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

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

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5735-5752
Number of pages18
JournalOncotarget
Volume8
Issue number4
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
This work is supported in part by grants from Ministry of Science and Technology of China "973" and "863" programs (2011CB966200, 2010CB945600 and 2014AA021103), National Nature Science Foundation of China (81301781, 81402539 and 81472719), Beijing Municipal Commission of Science and Technology, and Doctorial Innovation Fund of Chinese PLA Medical School (B14013).

Keywords

  • Epithelial-mesenchymal transition
  • Esophageal squamous cell carcinoma
  • MiR-205
  • Radioresistance
  • Sp1

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