Sp1-mediated transcriptional activation of miR-205 promotes radioresistance in esophageal squamous cell carcinoma
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Fei Pan1,3,*, Hui Mao1,*, Fangfang Bu1,2,4,*, Xin Tong1,2,4, Jingjing Li1, Sujie Zhang1, Xing Liu5, Lingxiong Wang1, Liangliang Wu1, Rui Chen2, Huafeng Wei1,4, Bohua Li2, Cheng Li1, Yunsheng Yang3, Clifford J. Steer6, Jian Zhao1,2,4 and Yajun Guo7
1 Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China
2 International Joint Cancer Institute, the Second Military Medical University, Shanghai, P.R. China
3 Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, P.R. China
4 Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China
5 The 150th Hospital of Chinese PLA, Luoyang, P.R. China
6 Departments of Medicine and Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, Minnesota, USA
7 State Key Laboratory of Antibody Medicine and Targeting Therapy, Shanghai, P.R. China
* These authors have contributed equally to this work
Jian Zhao, email:
Keywords: miR-205; Sp1; radioresistance; epithelial-mesenchymal transition; esophageal squamous cell carcinoma
Received: October 19, 2016 Accepted: November 24, 2016 Published: December 11, 2016
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.
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