Our acquiring that CagA expression can induce JNK dependent apoptosis within a polarized epithelium is exciting with respect to information suggesting that JNK signaling has evolved being a cell editing mechanism to take out aberrant cells from inside of an epithelium . Activation of JNK signaling could represent a host response aimed at removing cells containing CagA protein in the gastric epithelium. Similarly, P. aeruginosa mediated activation of JNK signaling during the intestinal epithelium of Drosophila can set off epithelial renewal as a host defense mechanism. On the other hand, this procedure can turned out to be pathogenic and lead to dramatic overproliferation of intestinal cells in animals harboring oncogenic Ras mutations . In H. pylori infection, which might persist for several years prior to the development of gastric cancer, JNK mediated apoptosis may very well be an efficient mechanism to restrict pathogenic results over the gastric epithelium.
Even so, this method of tissue editing may also increase cell turnover, contributing to accumulation of genetic mutations in host cells. Our information display that acquisition of an oncogenic mutation in host epithelial cells encountering CagA mediated JNK Tyrphostin 9 pathway activation can advertise tumor progression, suggesting that this likely host defense approach can become tumorigenic in specified genetic contexts . Transgenic expression of CagA was lately noticed to bring about neoplastic transformation within a mouse model, giving proof for CagA?s part being a bacterial oncoprotein in mammals . The low incidence and delayed advancement of gastrointestinal tumors in these mice was attributed to reduced expression of CagA inside the surviving animals, as higher expression was assumed for being lethal throughout embryogenesis.
Furthermore, secondary mutations have been identified while in the tumors, but their possible cooperation with host cell signaling pathways activated by CagA expression was not addressed . Infection with CagA optimistic H. pylori can be acknowledged to induce an invasive discover this phenotype in tissue culture cells , but likely results within the oncogenic mutations existing in these immortalized cell lines is unknown. Even though we didn’t demonstrate the sufficiency of CagA to induce tumor phenotypes in our Drosophila model, our data support a vital part for CagA in selling tumor progression in combination with oncogene activation. We believe that employing an inducible expression process in Drosophila permitted us to bypass the toxicity observed upon CagA expression in mice and cell culture designs, consequently revealing novel interactions between CagA and host cell proteins with downstream results on apoptosis and tumorigenesis.
Though half the world?s population is considered to get contaminated with H. pylori, a minor percentage of those men and women will build gastric cancer .