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.
Bibliographical noteFunding Information:
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2015R1A2A1A05001884), a Translational Research Centre for Protein Function Control Grant (2016R1A5A11004694), and a National R&D Program for Cancer Control grant from the Ministry for Health, Welfare, and Family Affairs (Republic of Korea; 0920050), and the 2011 Post-Doc. Development Program of Pusan National University. The authors have no competing financial interests related to this study. The authors thank Dr Woo Song Ha and Dr Kyoung Hyuk Ko (Gyeongsang National University Hospital) for providing GC tissue samples.
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine