Sp1-mediated transcriptional activation of miR-205 promotes radioresistance in esophageal squamous cell carcinoma

作者：Pan, Fei; Mao, Hui; Bu, Fangfang; Tong, Xin; Li, Jingjing; Zhang, Sujie; Liu, Xing; Wang, Lingxiong; Wu, Liangliang; Chen, Rui; Wei, Huafeng; Li, Bohua; Li, Cheng; Yang, Yunsheng; Steer, Clifford J.; Zhao, Jian^*; Guo, Yajun

来源：Oncotarget, 2017, 8(4): 5735-5752.

DOI：10.18632/oncotarget.13902

• miR-205
• Sp1
• radioresistance
• epithelial-mesenchymal transition
• esophageal squamous cell carcinoma

Radiotherapy for esophageal squamous cell carcinoma (ESCC) patients is limited by resistance to ionizing radiation (IR). However, the roles and mechanisms of microRNAs in radioresistance are obscure. Here, we investigated that microRNA-205 (miR-205) was upregulated in radioresistant (RR) ESCC cells compared with the parental cells. Overexpression of miR-205 promoted colony survival post-IR, whereas depletion of miR-205 sensitized ESCC cells to IR in vitro and in vivo. Further, we demonstrated that miR-205 promoted radioresistance by enhancing DNA repair, inhibiting apoptosis and activating epithelial-mesenchymal transition (EMT). Mechanistically, miR-205, upregulated post-IR, was demonstrated to be activated by Sp1 in parallel with its host gene, miR-205HG, both of which showed a perfect correlation. We also identified and validated phosphatase and tensin homolog (PTEN), as a target of miR-205 that promoted radioresistance via PI3K/AKT pathway. Lastly, increased miR-205 expression was closely associated with decreased PTEN expression in ESCC tissues and miR-205 expression predicted poor prognosis in patients with ESCC. Taken together, these findings identify miR-205 as a critical determinant of radioresistance and a biomarker of prognosis. The Sp1-mediated transcriptional activation of miR-205 promotes radioresistance through PTEN via PI3K/AKT pathway in ESCC. Inhibition of miR-205 expression may be a new strategy for radiotherapy in ESCC.

• 出版日期2017-1-24
• 单位中国人民解放军第二军医大学; 中国人民解放军总医院; 中国人民解放军第150中心医院