Shaan Xi, 710054, P.R.China Correspondence to: Xiaozhi Zhang, email: zhang9149@sina.com Shaomin Che, email: chersm@126.com Keywords: esophageal squamous cell carcinoma, HPV16 E6-E7, CSCs, PI3K, p75NTR Received: October 22, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: July 16, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: July 30, 2016 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.