SATB2 promotes radiationresistance of esophageal squamous cell carcinoma by regulating epithelial-to-mesenchymal transition via Wnt/β-catenin pathway

Chen Lin ¹ Youyi Wu ² Yuchen Qian ¹ Jiayi Li ¹ Youdi He ¹ Huang Yu ¹ Cong-Ying Xie ¹ Huafang Su ^1*

• ¹ First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
• ² Department Oncology Radiotherapy, The Third Affiliated Hospital of Wenzhou Medical University, Rui'an People Hospital, Rui'an, China

Purpose: radioresistance remains predominant factor contributing to local recurrence in esophageal squamous cell carcinoma (ESCC). SATB2, as a transcriptional co-gene, may affect the radioresistance of cancer cells. Consequently, this study aims to elucidate the mechanism by which SATB2 modulates radiotherapy resistance in esophageal cancer. Methods: we identified highly expressed genes associated with radioresistance in ESCC using the MsigDB database and conducted survival correlation analysis. A radioresistant esophageal squamous cell carcinoma cell line (KYSE150R) was established using the gradient dose method, and RT-qPCR was used to detect the expression of SATB2 in KYSE150 and KYSE150R cells. CCK-8, Transwell, colony formation assay, and cell scratching were performed to determine and evaluate cell proliferation, cell migration, and cell invasion. Furthermore, the expression levels of mRNA and protein were correlated using WB and RT-qPCR. Mitochondrial membrane potential and apoptosis detection kits were used to evaluate the level of apoptosis. Finally, a mouse subcutaneous xenograft tumor model was employed to elucidate the role of SATB2 on the radiotherapy resistance of ESCC in vivo. Results: Bioinformatics analysis indicate that SATB2 is linked to increased drug resistance in esophageal cancer. The results demonstrate that suppression of SATB2 decelerates cell proliferation and migration, accelerate apoptosis, inhibits the GSK-3β(Ser9) phosphorylation, and reduces β-catenin and target gene C-myc. The addition of the Wnt/β-catenin signaling pathway agonist (CHIR-99021) reversed these effects. Xenograft studies in mice revealed that knockdown of SATB2 reduced ESCC radioresistance. Conclusion: we concluded SATB2 may dysregulate the Wnt/β-catenin pathway, thereby facilitating EMT progression and conferring radioresistance.