STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma.

Zhen-Yuan Zheng,Lian-Di Liao,He-Cheng Huang,Shuai-Xia Yu,Xiu-E Xu,Hong-Yao Xu,Li-Yan Xu,Ying Huang,Shao-Hong Wang,Rong-Yao Li,Ping-Lian Yang,Wei Luo,Yang Chen,En-Min Li

doi:10.3390/cancers13040901

Abstract

Simple SummaryThe prognosis of esophageal squamous cell carcinoma (ESCC) patients is poor, with a five-year survival of 15–34%. We examined the expression of STAT3α and STAT3β in pretreatment tumor biopsies of 105 ESCC patients who received concurrent chemoradiotherapy (CCRT) by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3α expression and high STAT3β expression in the cytoplasm have a significantly better survival rate. Moreover, the ESCC patients with high STAT3β expression have a complete response to concurrent chemoradiotherapy. STAT3β-overexpressed ESCC cell lines exhibit CCRT (platinum plus radiation therapy) sensitivity, resulting in cell death. RNA sequencing found that ESCC cells highly expressing STAT3β undergo necrosis after CCRT. In summary, STAT3β could be potentially used to predict the response to CCRT, which may provide an important insight into the treatment of ESCC.Concurrent chemoradiotherapy (CCRT), especially platinum plus radiotherapy, is considered to be one of the most promising treatment modalities for patients with advanced esophageal cancer. STAT3β regulates specific target genes and inhibits the process of tumorigenesis and development. It is also a good prognostic marker and a potential marker for response to adjuvant chemoradiotherapy (ACRT). We aimed to investigate the relationship between STAT3β and CCRT. We examined the expression of STAT3α and STAT3β in pretreatment tumor biopsies of 105 ESCC patients who received CCRT by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3α expression and high STAT3β expression in the cytoplasm have a significantly better survival rate, and STAT3β expression is an independent protective factor (HR = 0.424, p = 0.003). Meanwhile, ESCC patients with high STAT3β expression demonstrated a complete response to CCRT in 65 patients who received platinum plus radiation therapy (p = 0.014). In ESCC cells, high STAT3β expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3β enhances sensitivity to CCRT (platinum plus radiation therapy). Mechanistically, through RNA-seq analysis, we found that the TNF signaling pathway and necrotic cell death pathway were significantly upregulated in highly expressed STAT3β cells after CCRT treatment. Overall, our study highlights that STAT3β could potentially be used to predict the response to platinum plus radiation therapy, which may provide an important insight into the treatment of ESCC.

Highlights

Signal transducer and activator of transcription 3 (STAT3) was initially identified as an acute-phase response factor activated by cytokines and is activated by growth factors and oncogenes [1,2,3]
These results suggest STAT3β to be a new marker for concurrent chemoradiotherapy (CCRT) treatment in patients with esophageal cancer
We found that cyclin A2, cyclin B2, and PLK1 were downregulated, and receptor-interacting serine/threonine-protein kinases 1 (RIPK1) and mixed lineage kinase domain-like protein (MLKL) were upregulated in STAT3β expression cells after treatment with

Summary

Introduction

Signal transducer and activator of transcription 3 (STAT3) was initially identified as an acute-phase response factor activated by cytokines and is activated by growth factors and oncogenes [1,2,3]. STAT3 dimerization, nuclear translocation and the initiation of transcription occur [4,5]. STAT3 is aberrantly hyperactivated in various human cancers and correlates with a poor prognosis. It is crucial for regulating cell proliferation, resistance to apoptosis, angiogenesis, invasion, and metastasis [2,6,7,8]. Clinical observations support the tumor suppressor role of STAT3 in head and neck cancer and breast cancer [13,14,15,16]. STAT3 knockout mice demonstrated higher levels of astrocyte proliferation and invasion [10]. Conditional ablation of STAT3 in intestinal epithelial cells was shown to enhance the progression of benign adenomas in ApcMin mice [11]

Objectives

Methods

Results

Conclusion