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Article

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

1
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
2
Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
3
Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China
4
Departments of Radiation Oncology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou 515041, China
5
Departments of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou 515041, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Samuel C. Mok
Cancers 2021, 13(4), 901; https://doi.org/10.3390/cancers13040901
Received: 2 February 2021 / Revised: 12 February 2021 / Accepted: 14 February 2021 / Published: 21 February 2021
(This article belongs to the Special Issue Neoadjuvant- and Immuno-Therapy in Esophageal Cancer)
The 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. View Full-Text
Keywords: STAT3β; concurrent chemoradiotherapy; necroptosis; esophageal squamous cell carcinoma STAT3β; concurrent chemoradiotherapy; necroptosis; esophageal squamous cell carcinoma
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MDPI and ACS Style

Zheng, Z.-Y.; Yang, P.-L.; Luo, W.; Yu, S.-X.; Xu, H.-Y.; Huang, Y.; Li, R.-Y.; Chen, Y.; Xu, X.-E.; Liao, L.-D.; Wang, S.-H.; Huang, H.-C.; Li, E.-M.; Xu, L.-Y. STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma. Cancers 2021, 13, 901. https://doi.org/10.3390/cancers13040901

AMA Style

Zheng Z-Y, Yang P-L, Luo W, Yu S-X, Xu H-Y, Huang Y, Li R-Y, Chen Y, Xu X-E, Liao L-D, Wang S-H, Huang H-C, Li E-M, Xu L-Y. STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma. Cancers. 2021; 13(4):901. https://doi.org/10.3390/cancers13040901

Chicago/Turabian Style

Zheng, Zhen-Yuan, Ping-Lian Yang, Wei Luo, Shuai-Xia Yu, Hong-Yao Xu, Ying Huang, Rong-Yao Li, Yang Chen, Xiu-E Xu, Lian-Di Liao, Shao-Hong Wang, He-Cheng Huang, En-Min Li, and Li-Yan Xu. 2021. "STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma" Cancers 13, no. 4: 901. https://doi.org/10.3390/cancers13040901

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