Expression of nuclear factor-kappa B and target genes in gastric precancerous lesions and adenocarcinoma: association with Helicobactor pylori cagA (+) infection

Abstract

Aim: To examine the expression of nuclear factor kappaB (NF-kappaB) and its target genes in intestinal metaplasia (IM), dysplasia (DYS) and gastric carcinoma (GC) infected with Helicobacter pylori (H pylori) and to investigate the mechanism underlying H pylori cytotoxin associated gene A (cag A) infection leading to gastric adenocarcinoma.

Methods: Expressions of NF-kappaB/p65 and its target genes: c-myc, cyclinD1 and bcl-xl were immunohistochemically examined in 289 cases of gastric biopsy and resection specimens from patients with IM, DYS and GC infected with H pylori. H pylori in the above mentioned tissues was detected by Warthin-Starry stain and rapid urease tests. IgG antibody to cagA in sera of the patients was measured by ELISA.

Results: The positive rates of NF-kappaB/p65 were significantly higher in groups with cagA of IMI-II(28/33), IM III(48/52), DYSI(27/31), DYS II-III(28/32), GC(35/40) than in groups without cagA of IMI-II(4/17), IMIII(3/20), DYSI(3/20), DYSII-III(6/21), GC(10/23). The expressions of c-myc, cyclinD1, and bcl-xl were significantly higher in groups with cagA of IM III(47/52, 49/52, 46/52), DYSII-III(29/32, 26/32, 25/32) than in groups without cagA of IM III(8/20, 7/20, 5/20), DYSII-III(10/21, 8/21, 3/21), which were in conformity with the expression of NF-kappaB in IM III, and DYSII-III. A significantly higher expression level of NF-kappaB/p65, c-myc, cyclinD1 and bcl-xl was detected in intestinal type GC(27/28, 18/28, 22/28, 24/28) than in diffuse type GC(8/12, 3/12, 3/12, 6/12), respectively.

Conclusion: There may be two different molecular mechanisms in the occurrence of intestinal and diffuse type gastric carcinomas. Intestinal type gastric carcinoma is strongly associated with high expression of c-myc, cyclinD1 and bcl-xl through NF-kappaB/p65 activated by H pylori cagA. Inhibiting the activity of NF-kappaB is an effective and promising way to prevent intestinal type gastric carcinoma.

Figure 1

Type III intestinal metaplasia. Blue and brown stained mucin in cells. HID/AB/PAS stain × 200.

Figure 2

Dark-brown stained bacillary structures of positive H pylori in epithelium of mucosa. Warthin-Starry stain × 400.

Figure 3

A: Positive expression of NF-κB/p65 in IM. Some inflammatory cells showed plasmatic stain. Immunohistochemical stain × 200. B: Positive expression of cyclinD1 in IM. Some inflammatory cells showed nuclear and plasmatic stains. Immunohistochemical stain × 200. C: Positive expres-sion of c-myc in IM. Some inflammatory cells showed nuclear and plasmatic stains. Immunohistochemical stain × 200. D: Positive expression of bcl-xl in IM. Some inflammatory cells showed plasmatic stain. Immunohistochemical stain × 200.

Figure 4

A: Positive expression of NF-κB/p65 in DYS. Some inflammatory cells showed plasmatic stain. Immunohistochemical stain × 200. B: Positive expression of c-myc in DYS III. Some inflammatory cells showed nuclear and plasmatic stains. Immunohistochemical stain × 400.

Figure 5

A: Positive expression of NF-κB/p65 in intestinal type gastric carcinoma. Immunohistochemical stain × 200. B: Positive expression of c-myc in intestinal type gastric carcinoma. Immunohistochemical stain × 200. C: Positive expression of cyclinD1 in intestinal type gastric carcinoma. Immunohistochemical stain × 200. D: Positive expression of bcl-xl in intestinal type gastric carcinoma. Immunohistochemical stain × 400.