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

• Published in: The Journal of pathology 2017-04, Vol.241 (5), p.614-625
• Main Authors: Kang, Dong Woo, Yang, Eun Sun, Noh, Yu Na, Hwang, Won Chan, Jo, Se‐Young, Suh, Young‐Ah, Park, Won Sang, Choi, Kang‐Yell, Min, Do Sik
• Format: Article
• Language: English
• Subjects: ABCG2; Antigens, Bacterial - genetics; Antigens, Bacterial - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Carcinogenesis; Cell Self Renewal; Cell Transformation, Neoplastic; chemoresistance; Cytotoxins - genetics; Cytotoxins - metabolism; Down-Regulation; gastric cancer‐initiating cells; Gene Expression Regulation, Neoplastic; Helicobacter Infections - genetics; Helicobacter Infections - metabolism; Helicobacter Infections - microbiology; Helicobacter pylori; Helicobacter pylori - pathogenicity; Helicobacter pylori - physiology; Helicobacter pylori CagA; Humans; MicroRNAs - genetics; miR‐320a; miR‐4496; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Stomach Neoplasms - genetics; Stomach Neoplasms - microbiology; Stomach Neoplasms - pathology; Up-Regulation; Virulence Factors - genetics; Virulence Factors - metabolism; β‐catenin
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.4866

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.