Expression of hepatocyte growth factor, transforming growth factor alpha, apoptosis related proteins Bax and Bcl-2, and gastrin in human gastric cancer.
BACKGROUND
Gastric cancer is one of the most frequent neoplasms and a leading cause of the death world-wide. In recent years, epidemiological and animal studies demonstrated a link between gastric cancer and chronic infection with H. pylori. The exact mechanism responsible for the development of gastric cancer in H. pylori-infected patients still remains unclear. There is evidence that the up-regulation of certain growth factors could play an important role in the promotion of the gastric carcinogenesis.


OBJECTIVE
The present study was designed to determine the gene expression of major known growth factors such as transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and gastrin in the gastric cancer tissue, the surrounding mucosa and, for comparison, in the normal gastric mucosa. Furthermore, the luminal and plasma levels of gastrin in patients with gastric cancer were determined. In addition, the gene and protein expressions of apoptosis-related proteins such as Bax and Bcl-2 were investigated by reverse transcription-polymerase chain reaction and Western blot. Twenty-five gastric cancer patients and 40 age- and gender-matched control subjects hospitalized with non-ulcer dyspepsia were included into this study.


RESULTS
An overall H. pylori-seropositivity among gastric cancer patients was about 72% and was significantly higher than in the controls (56%). The prevalence of CagA-positive strains was also significantly higher among gastric cancer patients than in controls (56% vs. 32%). The gene expression of HGF and TGFalpha was detected more frequently in gastric cancer tissue samples than in normal gastric mucosa (52% vs. 12% for HGF and 48% vs. 24% for TGFalpha). The extent of protein expression in Western blotting analysis for HGF and TGFalpha correlated with the mRNA expression of these factors. Gene expression of gastrin was detected in the antrum of all tested patients and in the majority (84%) of gastric cancer patients. The median plasma and luminal concentrations of gastrin in gastric cancer patients were significantly higher than in controls. The gene expression of bcl-2 was detected in all (100%) and that of proapoptotic bax only in 56% of gastric cancer samples. In comparison to the surrounding non-tumorous tisssue, the gene expression of bax was significantly down-regulated and the gene expression of bcl-2 was up-regulated in gastric cancer tissue. At the protein level, Bax was not detectable and Bcl-2 was seen in 80% of gastric cancer samples.


CONCLUSIONS
It is concluded that the patients infected with H. pylori, especially with CagA-positive strains, are at a higher risk of developing a gastric cancer. An increased production and release of gastrin, as well as an over-expression of growth factors such as HGF and TGFalpha, might contribute to the gastric carcinogenesis. In addition, a dysregulation of the Bax/Bcl-2 system with significant up-regulation of Bcl-2 is observed in gastric cancer.
Konturek
P C
PC
First Department of Medicine, University Erlangen-Nuremberg, Germany. pkonturek@aol.com
Konturek
S J
SJ
Sulekova
Z
Z
Meixner
H
H
Bielanski
W
W
Starzynska
T
T
Karczewska
E
E
Marlicz
K
K
Stachura
J
J
Hahn
E G
EG
D000328:Adult; D000368:Aged; D017209:Apoptosis; D016022:Case-Control Studies; D004273:DNA, Neoplasm / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D005755:Gastrins / Q000032:analysis / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori / Q000472:pathogenicity; D017228:Hepatocyte Growth Factor / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000096:biosynthesis*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004273:DNA, Neoplasm; D005755:Gastrins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016211:Transforming Growth Factor alpha; D051028:bcl-2-Associated X Protein; D017228:Hepatocyte Growth Factor