title: H. pylori-encoded CagA disrupts tight junctions and induces invasiveness of AGS gastric carcinoma cells via Cdx2-dependent targeting of Claudin-2.
abstract: Helicobacter pylori encoded CagA is presently the only known virulence factor that is injected into gastric epithelial cells where it destroys apical junctional complexes and induces dedifferentiation of gastric epithelial cells, leading to H. pylori-related gastric carcinogensis. However, little is known about the molecular mechanisms by which CagA mediates these changes. Caudal-related homeobox 2 (Cdx2) is an intestine-specific transcription factor highly expressed in multistage tissues of dysplasia and cancer. One specific target of Cdx2, Claudin-2, is involved in the regulation of tight junction (TJ) permeability. In this study, our findings showed that the activity of Cdx2 binding to Cdx binding sites of CdxA (GTTTATG) and CdxB (TTTTAGG) of probes corresponding to claudin-2 flanking region increased in AGS cells, infected with CagA positive wild-type strain of H. pylori, compared to CagA negative isogenic mutant-type strain. Moreover, Cdx2 upregulated claudin-2 expression at transcriptional level and translational level. In the meantime, we found that TJs of AGS cells, infected with CagA positive wild-type strain of H. pylori, compared to CagA negative isogenic mutant-type strain, were more severely destroyed, leading to wider cell gap, interference of contact, scattering and highly elevated migration of cells. Herein, this study is firstly demonstrated that H. pylori-encoded CagA disrupts TJs and induces invasiveness of AGS gastric carcinoma cells via Cdx2-dependent targeting of Claudin-2. This provides a new mechanism whereby CagA induced dedifferentiation of AGS cells, leading to malignant behavior of biology.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Third Affiliated Hospital, Xiangya School of Medicine, Central South of University, Changsha, PR China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Xi-Yun
authors.initials: XY
authors.lastname: Deng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Yin-Xue
authors.initials: YX
authors.lastname: Xi
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Tie-Li
authors.initials: TL
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, PR China.
authors.forename: Benjamin Chun-Yu
authors.initials: BC
authors.lastname: Wong
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China. Electronic address: chenminhu@vip.163.com.
authors.forename: Min-Hu
authors.initials: MH
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D000942:Antigens, Bacterial / Q000235:genetics* / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D000071616:CDX2 Transcription Factor; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D062446:Claudin-2 / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005786:Gene Expression Regulation; D016480:Helicobacter pylori / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D062446:Claudin-2; D018398:Homeodomain Proteins; C080866:cagA protein, Helicobacter pylori
keywords: AJC; CagA; Cdx2; Claudin-2; DS; EDTA; EMSA; FCS; HNF; Helicobacter pylori; IBD; Invasiveness; PI; Signal transduction; TJ; TJ zone; TJz; Tight junction; ZO-1; apical junctional complex; cytotoxin-associated gene A; desmosome; electrophoretic mobility shift assay; ethylenediaminetetraacetic acid disodium salt; fetal calf serum; hepatocyte nuclear factor; inflammatory bowel disease; propidium iodide; tight junction; zonulae occludentes-1