title: Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer.
abstract: Helicobacter pylori (H. pylori) infection is considered a major risk factor for gastric cancer. CagA behaves as a major bacterial oncoprotein playing a key role in H. pylori-induced tumorigenesis. Cancer stem cells (CSCs) are believed to possess the ability to initiate tumorigenesis and promote progression. Although studies have suggested that cancer cells can exhibit CSC-like properties in the tumor microenvironment, it remains unclear whether H. pylori infection could induce the emergence of CSC-like properties in gastric cancer cells and, the underlying mechanism. Here, gastric cancer cells were co-cultured with a CagA-positive H. pylori strain or a CagA isogenic mutant strain. We found that H. pylori-infected gastric cancer cells exhibited CSC-like properties, including an increased expression of CSC specific surface markers CD44 and Lgr5, as well as that of Nanog, Oct4 and c-myc, which are known pluripotency genes, and an increased capacity for self-renewal, whereas these properties were not observed in the CagA isogenic mutant strain-infected cells. Further studies revealed that H. pylori activated Wnt/β-catenin signaling pathway in a CagA-dependent manner and that the activation of this pathway was dependent upon CagA-positive H. pylori-mediated phosphorylation of β-catenin at the C-terminal Ser675 and Ser552 residues in a c-met- and/or Akt-dependent manner. We further demonstrated that this activation was responsible for H. pylori-induced CSC-like properties. Moreover, we found the promoter activity of Nanog and Oct4 were upregulated, and β-catenin was observed to bind to these promoters during H. pylori infection, while a Wnt/β-catenin inhibitor suppressed promoter activity and binding. Taken together, these results suggest that H. pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote CSC-like properties in gastric cancer cells.
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yong
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xiao
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China; Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, CA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China. Electronic address: shimingyang@yahoo.com.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Yang
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016480:Helicobacter pylori / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D015533:Transcriptional Activation; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C495270:CTNNB1 protein, human; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori
keywords: Gastric cancer; Helicobacter pylori; Nanog; Oct4; Wnt/β-catenin