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Abstract

DLC1 is a tumor suppressor protein downregulated in gastric cancer. It is a negative regulator of RHOA, which is the major oncogenic driver mutation of human diffuse gastric cancer. Helicobacter infection leads to chronic gastric inflammation, which is a risk factor for the development of carcinoma. The Helicobacter toxin CagA activates numerous signaling pathways including RHOA. The role of DLC1 in Helicobacter-related gastric disease is unknown and was analyzed by this thesis. DLC1gt/+ mice showed increased gastric inflammatory infiltration. Involvement of DLC1 in the regulation of the immune response was confirmed by RT-qPCR analyses. Furthermore, DLC1 was shown to be localized to enterochromaffin-like cells. Quantitative gene expression analyses verified a crucial role of the tumor suppressor in homeostasis of gastric acid in vivo, thereby preventing the development of gastric cancer. This study further demonstrates an interaction between DLC1 and CagA. DLC1 was transcriptionally downregulated by CagA and the two proteins fulfilled antagonizing functions by complex formation. DLC1 counters the oncogenic signaling of CagA in vitro by promoting adhesion, suppressing proliferation and antagonizing CagA concerning the hypoxic stress response. DLC1 furthermore inhibited CagA-mediated G-protein-coupled RHOA activation. In vivo therapy of a preclinical model for human gastric cancer with an inhibitor of the RHO/ROCK-pathway efficiently reduced tumor growth. These findings propose inhibition of this pathway as a novel treatment strategy for human gastric cancer. In summary, this thesis postulates a protective role of DLC1 in initial steps of gastric disease by antagonizing CagA-mediated oncogenic signaling. Transcriptional downregulation of DLC1 by CagA promotes oncogenic effects and constitutes DLC1 as an early molecular marker for Helicobacter-related gastric disease. Due to the involvement of CagA and DLC1 in the regulation of RHOA, Helicobacter-related gastric disease can be assigned to diffuse genomically stable gastric cancer. This represents a new risk stratification for Helicobacter-infected gastric cancer patients. Suppression of tumor growth using an inhibitor of the RHOA downstream effector ROCK proposes DLC1 as a future druggable target in human gastric cancer.