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

Fang Tian,Xiao Yuan,Jimin Zhao,Jing Lu,Yili Yang,Yanan Jiang,Ziming Dong,Ying Liu,Fanmiao Zhang,Tianli Fan,Xiawen Yang

doi:10.18632/oncotarget.20838

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.

Highlights

Esophageal cancer is one of the most common malignancies that causes the death of more than 400,000 people annually worldwide [1]
The close association between inflammation and esophageal cancers prompted us to examine the expression of STAT3 and its activation in primary esophageal squamous cell carcinomas
In EC9706 cells, IL-6, EGF, LIF and INF-γall activated STAT3 in a dose-dependent manner, the level of total STAT3 was not increased during the 30-minutes treatment (Figure 1C)

Summary

Introduction

Esophageal cancer is one of the most common malignancies that causes the death of more than 400,000 people annually worldwide [1]. STAT family transcription factors (STAT1, 2, and 3) to regulate the expression of a diverse set of target genes [4], and affects profoundly cell growth, differentiation, and apoptosis [5]. It plays a critical role in inflammation, innate and adaptive immunity, and involved in the development of human disorders, including autoimmune diseases and cancers [6]. STAT3 has been an actively soughtafter target for anti-cancer drug discovery, and a number of specific inhibitors have been developed for further clinical studies [11]

Methods

Results

Conclusion