Methylseleninic acid activates Keap1/Nrf2 pathway via up-regulating miR-200a in human oesophageal squamous cell carcinoma cells.
Oesophageal squamous cell carcinoma (ESCC) occurs at a very high rates in certain regions of China. There are increasing evidences demonstrating that selenium could act as a potential anti-oesophageal cancer agent, but the precise mechanisms involved are still not completely understood. Methylseleninic acid (MSA), as a potent second-generation selenium compound, is a promising chemopreventive agent. Previous studies demonstrated that the kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) system plays a critical role in cancer prevention, but little is known about its association with MSA in ESCC cells. In the present study, we observed that MSA treatment significantly down-regulated Keap1, induced nuclear accumulation of Nrf2 and enhance the antioxidant response element (ARE) promoter activity in ESCC cells. MSA could also significantly induce miR-200a expression and inhibit Keap1 directly. Antagomir-200a could attenuate MSA treatment-induced Keap1 down-regulation in ESCC cells. Moreover, MSA-induced miR-200a expression was dependent on the mediation of Krüpple-like factor 4 (KLF4). These results reaffirm the potential role of MSA as a chemopreventive agent via the regulation of KLF4/miR-200a/Keap1/Nrf2 axis in ESCC cells.
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
Mei
M
Liu
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
Chenfei
C
Hu
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
Qing
Q
Xu
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
Lechuang
L
Chen
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
Kai
K
Ma
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China xuningzhi@cicams.ac.cn drhxzhu@cicams.ac.cn.
Ningzhi
N
Xu
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China xuningzhi@cicams.ac.cn drhxzhu@cicams.ac.cn.
Hongxia
H
Zhu
D021581:Active Transport, Cell Nucleus; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D016588:Anticarcinogenic Agents; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C000715467:KLF4 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016566:Organoselenium Compounds; C008493:methylselenic acid
Krüpple-like factor 4 (KLF4); kelch-like ECH-associated protein 1 (Keap1); methylseleninic acid (MSA); micro-ribonucleic acid-200a (miR-200a); nuclear factor E2-related factor 2 (Nrf2); oesophageal squamous cell carcinoma (ESCC)