title: Sp1-mediated transcriptional activation of miR-205 promotes radioresistance in esophageal squamous cell carcinoma.
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.
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.|Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Pan
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.|International Joint Cancer Institute, the Second Military Medical University, Shanghai, P.R. China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Bu
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.|International Joint Cancer Institute, the Second Military Medical University, Shanghai, P.R. China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.
authors.forename: Sujie
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The 150th Hospital of Chinese PLA, Luoyang, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.
authors.forename: Lingxiong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Wu
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, P.R. China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, P.R. China.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Departments of Medicine and Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Steer
authors.affiliation: Key Laboratory of Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, P.R. China.|International Joint Cancer Institute, the Second Military Medical University, Shanghai, P.R. China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Antibody Medicine and Targeting Therapy, Shanghai, P.R. China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011836:Radiation Tolerance; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics*; D016019:Survival Analysis; D015533:Transcriptional Activation
chemical_list: D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D016329:Sp1 Transcription Factor; C534425:MIR205, human; C108209:SP1 protein, human; C494929:PTEN protein, human
keywords: Sp1; epithelial-mesenchymal transition; esophageal squamous cell carcinoma; miR-205; radioresistance