Helicobacter pylori promotes the expression of Krüppel-like factor 5, a mediator of carcinogenesis, in vitro and in vivo.
Helicobacter pylori is the strongest known risk factor for the development of gastric adenocarcinoma. H. pylori expresses a repertoire of virulence factors that increase gastric cancer risk, including the cag pathogenicity island and the vacuolating cytotoxin (VacA). One host element that promotes carcinogenesis within the gastrointestinal tract is Krüppel-like factor 5 (KLF5), a transcription factor that mediates key cellular functions. To define the role of KLF5 within the context of H. pylori-induced inflammation and injury, human gastric epithelial cells were co-cultured with the wild-type cag(+) H. pylori strain 60190. KLF5 expression was significantly upregulated following co-culture with H. pylori, but increased expression was independent of the cag island or VacA. To translate these findings into an in vivo model, C57BL/6 mice were challenged with the wild-type rodent-adapted cag(+) H. pylori strain PMSS1 or a PMSS1 cagE(-) isogenic mutant. Similar to findings in vitro, KLF5 staining was significantly enhanced in gastric epithelium of H. pylori-infected compared to uninfected mice and this was independent of the cag island. Flow cytometry revealed that the majority of KLF5(+) cells also stained positively for the stem cell marker, Lrig1, and KLF5(+)/Lrig1(+) cells were significantly increased in H. pylori-infected versus uninfected tissue. To extend these results into the natural niche of this pathogen, levels of KLF5 expression were assessed in human gastric biopsies isolated from patients with or without premalignant lesions. Levels of KLF5 expression increased in parallel with advancing stages of neoplastic progression, being significantly elevated in gastritis, intestinal metaplasia, and dysplasia compared to normal gastric tissue. These results indicate that H. pylori induces expression of KLF5 in gastric epithelial cells in vitro and in vivo, and that the degree of KLF5 expression parallels the severity of premalignant lesions in human gastric carcinogenesis.
Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America. jennifer.noto@vanderbilt.edu
Jennifer M
JM
Noto
Tinatin
T
Khizanishvili
Rupesh
R
Chaturvedi
M Blanca
MB
Piazuelo
Judith
J
Romero-Gallo
Alberto G
AG
Delgado
Shradha S
SS
Khurana
Johanna C
JC
Sierra
Uma S
US
Krishna
Giovanni
G
Suarez
Anne E
AE
Powell
James R
JR
Goldenring
Robert J
RJ
Coffey
Vincent W
VW
Yang
Pelayo
P
Correa
Jason C
JC
Mills
Keith T
KT
Wilson
Richard M
RM
Peek
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000209:etiology / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D015870:Gene Expression; D044404:Genomic Islands; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics* / Q000382:microbiology / Q000473:pathology
D001426:Bacterial Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; C074689:VacA protein, Helicobacter pylori