title: Slug-upregulated miR-221 promotes breast cancer progression through suppressing E-cadherin expression.
abstract: It is generally regarded that E-cadherin is downregulated during tumorigenesis via Snail/Slug-mediated E-cadherin transcriptional reduction. However, this transcriptional suppressive mechanism cannot explain the failure of producing E-cadherin protein in metastatic breast cancer cells after overexpressing E-cadherin mRNA. Here we reveal a novel mechanism that E-cadherin is post-transcriptionally regulated by Slug-promoted miR-221, which serves as an additional blocker for E-cadherin expression in metastatic tumor cells. Profiling the predicted E-cadherin-targeting miRNAs in breast cancer tissues and cells showed that miR-221 was abundantly expressed in breast tumor and metastatic MDA-MB-231 cells and its level was significantly higher in breast tumor or MDA-MB-231 cells than in distal non-tumor tissue and low-metastatic MCF-7 cells, respectively. MiR-221, which level inversely correlated with E-cadherin level in breast cancer cells, targeted E-cadherin mRNA open reading frame (ORF) and suppressed E-cadherin protein expression. Depleting or increasing miR-221 level in breast cancer cells induced or decreased E-cadherin protein level, leading to suppressing or promoting tumor cell progression, respectively. Moreover, miR-221 was specifically upregulated by Slug but not Snail. TGF-β treatment enhanced Slug activity and thus increased miR-221 level in MCF-7 cells. In summary, our results provide the first evidence that Slug-upregulated miR-221 promotes breast cancer progression via reducing E-cadherin expression.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.|Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liang
authors.affiliation: Center for Inflammation, Immunity and Infection &Department of Biology, Georgia State University, Atlanta, GA30302, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.|Center for Inflammation, Immunity and Infection &Department of Biology, Georgia State University, Atlanta, GA30302, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences (NAILS), Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.|Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, Nanjing, Jiangsu 210093, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D015820:Cadherins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D035683:MicroRNAs; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; C513384:CDH1 protein, human; C525709:MIR221, human