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

Abstract

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.

Esophageal squamous cell carcinoma: Integrated bioinformatics analysis for differential gene expression with identification of hub genes and lncRNA

“…This study identified five pathways for ESCC pathogenesis. Transcriptional misregulation in cancer was the most significant pathway, a similar route acknowledged by previous authors [ 6 , 12 , 23 , 39 ].…”

Blocking STAT3 signaling augments MEK/ERK inhibitor efficacy in esophageal squamous cell carcinoma

“…Both MAPK and STAT3 signaling pathways are activated downstream of EGFR [ 16 , 44 ]. We have previously identified that blocking STAT3 signaling using STAT3β, a splice variant of STAT3 can enhance chemotherapy and chemoradiotherapy sensitivity in ESCC [ 45 – 47 ]. Here, we observed a negative correlation between pERK and pSTAT3 expression in ESCC cell lines (Fig.…”

“…RNA was extracted using TRIzol (15596018, Life Technologies) as previously described [ 47 ]. Total RNA was reverse transcribed using HiScript ® III RT SuperMix for qPCR (+gDNA wiper) (R323-01, Vazyme) according to the manufacturer’s instructions.…”

Carnosic Acid Induces Antiproliferation and Anti-Metastatic Property of Esophageal Cancer Cells via MAPK Signaling Pathways

“…ESCC is one of the most aggressive cancers and ranked the sixth leading cause of cancer death in the world [17]. Although progress has been made in clarifying the molecular mechanisms of its pathogenesis, ESCC still carries high mortality rates, early metastasis, and poor prognosis [18,19]. CA is a functional ingredient of rosemary that has been used as an antioxidant food for many years [20,21].…”