| Summary: | 博士 === 國立臺灣大學 === 分子與細胞生物學研究所 === 99 === Helicobacter pylori is one of the most common human pathogens and the first formally recognized bacterial carcinogens associated with gastric cancer. In this study, we used a proteomics approach to discover differentially expressed proteins between normal and tumor tissues in gastric cancer patients infected with H. pylori. We found that annexin A4 was over-expressed in patients infected with H. pylori and in gastric cancer cells after H. pylori infection. We also found the same results for gastric cancer tissues by immunohistochemical staining. Through homology modeling, human annexin A4 was predicted to have the same Ca2+ binding site as several proteins with known bovine structures (PDB code, 1ANN). Previous studies have shown that interleuken-8 (IL-8) expression could be activated by H. pylori infection. In our results, IL-8 expression was inhibited by annexin A4-specific siRNA after infection. Combining these results, over-expression of annexin A4 in H. pylori-infected cells may subsequently induce IL-8, which has been found to cause tumor angiogenesis. Additionally, reports have found that annexins are associated with cell membrane repair. Thus, we investigated the role of annexin A4 in membrane repair and the downstream signal transduction pathway after H. pylori infection. Membrane repair is a universal response against physical and biological insults and enables cell survival. However, little is known about host membrane repair in the context of H. pylori infection. In our results, H. pylori disrupted the host plasma membrane and induced Ca2+ influx, which triggers the translocation of annexin family members A1 and A4 to the plasma membrane. This in turn activates a membrane repair response through the recruitment of lysosomal membranes and the induction of downstream signaling transduction pathways that promote cell survival and proliferation. Based on our data, we propose a new model by which H. pylori infection activates annexin A1 and A4 for membrane repair and how annexin A4 over-expression induced signaling promotes cell proliferation. However, continual activation of this membrane repair response signaling cascade may cause abnormal cellular states leading to carcinogenesis. This study identifies annexin A4 as a novel molecular marker for gastric cancer and links H. pylori infection to membrane repair, providing insight into potential mechanisms of carcinogenesis resulting from membrane damage.
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