Helicobacter pylori is a gram-negative bacterium that has been colonized in the gastric pylor area of more than half the world's population (1). In developing countries, the prevalence of H. pylori infection is up to 80%, while it is less than 30% in developed countries (1). The prevalence of H. pylori infection in Iran, as a developing country in the west of asia, has been reported between 36% to 90% (1). The H. pylori persistent colonization in infected people lead to inflammation and gastrointestinal diseases (2-3). H. pylori pathogenesis is attributed to virulence factors including CagA, VacA, and surface adhesins (3-4). H. pylori binds to the surface of gastric antral epithelial cells (GAECs) and injects CagA protein, activating the mitogen-activating protein kinase (MAPK) signaling (5-6).
MAPK is a member of the serine/threonine kinase family, activated by a rang of proteins, including extracellular signal-regulated kinases (ERK1/2), Jun N-terminal kinase (c-JNK), and P38 (6-7). The MAPK signaling pathway plays a vital role as a mediator in cell physiological events, including mitosis, motility, adhesion, metabolism, and apoptosis (8). Besides, MAPK members contribute in cell signal cascades during infection (6). The imbalance between H. pylori infection and MAPK signaling in GAECs conduct fate of infection to proliferation or apoptosis. In contrast, a balance leads to symbiosis and long survival of the pathogen (5-9).
MLKs are a family of serine/threonine protein kinases whose is mediated by mitogen activating protein kinases (MAPKKKs) (10). The set of MLKs is divided into three groups based on sequence similarity in the catalytic domain, including MLKs, leucine zipper containing kinase AZK (ZAK), and sterile- alpha-motif kinase (7, 10-11).
Zak [mitogen-activated protein kinase kinase kinase 20 (MAP3K20)] has two isoforms, zakα and zakβ, as a critical regulator of the MAPK pathway that conduct cell survival and the inflammatory response (12-13). Zak is a mediator in oxidatve stress as a pro-apoptotic factor, positive regulator of epidermal growth factor (EGFR), regulator of WNT signaling pathways, and finally a proliferation signaling factor in adenocarcinoma cells (14-15). Previous studies report that the mixed-lineage kinases (MLK) modulat prolifration in gastric adenocarcinoma cells (16-17). As a contradictory finding, recent Zak protein studies suggest an antitumor impact on gastric adenocarcinoma (7, 10-12, 16). This is a confusing finding that results of other studies indicate zak gene overexpression in the other types of adenocarcinomas, including the stomach, breast, bladder, and colorectal (13). A study on the EGFR pathway showed that both zak isoforms regulate adenocarcinoma cell proliferation in a kinase-dependent manner (17). Decreased activity of ZAK protein reduces Hela and HCT116 cells' motility, and increases expression of the MAPKs genes, including JNK and ERK (18). Since JNK regulates cellular processes including inflammation and apoptosis, and ERK is usually activated in response to various mitogens, ZAK can be considered as the confocal key to determine cell fate (18).
The previous studies show a high prevalence of H. pylori infection and gastric adenocarcinoma in Iran. This study aimed to survey zak gene expression in GAECs of gastric adenocarcinoma and gastritis patients with H. pylori infection.