title: The reciprocal regulation loop of Notch2 pathway and miR-23b in controlling gastric carcinogenesis.
abstract: Gastric carcinoma is one of the most common malignancies and the third highest cause of global cancer-related death. Notch2 receptor intracellular domain (N2IC), the activated form of Notch2 receptor, enhances gastric carcinogenesis. MicroRNAs (miRNAs) act as either oncogenes or tumor suppressors in tumorigenesis and cross-talk with Notch pathways. Herein, microRNA-23b (miR-23b) was identified as a Notch2 receptor-related miRNA and its role in gastric carcinogenesis was investigated. Levels of miR-23b in stomach adenocarcinoma samples were down-regulated, whereas those of Notch2 receptor, v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1), and E2F1 transcripts were up-regulated. Results also showed that N2IC down-regulated miR-23b expression in gastric cancer cells through up-regulating E2F1. The miR-23b inhibited gastric tumorigenesis including growth, viability, epithelial-mesenchymal transition, and abilities of colony formation, migration, invasion, and tumorsphere formation. Mechanistically, miR-23b suppressed tumor progression and pluripotency gene expression and affected tumorsphere ultra-structure in gastric cancer cells via targeting Notch2 receptor or Ets1. Furthermore, miR-23b diminished the xenografted tumor growth and lung metastasis of SC-M1 gastric cancer cells through Notch2 pathway. Our results suggest that Notch2 pathway and miR-23b interplay in a reciprocal regulation loop in gastric cancer cells and this axis plays an important role in gastric carcinogenesis.
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, 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, Taiwan.
authors.forename: Yueh-Hsin
authors.initials: YH
authors.lastname: Ping
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: An-Ming
authors.initials: AM
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Ke
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei, 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, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Kuo-Hung
authors.initials: KH
authors.lastname: Huang
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.|Genome Research Center, National Yang-Ming University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tien-Shun
authors.initials: TS
authors.lastname: Yeh
mesh_terms: D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary / Q000628:therapy; D008297:Male; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C494041:ETS1 protein, human; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C497764:NOTCH2 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D051883:Receptor, Notch2
keywords: E2F1; Ets1; Notch2 receptor; gastric carcinogenesis; miR-23b