Stat3 Beta Enhances Sensitivity To Concurrent Chemoradiotherapy By Inducing Cellular Necroptosis In Esophageal Squamous Cell Carcinoma

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 STAT3 alpha and STAT3 beta 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 STAT3 alpha expression and high STAT3 beta expression in the cytoplasm have a significantly better survival rate. Moreover, the ESCC patients with high STAT3 beta expression have a complete response to concurrent chemoradiotherapy. STAT3 beta-overexpressed ESCC cell lines exhibit CCRT (platinum plus radiation therapy) sensitivity, resulting in cell death. RNA sequencing found that ESCC cells highly expressing STAT3 beta undergo necrosis after CCRT. In summary, STAT3 beta 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. STAT3 beta 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 STAT3 beta and CCRT. We examined the expression of STAT3 alpha and STAT3 beta in pretreatment tumor biopsies of 105 ESCC patients who received CCRT by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3 alpha expression and high STAT3 beta expression in the cytoplasm have a significantly better survival rate, and STAT3 beta expression is an independent protective factor (HR = 0.424, p = 0.003). Meanwhile, ESCC patients with high STAT3 beta expression demonstrated a complete response to CCRT in 65 patients who received platinum plus radiation therapy (p = 0.014). In ESCC cells, high STAT3 beta expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3 beta 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 STAT3 beta cells after CCRT treatment. Overall, our study highlights that STAT3 beta could potentially be used to predict the response to platinum plus radiation therapy, which may provide an important insight into the treatment of ESCC.