Gene expression profiling in human gastric mucosa infected with Helicobacter pylori.
Pathogenic mechanisms associated with Helicobacter pylori infection enhance susceptibility of the gastric epithelium to carcinogenic conversion. We have characterized the gene expression profiles of gastric biopsies from 69 French Caucasian patients, of which 43 (62%) were infected with H. pylori. The bacterium was detected in 27 of the 42 antral biopsies examined and in 16 of the 27 fundic biopsies. Infected biopsies were selected for the presence of chronic active gastritis, in absence of metaplasia and dysplasia of the gastric mucosa. Infected antral and fundic biopsies exhibited distinct transcriptional responses. Altered responses were linked with: (1) the extent of polymorphonuclear leukocyte infiltration, (2) bacterial density, and (3) the presence of the virulence factors vacA, babA2, and cagA. Robust modulation of transcripts associated with Toll-like receptors, signal transduction, the immune response, apoptosis, and the cell cycle was consistent with expected responses to Gram-negative bacterial infection. Altered expression of interferon-regulated genes (IFITM1, IRF4, STAT6), indicative of major histocompatibility complex (MHC) II-mediated and Th1-specific responses, as well as altered expression of GATA6, have previously been described in precancerous states. Upregulation of genes abundantly expressed in cancer tissues (UBD, CXCL13, LY96, MAPK8, MMP7, RANKL, CCL18) or in stem cells (IFITM1 and WFDC2) may reveal a molecular switch towards a premalignant state in infected tissues. Tissue microarray analysis of a large number of biopsies, which were either positive or negative for the cag-A virulence factor, when compared to each other and to noninfected controls, confirmed observed gene alterations at the protein level, for eight key transcripts. This study provides 'proof-of-principle' data for identifying molecular mechanisms driving H. pylori-associated carcinogenesis before morphological evidence of changes along the neoplastic progression pathway.
Hofman
Véronique J
VJ
Faculty of Medicine, INSERM ERI-21, Nice Cedex, France. hofman.p@chu-nice.fr
Moreilhon
Chimène
C
Brest
Patrick D
PD
Lassalle
Sandra
S
Le Brigand
Kevin
K
Sicard
Dominique
D
Raymond
Josette
J
Lamarque
Dominique
D
Hébuterne
Xavier A
XA
Mari
Bernard
B
Barbry
Pascal Jp
PJ
Hofman
Paul M
PM
D000328:Adult; D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D016022:Case-Control Studies; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D005602:France; D005748:Gastric Fundus / Q000737:chemistry / Q000382:microbiology* / Q000473:pathology; D005753:Gastric Mucosa / Q000737:chemistry / Q000382:microbiology* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods*; D015964:Gene Expression Regulation, Bacterial; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000302:isolation & purification* / Q000472:pathogenicity; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D020556:Neutrophil Infiltration; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000235:genetics; D010641:Phenotype; D011706:Pyloric Antrum / Q000737:chemistry / Q000382:microbiology* / Q000473:pathology; D012329:RNA, Bacterial / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000382:microbiology* / Q000473:pathology; D046888:Tissue Array Analysis; D014158:Transcription, Genetic
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D012329:RNA, Bacterial; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori; D010447:Peptide Hydrolases