title: MicroRNA 34c gene down-regulation via DNA methylation promotes self-renewal and epithelial-mesenchymal transition in breast tumor-initiating cells.
abstract: Tumor-initiating cells (T-ICs), a subpopulation of cancer cells with stem cell-like properties, are related to tumor relapse and metastasis. Our previous studies identified a distinct profile of microRNA (miRNA) expression in breast T-ICs (BT-ICs), and the dysregulated miRNAs contribute to the self-renewal and tumorigenesis of these cells. However, the underlying mechanisms for miRNA dysregulation in BT-ICs remain obscure. In the present study, we demonstrated that the expression and function of miR-34c were reduced in the BT-ICs of MCF-7 and SK-3rd cells, a breast cancer cell line enriched for BT-ICs. Ectopic expression of miR-34c reduced the self-renewal of BT-ICs, inhibited epithelial-mesenchymal transition, and suppressed migration of the tumor cells via silencing target gene Notch4. Furthermore, we identified a single hypermethylated CpG site in the promoter region of miR-34c gene that contributed to transcriptional repression of miR-34c in BT-ICs by reducing DNA binding activities of Sp1. Therefore, miR-34c reduction in BT-ICs induced by a single hypermethylated CpG site in the promoter region promotes self-renewal and epithelial-mesenchymal transition of BT-ICs.
authors.affiliation: Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Yu
authors.affiliation: School of Life Sciences, Sun-Yat-Sen University, Guangzhou 510006, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: School of Life Sciences, Sun-Yat-Sen University, Guangzhou 510006, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cancer Epigenetics and Gene Therapy Group, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Jingde
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Center of Medical Research, Sun Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cancer Epigenetics and Gene Therapy Group, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: Cancer Epigenetics and Gene Therapy Group, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center of Medical Research, Sun Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Lv
authors.affiliation: Cancer Epigenetics and Gene Therapy Group, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Kelong
authors.initials: K
authors.lastname: Ma
authors.affiliation: Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
authors.forename: Fengxi
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul 140-742, Republic of Korea. Electronic address: parkjh@sookmyung.ac.kr.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China; School of Life Sciences, Sun-Yat-Sen University, Guangzhou 510006, China. Electronic address: songerwei02@yahoo.com.cn.
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D016329:Sp1 Transcription Factor
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