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Infection with the gut-pathogen Helicobacter pylori is the single, most important risk factor in the development of gastric cancer. Although there is a rising incidence in mortality resulting from this malignancy, the exact mechanism underlying the initiation and progression of bacterial-induced gastric tumorigenesis is still not completely understood. Several studies implicate the activation of the Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway as a cellular trigger for promoting carcinogenes. In this thesis, I studied the role of the STAT3 signaling pathway in H. pylori mediated tumorigenesis, and attempted to delineate mechanisms involved. I have found that H. pylori activates the STAT3 signaling pathway both in vitro and in vivo, to promote carcinogenesis. Pivotal for H. pylori mediated STAT3 activation are the bacterial effector protein CagA and host receptor components, the gp130 and the IL-6αR subunits. Further investigation into the mechanism of STAT3 induction identified a key role for cholesterol-enriched membrane lipid rafts. Bacterial invasion and CagA injection into host cells was also dependent on lipid raft integrity. Co-fractionation via the use of sucrose gradients, which permits the isolation of lipid rafts, identified H. pylori CagA to be associated with these membrane microdomains. CagA, once injected into the cell, appears to interact with the inner leaflet of the host plasma membrane via a charge association that either directly or indirectly anchors it to the negatively charged anionic lipids in the cytoplasmic membrane. In addition, janus kinases were recruited to rafts upon H. pylori infection. In this thesis, I present a dynamic model of STAT3 activation, which requires the interaction of lipid raft associated proteins, H. pylori CagA and recruited JAKs with non-lipid raft receptor components to support STAT3 signaling. This study is significant since it provides insight into the possible mechanisms by which H. pylori induces gastric cancer and furthermore, it facilitates the development of novel therapeutic targets directed against bacterial induced carcinogenesis.

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Introduction: Since the era of Marshall, H. pylori has been to be implicated in many upper digestive tract diseases, such as gastritis, peptic ulcer disease, mucosa- associated lymphoid tissue lymphoma, and even gastric adenocarcinoma. In 1994, WHO recognized H. pylori as a definite carcinogen for gastric cancer. Many study had shown that microbial pathogens may induce oxidative stress in infected host cell. And this may also represent an important mechanism leading to epithelial injury in H. pyloric infection. Oxidative stress plays a role in altering epithelial cell turnover, accelerating apoptosis and increasing oxidative DNA damage. One of the evidences for this phenomenon is increasing level of reactive oxygen species (ROS) measured in the mucosa of infected stomach. ROS may activate HIF-11£\ transcription. HIF-1£\ overexpression had been detected in several human cancers. Furthermore its overexpression correlates significantly with highly aggressive disease, lymph node metastasis, clinicopathological status and poor prognosis in some cancer types. It may up regulate hypoxia-induced gene, such as the vascular endothelial growth factor (VEGF) transcription and angiogenesis. Therefore we propose Sp1-pVHL-HIF-1£\ pathway may play a role the carcinogenesis in Hp -associated gastric cancer. Material and methods: We took Paraffin-embedded specimens from 89patients, who had undergone UGI endoscopy and gastric mucosa biopsy. We assessed the Sp1, pVHL, HIF-1£\ in all cases by immunohistochemistry and then evaluated their correlation with the H pylori infection. Chi-square and Fisher¡¦s exact test was performed to determine the significance of the difference between Sp1, pVHL, HIF-1£\. Results: There are not significant difference in nuclear Sp1 expression and H. pylori different (p=0.59). Sp1 expression was not significant, (p=0.91, 0.93, 0.36, 0.42, 0.51) with sex, age, location, TNM stage and cell differentiation. pVHL protein was mainly expressed in the cytoplasm. There are no significant difference with H. pylori infection (p=0.14). The relationship pVHL protein expression between with sex, age, lesion site, TNM stage and cell differentiation were not significant (p=0.39, 0.70, 0.69, 0.83, 0.70). HIF-1£\ protein was mainly expressed in the nuclei. There are not significant association with H. pylori infection (p=0.49). There were no significant differences between HIF-1£\ protein expression with sex, age, location, TNM stage and cell differentiation (p=0.94, 0.32, 0.75, 0.35, 0.60). Furthermore, In normal tissue the expression of HIF-1£\ had significant association with pVHL(p=0.0002), and the expression also had no a mariginally significant association with Sp1(p=0.096). Expression of Sp1 had significant association with pVHL(p=0.0016)in tumor tissue, Therewas a significant association between normal and tumor tissue expression of the pVHL and Sp1(p=0.038, 0.019), but the expression of HIF-1£\ had no significant(p=0.23). Conclusion: In this study, we attempt to determine the association between Sp1-pVHL -HIF-1£\ pathway and a role in the carcinogenesis in H. pylori infection. Although we didn¡¦t confirm the hypothesis Sp1-pVHL -HIF-1£\ pathway playing an critical role in the mechanism of gastric cancer. We concluded that there is no significance between the expression of Sp1, pVHL and HIF-1£\ and gastric cancer, but the role of this pathway in the Hp infection associated carcinogenesis is still to be clarified.

Thesis (M. Phil.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 158-179).

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy