Constitutive activated STAT3 is an essential regulator and therapeutic target in esophageal squamous cell carcinoma

// Fang Tian 1, 2 , Xiawen Yang 4 , Ying Liu 1, 2 , Xiao Yuan 3 , Tianli Fan 1, 2 , Fanmiao Zhang 3 , Jimin Zhao 1, 2 , Jing Lu 1, 2 , Yanan Jiang 1, 2 , Ziming Dong 1, 2 and Yili Yang 3 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P. R. China 2 Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, Henan, P. R. China 3 Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, P. R. China 4 Division of Molecular Signaling, Department of Advanced Biomedical Research, University of Yamanashi, Yamanashi, Japan Correspondence to: Fang Tian, email: tianfang418@163.com Yili Yang, email: yyl@ism.cams.cn Keywords: esophageal squamous cell carcinoma, STAT3, apoptosis, patient-derived xenograft, targeting therapy Received: March 14, 2017     Accepted: August 07, 2017     Published: September 12, 2017 ABSTRACT Esophageal carcinoma is among the most common cancers worldwide and a leading cause of cancer death [ 1 ]. Large numbers of studies indicated that chronic inflammation is closely associated with its development [ 21 , 25 ]. Furthermore, the JAK/STAT pathway, which plays a critical role in inflammation and immunity, has been implied in a number of malignancies [ 11 ]. It has been shown that targeting the pathway affected the growth, apoptosis, and metastasis of cultured esophageal squamous cell carcinoma cells [ 26 ]. We found in the present study that STAT3 is constitutively activated in a subgroup of esophageal squamous cell carcinoma cell lines and primary tumors. Altered expressions of STAT3 target genes were found in these tumors by using RNAseq and qPCR analysis. Cytokines that activate STAT3 affected the expression of STAT3 target genes and promoted the growth of the ESCC cells, which could be blocked by STAT3 inhibitor and specific siRNA. Inhibition of STAT3 also suppressed the growth and colony formation, and induced apoptosis in the esophageal squamous cell carcinoma cells containing constitutively activated STAT3. Furthermore, the STAT3 inhibitor effectively blocked the growth of patient-derived tumor xenografts that harbored phosphorylated STAT3, but acted less effective on the xenografts derived from primary tumors that contained low levels of activated STAT3. These results indicated that activated STAT3 plays a critical role in the survival and growth of a subgroup of esophageal squamous cell carcinoma, and may serve as a target for precision therapeutic intervention.