title: MicroRNA-320a and microRNA-4496 attenuate Helicobacter pylori cytotoxin-associated gene A (CagA)-induced cancer-initiating potential and chemoresistance by targeting β-catenin and ATP-binding cassette, subfamily G, member 2.
abstract: Infection with Helicobacter pylori is closely linked to an increased risk of gastric cancer. Although cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is known to be a causal factor for gastric carcinogenesis, the molecular link between CagA and gastric cancer-initiating cell (CIC)-like properties remains elusive. Here, we demonstrate that CagA is required for increased expression of β-catenin and its target CIC markers via downregulation of microRNA (miR)-320a and miR-4496. CagA promoted gastric CIC properties and was responsible for chemoresistance. miR-320a and miR-4496 attenuated the in vitro self-renewal and tumour-initiating capacity of CagA-expressing CICs by targeting β-catenin. Moreover, miR-320a and miR-4496 decreased CagA-induced chemoresistance by targeting ATP-binding cassette, subfamily G, member 2 (ABCG2) at the transcriptional and post-transcriptional levels, respectively. Combination therapy with 5-fluorouracil and miR-320a/miR-4496 suppressed gastric tumourigenesis and metastatic potential in an orthotopic mouse model, probably via suppression of CagA-induced CIC properties and chemoresistance. Our results provide novel evidence that CIC properties, chemoresistance and tumourigenesis associated with H. pylori are linked to CagA-induced upregulation of β-catenin and ABCG2. These data provide novel insights into the molecular mechanisms of CagA-induced carcinogenisis and the therapeutic potential of of miR-320a and miR-4496. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.|Institute of Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Kang
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors.forename: Yu Na
authors.initials: YN
authors.lastname: Noh
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors.forename: Won Chan
authors.initials: WC
authors.lastname: Hwang
authors.affiliation: Institute of Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Jo
authors.affiliation: Institute of Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Suh
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.|Translational Research Centre for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.|Translational Research Centre for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
authors.forename: Do Sik
authors.initials: DS
authors.lastname: Min
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D000942:Antigens, Bacterial / Q000235:genetics* / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis; D000066673:Cell Self Renewal; D002471:Cell Transformation, Neoplastic; D003603:Cytotoxins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D016480:Helicobacter pylori / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D015854:Up-Regulation; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D003603:Cytotoxins; C572916:MIRN320 microRNA, human; C000622117:MIRN4496 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D037521:Virulence Factors; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori
keywords: ABCG2; Helicobacter pylori CagA; chemoresistance; gastric cancer-initiating cells; miR-320a; miR-4496; β-catenin