Significance of PI3K/AKT signaling pathway in metastasis of esophageal squamous cell carcinoma and its potential as a target for anti-metastasis therapy

// Bin Li 1, 2, 3, 4 , Wen Wen Xu 1, 2, 4 , Alfred King Y. Lam 5 , Yang Wang 2 , Hui-Fang Hu 2 , Xin Yuan Guan 3, 6 , Yan Ru Qin 7 , Nassim Saremi 5 , Sai Wah Tsao 1, 3 , Qing-Yu He 2 and Annie L. M. Cheung 1, 3, 4 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China 2 College of Life Science and Technology, Jinan University, Guangzhou, China 3 Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China 4 The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China 5 Department of Pathology, Griffith Medical School and Menzies Health Institute Queensland, Gold Coast Campus, Gold Coast, QLD, Australia 6 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China 7 Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China Correspondence to: Annie L. M. Cheung, email: lmcheung@hku.hk Keywords: PI3K/AKT, esophageal squamous cell carcinoma, metastasis, targeted therapy Received: July 04, 2016      Accepted: February 20, 2017      Published: March 17, 2017 ABSTRACT Metastasis is the most lethal hallmark of esophageal squamous cell carcinoma (ESCC). The aim of the study is to identify key signaling pathways that control metastasis in ESCC. Highly invasive ESCC sublines (designated I3 cells) were established through three rounds of selection of cancer cells invading through matrigel-coated chambers. Gene expression profile of one of the I3 sublines was compared with that of its parental cell line using cDNA microarray analysis. Gene ontology and pathway analyses of the differentially expressed genes (both upregulated and downregulated) indicated that genes associated with cellular movement and the AKT pathway were associated with increased cancer cell invasiveness. Western blot analysis confirmed increased phosphorylated AKT (p-AKT), N-cadherin and decreased E-cadherin expression in the I3 cells. Immunohistochemistry was used to evaluate the clinical significance of p-AKT expression in ESCC, and the results showed higher p-AKT nuclear expression in lymph node metastases when compared with primary carcinoma. Inactivation of the PI3K/AKT pathway with specific inhibitors, or with PTEN overexpression, resulted in reversed cadherin switching and inhibited cancer cell motility. Inhibition of the pathway by treatment with wortmannin markedly suppressed experimental metastasis in nude mice. Our data demonstrated the importance of the PI3K/AKT signaling pathway in ESCC metastasis and support PI3K/AKT as a valid therapeutic target in treatment of metastatic ESCC.