title: miRNA-200c increases the sensitivity of breast cancer cells to doxorubicin through the suppression of E-cadherin-mediated PTEN/Akt signaling.
abstract: Doxorubicin (ADR) is successfully used to treat breast cancer, however, it is often associated with the acquired resistance of breast cancer cells which eliminates the therapeutic efficiency of ADR, leading to relapse and a poorer prognosis. It has been reported that microRNA-200c (miRNA-200c), a non-coding RNA, is important in the epithelial to mesenchymal transition (EMT) and metastasis in breast cancer cells. Recent evidence demonstrated that miRNA-200c is also regulated in chemotherapeutic drug resistance, however, the precise mechanism by which this occurs remains unclear. In this study, we demonstrated that the loss of miRNA-200c correlates with the acquired resistance of breast cancer cells to ADR. In addition, the loss of miRNA-200c correlated with decreased levels of E-cadherin and PTEN, and increased levels of ZEB1 and phospho-Akt (p-Akt) in ADR-resistant breast cancer cells (MCF-7/ADR cells). More importantly, we demonstrated that the gain of miRNA-200c results in an increased sensitivity of cells to ADR, downregulation of ZEB1, upregulation of E-cadherin and PTEN, and inactivation of Akt signaling. Following the co-transfection of E-cadherin siRNA, the miRNA-200c-mediated regulation of Akt signaling and PTEN was inhibited. Results of the present study also demonstrated that Akt signaling is involved in the ADR resistance of breast cancer cells since LY294002, an inhibitor of Akt signaling, partially restored the sensitivity of MCF-7/ADR cells to ADR. In conclusion, miRNA-200c inhibited Akt signaling through its effects on E-cadherin and PTEN, resulting in the inhibition of ADR resistance in breast cancer cells.
authors.affiliation: Department of Medical Oncology, Subei People's Hospital, Yangzhou, Jiangsu 225000, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
authors.forename: Xingxiang
authors.initials: X
authors.lastname: Xu
authors.forename: Xizhi
authors.initials: X
authors.lastname: Zhang
authors.forename: Buhai
authors.initials: B
authors.lastname: Wang
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Min
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D015703:Antigens, CD; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D015820:Cadherins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human