title: Effect of myeloid differentiation primary response gene 88 on expression profiles of genes during the development and progression of Helicobacter-induced gastric cancer.
abstract: Gastric cancer is one of the most common and lethal type of cancer worldwide. Infection with Helicobacter pylori (H. pylori) is recognized as the major cause of gastric cancer. However, it remains unclear the mechanism by which Helicobacter infection leads to gastric cancer. Furthermore, the underlying molecular events involved during the progression of Helicobacter infection to gastric malignancy are not well understood. In previous studies, we demonstrated that that H. felis-infected Myd88-/-mice exhibited dramatic pathology and an accelerated progression to gastric dysplasia; however, the MyD88 downstream gene targets responsible for this pathology have not been described. This study was designed to identify MyD88-dependent genes involved in the progression towards gastric cancer during the course of Helicobacter infection.
  
  
  
  Wild type (WT) and Myd88 deficient mice (Myd88-/-) were infected with H. felis for 25 and 47 weeks and global transcriptome analysis performed on gastric tissue using MouseWG-6 v2 expression BeadChips microarrays. Function and pathway enrichment analyses of statistically significant, differential expressed genes (p < 0.05) were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tools.
  
  
  
  Helicobacter infection affected the transcriptional profile of more genes in Myd88-/-mice compared to WT mice. Infection of Myd88-/-mice resulted in the differential expression of 1,989 genes at 25 weeks (1031 up and 958 downregulated). At 47 weeks post-H.felis infection, 2,162 (1140 up and 1022 downregulated) were differentially expressed. The most significant differentially upregulated gene during Helicobacter infection in Myd88-/-mice was chitinase-like 4 (chil4), which is involved in tissue remodeling and wound healing. Other highly upregulated genes in H. felis-infected Myd88-/-mice included, Indoleamine 2,3-Dioxygenase 1 (Ido1), Guanylate binding protein 2 (Gbp2), ubiquitin D (Ubd), β2-Microglobulin (B2m), CD74 antigen (Cd74), which have been reported to promote cancer progression by enhancing angiogenesis, proliferation, migration, metastasis, invasion, and tumorigenecity. For downregulated genes, the highly expressed genes included, ATPase H+/K+ transporting, alpha subunit (Atp4a), Atp4b, Mucin 5 AC (Muc5ac), Apolipoprotein A-1 (Apoa1), and gastric intrinsic factor (Gif), whose optimal function is important in maintaining gastric hemostasis and lower expression has been associated with increased risk of gastric carcinogenesis.
  
  
  
  These results provide a global transcriptional gene profile during the development and progression of Helicobacter-induced gastric cancer. The data show that our mouse model system is useful for identifying genes involved in gastric cancer progression.
authors.affiliation: Department of Medicine, University of California, La Jolla, CA, USA.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Lozano-Pope
authors.affiliation: Department of Biology, San Diego State University, San Diego, CA, USA.
authors.forename: Arnika
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Medicine, University of California, La Jolla, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Matthias
authors.affiliation: Department of Biology, San Diego State University, San Diego, CA, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Doran
authors.affiliation: Department of Medicine, University of California, La Jolla, CA, USA. mobonyo@ucsd.edu.
authors.forename: Marygorret
authors.identifier: 0000-0001-8703-8404
authors.initials: M
authors.lastname: Obonyo
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88
keywords: Gastric cancer; Gene regulation; Helicobacter; Microarray; MyD88