title: Notch1 pathway-mediated microRNA-151-5p promotes gastric cancer progression.
abstract: Gastric carcinoma is the third leading cause of lethal cancer worldwide. Previous studies showed that Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor, promotes gastric cancer progression. It has been demonstrated that a significant cross-talk interplays between Notch pathways and microRNAs (miRNAs) in controlling tumorigenesis. This study identified an intronic microRNA-151 (miR-151), which consists of two mature miRNAs, miR-151-3p and miR-151-5p, as a Notch1 receptor-induced miRNA in gastric cancer cells. Activation of Notch1 pathway enhanced expressions of miR-151 and its host gene, focal adhesion kinase (FAK), in gastric cancer cells. The levels of miR-151 in gastric cancer samples were higher than those of adjacent non-tumor samples. Activated Notch1 pathway induced CBF1-dependent FAK promoter activity. The ectopic expression of miR-151 promoted growth and progression of SC-M1 gastric cancer cells including cell viability and colony formation, migration, and invasion abilities. Activated Notch1 pathway could augment progression of gastric cancer cells through miR-151-5p and FAK. The mRNA levels of pluripotency genes, Nanog and SOX-2, tumorsphere formation ability, tumor growth, and lung metastasis of SC-M1 cells were elevated by activated Notch1 pathway through miR-151-5p. Furthermore, miR-151-5p could target 3'-untranslated region (3'-UTR) of p53 mRNA and down-regulate p53 level in SC-M1 cells. Mechanistically, Notch1/miR-151-5p axis contributed to progression of SC-M1 cells through down-regulation of p53 which in turn repressed FAK promoter activity. Taken together, these results suggest that Notch1 pathway and miR-151-5p interplay with p53 in a reciprocal regulation loop in controlling gastric carcinogenesis.
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Present address: Research Center for Tumor Medical Science, China Medical University, Taichung 404, Taiwan.
authors.forename: Kai-Wen
authors.initials: KW
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Fang
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Kuo-Hung
authors.initials: KH
authors.lastname: Huang
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Tzu-Ting
authors.initials: TT
authors.lastname: Huang
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.affiliation: School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Rong-Hong
authors.initials: RH
authors.lastname: Hsieh
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.|Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Tien-Shun
authors.initials: TS
authors.lastname: Yeh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D051417:Focal Adhesion Kinase 1 / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C548886:MIRN151a microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; C497570:RBPJ protein, human; D051881:Receptor, Notch1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: FAK; Notch1 receptor; gastric carcinogenesis; miR-151; p53