Thalidomide attenuates oral epithelial cell apoptosis and pro-inflammatory cytokines secretion induced by radiotherapy via the miR-9-3p/NFATC2/NF-κB axis

• Published in: Biochemical and biophysical research communications 2022-05, Vol.603, p.102-108
• Main Authors: Liang, Leifeng, Chen, Liangwen, Liu, Gongwei, Jiang, Liujun, Que, Lilin, Chen, Jie, Wang, Rensheng, Zhu, Haisheng
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Cytokines - metabolism; Epithelial Cells - cytology; Epithelial Cells - metabolism; Humans; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miR-9-3p; NF-kappa B - metabolism; NF-κB; NFATC Transcription Factors - genetics; NFATC2; Quality of Life; Radiation-induced oral mucositis; Stomatitis; Thalidomide; Thalidomide - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.03.030

Oral mucositis is the most common oral complication of cancer patients receiving radiotherapy or chemotherapy, leading to poor quality of life. Increasing clinical studies demonstrated that thalidomide (THD) can effectively ameliorate radiation-induced oral mucositis (RIOM). Here we established an experimental mouse model, radiation-induced human oral epithelial cells (HOECs), and further investigate the underlying mechanism the THD protective effect against RIOM. Combined with RNA sequencing result, we selected the gene nuclear factor of activated T cells c2 (NFATC2) as the most interesting candidate. THD downregulated NFATC2 expression, attenuated human oral epithelial cells (HOECs) apoptosis and promoted pro-inflammatory factors secretion. Further studies show that overexpression of NFATC2 in HOECs promotes cells apoptosis and pro-inflammatory cytokines level, while inhibition of NFATC2 present an opposite effect. Additionally, the regulatory miRNA of NFATC2 was predicted using StarBase, and the targeting relationship between miR-9-3p and NFATC2 was confirmed using a dual-luciferase reporter gene assay. miR-9-3p mimic reversed the elevated cell apoptosis and pro-inflammatory cytokines level by radiation or NFATC2-overexpression. Furthermore, NFATC2 upregulated the phosphorylation of p65, thus activating the NF-κB pathway in RIOM; while miR-9-3p reduced this effect. In conclusion, THD attenuates oral epithelial cell apoptosis and pro-inflammatory cytokines secretion induced by radiotherapy via the miR-9-3p/NFATC2/NF- NF-κB axis. •Thalidomide attenuates oral epithelial cell apoptosis and pro-inflammatory cytokines secretion induced by radiotherapy. NFATC2 plays an essential role in the protective function of Thalidomide towards radiation-induced oral mucositis (RIOM).•Increased NFATC2 expression promotes human oral epithelial cells (HOECs) apoptosis and pro-inflammatory cytokines secretion. While miR-9-3p downregulates NFATC2 expression and its effect on HOECs.•miR-9-3p and NFATC2 interaction in radiation treated HOECs works by regulating NF-κB signaling pathway. miR-9-3p/NFATC2/NF-κB axis might be suitable therapeutic targets in RIOM.