Rebamipide attenuates Helicobacter pylori CagA-induced self-renewal capacity via modulation of β-catenin signaling axis in gastric cancer-initiating cells.
Rebamipide, a mucosal-protective agent, is used clinically for treatment of gastritis and peptic ulcers induced by Helicobacter pylori (H. pylori) which is associated with increased risk of gastric cancer. Although rebamipide is known to inhibit the growth of gastric cancer cells, the action mechanisms of rebamipide in gastric carcinogenesis remains elusive. Here, we show that rebamipide suppresses H. pylori CagA-induced β-catenin and its target cancer-initiating cells (C-IC) marker gene expression via upregulation of miRNA-320a and -4496. Rebamipide attenuated in vitro self-renewal capacity of H. pylori CagA-infected gastric C-IC via modulation of miRNA-320a/-4496-β-catenin signaling axis. Moreover, rebamipide enhanced sensitivity to chemotherapeutic drugs in CagA-expressed gastric C-IC. Furthermore, rebamipide suppressed tumor-initiating capacity of gastric C-IC, probably via suppression of CagA-induced C-IC properties. These data provide novel insights for the efficacy of rebamipide as a chemoprotective drug against H. pylori CagA-induced carcinogenic potential.
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea; Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Dong Woo
DW
Kang
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Yu Na
YN
Noh
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Won Chan
WC
Hwang
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea; Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
Kang-Yell
KY
Choi
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea; Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea. Electronic address: minds@pusan.ac.kr.
Do Sik
do S
Min
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects*; D016481:Helicobacter Infections / Q000378:metabolism / Q000382:microbiology; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D016513:Mice, SCID; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C495270:CTNNB1 protein, human; D015363:Quinolones; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori; C052785:rebamipide; D000409:Alanine
5-Fluorouracil (PubChem CID: 3385); Gastric cancer-initiating cells; Helicobacter pylori CagA; Irinotecan hydrochloride (PubChem CID: 74990); Paclitaxel (PubChem CID: 36314); Rebamipide; Rebamipide (PubChem CID: 5042); microRNA-320a/-4496; β-Catenin