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Approximately 0.8 million people died from gastric cancer in the year 2018. It is the third leading cause of cancer-related mortality in Indian males and the incidence rate is fifth of total cancer cases when both sexes are combined. Although, various causative agents have been associated with this disease, Helicobacter pylori, a slowly growing, microaerophilic, gram-negative bacterium has been identified as the main carcinogen responsible for gastric cancer. Due to poor health, nutrition and hygiene practices, H. pylori manage to colonize in stomachs of ~50% of the human population during their childhood and take decades to show disease symptoms. H. pylori are broadly classified in two groups based on the presence or absence of the cytotoxin-associated gene (cag) pathogenicity island (PAI). cag+ strains are more virulent, cause increased gastric inflammation, peptic ulcer and gastric cancer. Infected people have at least two-fold increased risk of gastric cancer when compared with the uninfected individuals. Even though gastric cancer is of epithelial origin, phagocytes are responsible in modulating the disease pathogenesis to a significant extent. Phagocytes are recruited in infected gastric mucosa and actively secrete inflammatory modulators leading to generation of reactive oxygen species (ROS) that alter gastric epithelial cell (GEC) proliferation and death. H. pylori infection can also directly induce oxidative stress in GECs through generation of ROS and regulates proinflammatory cytokine production, inflammation as well as cell death. Gastric epithelial ROS, either endogenous or induced by H. pylori, enhance expression of hypoxia-inducible factor 1 (Hif1). Hif1 is the main transcription factor induced in hypoxia and is inevitably one of the key oncogenic factors expressed in solid tumors. This protein has a hypoxia-inducible α subunit and a constitutively expressed β subunit. Hif1α plays crucial roles in tumor development and carcinogenesis and has been associated with malignant progression of gastric cancer. Like many epithelial-origin solid tumours, dissemination or gastric cancer (gastric cancer metastasis) is mediated by the epithelial to mesenchymal transition (EMT), an important mechanism which converts immotile epithelial cells into motile and invasive mesenchymal cells. These motile cells have the capacity to dissolve the basement membrane and enter the blood vessels and lymphatics (intravasate) following extravasation and settling in distant organs. Several epithelial proteins are either degraded or compartmentalized and new set of mesenchymal markers are expressed in cells undergoing EMT which further modulate disease progression and development of resistance to therapies. A whole new transcriptional program is induced to maintain the mesenchymal phenotype. The role of oncoproteins in the whole process of cancer progression and metastasis is often dependent on their interaction with interacting partner proteins. As posttranslational modification of proteins regulate their stability, ability to interact with other proteins as well as functions, studying posttranslational modification of oncoproteins also can fetch a lot of important information which would help us in developing personalized therapies. As the above discussion reveals, molecular events in gastric cancer is complex and multi-factorial. Both pathogen and host-factors contribute in the disease pathogenesis. Based on these, we are currently investigating how H. pylori increase life span of host GECs; the role of E3 ubiquitin ligases in H. pylori-mediated gastric cancer metastasis and the effect of hypoxia on the EMT process of gastric cancer metastasis. --------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |