title: MicroRNA-200 (miR-200) cluster regulation by achaete scute-like 2 (Ascl2): impact on the epithelial-mesenchymal transition in colon cancer cells.
abstract: Ascl2, a basic helix-loop-helix transcription factor, is a downstream target of WNT signaling that controls the fate of intestinal cryptic stem cells and colon cancer progenitor cells. However, its involvement in colon cancer and downstream molecular events is largely undefined; in particular, the mechanism by which Ascl2 regulates the plasticity of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) programs in colon cancer cells remains unknown. In this study, we systematically demonstrate that Ascl2 loss of function in colon cancer cells promotes MET by derepressing the expression of microRNA (miR)-200s (i.e. miR-200b, miR-200a, miR-429, miR-200c, and miR-141) and further activating their expression through a transcriptional mechanism that involves direct binding to the most proximal E-box (E-box2) in the miR-200b-a-429 promoter. Activation of miR-200s due to Ascl2 deficiency led to the inhibition of ZEB1/2 expression and the alteration of epithelial and mesenchymal features. Transfection of miR-200b, miR-200a, and miR-429 inhibitors into Ascl2-deficient colon cancer cells promoted the epithelial-mesenchymal transition in a reversible manner. Transfection of miR-200a or miR-429 inhibitors into Ascl2-deficient colon cancer cells increased cellular proliferation and migration. Ascl2 mRNA levels and the miR-200a, miR-200b, miR-200c, miR-141, or miR-429 levels in the colon cancerous samples were inversely correlated. These results provide the first evidence of a link between Ascl2 and miR-200s in the regulation of EMT-MET plasticity in colon cancer.
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Yin
authors.initials: Y
authors.lastname: Tian
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Pan
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Shang
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and Department of Gastroenterology, Zunyi Medical University, Guizhou 563000, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhu
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Jun
authors.initials: J
authors.lastname: Ye
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhong
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: He
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and pengzhh@yahoo.com.cn.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Peng
authors.affiliation: From the Institute of Gastroenterology of People's Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, China and rongquanw@hotmail.com.
authors.forename: Rongquan
authors.initials: R
authors.lastname: Wang
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D012097:Repressor Proteins; D014157:Transcription Factors; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C065501:ASCL2 protein, human; C533896:MIRN200 microRNA, human; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human
keywords: Colon Cancer; Colorectal Cancer; Epithelial-Mesenchymal Transition (EMT); MicroRNA (miRNA); Transcription Regulation; Wnt Signaling