New carcinogenic mechanisms of Helicobacter pylori infection

PROJECT SUMMARY/ABSTRACT Gastric adenocarcinoma (GC) is one of the most common and deadliest malignancies in the world. The main- stay of current GC therapy is surgery that has notable morbidity and mortality. Therefore, it is critically im- portant to develop new effective therapeutic approaches to improve the standard of care for GC patients. The etiology of GC is linked to gastric infection with bacteria Helicobacter pylori (H. pylori). However, it not well understood how these bacteria cause GC. It is also unclear why some infected individuals are at higher risk developing GC than others. Our new studies suggest that H. pylori-induced dysregulation of C1qBP and ARF proteins plays an im- portant role in gastric carcinogenesis. Moreover, certain tumorigenic variants of H. pylori bacteria specifically inhibit functional interactions between these proteins, producing an environment that promotes GC develop- ment. This hypothesis is supported by strong preliminary data generated by combinatory approaches of prote- omics, computational analyses, testing of animal tissues, and gastric cancer cells. In Aim 1, we will dissect the interplay between ARF and C1gBP proteins and examine their carcinogenic characteristics. We will employ multiple H. pylori clinical isolates, primary gastric cells, and gastric organoids. In Aim 2, we will investigate the tumorigenic regulation of C1gBP and ARF in the stomach using animal models of H. pylori infection. In Aim 3, we will characterize how bacterial virulence factors contribute to GC develop- ment. We will also investigate the clinicopathological significance of C1gBP-ARF interactions using clinical specimens and H. pylori clinical isolates. Taken together, we expect that testing of our new hypothesis will open new translational opportunities for pre- vention and treatment of GC. In addition, analyses of the unique clinical material will allow us to generate the first data on the clinicopathological and prognostic significance of ARF/C1qBP signaling, and provide novel mechanistic insights into the contribution of bacterial variability to gastric carcinogenesis.