pH-dependent Wnt-Signaling Activation and Gastric Carcinogenesis

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Over-activation of Wnt-signaling and acidic extracellular pH correlate with cancer initiation/progression in patients and model organisms. Gastric cancer is one of the most common causes for cancer-related deaths. The gastric proton pump ATP4 acidifies the gastric lumen. ATP4 was shown to be required for Wnt-signaling activation in Xenopus, and inhibition of ATP4 induced selective apoptosis in human gastric cancer cells. This study will address how ATP4 and low pH act during Wnt-signaling activation and in gastric cancer. Experiments will be performed on human intestinal cell lines in order to test if and how changes in the extracellular pH promote Wnt-signaling activation via the co-receptor LRP6, and how this activation affects gene expression, epigenetic modifications and transformation of cells into cancer cells. In contrast to other model organisms, loss of proton pumps did not affect developmental Wnt-signaling in the mouse. Nevertheless, maturation of the stomach seemed to be affected in ATP4-deficient mice. This indicated context-dependent signaling properties of ATP4 in the mouse as well. Thus, Wnt-signaling activity will be monitored during development and maturation of the gastrointestinal tract in ATP4-deficient mice. Furthermore, the possibility that other transmembrane proton-transporters regulate Wnt-signaling during mouse development will be addressed by expression analysis in embryos and in loss-of-function experiments using murine cell lines. In summary, this project will elucidate the molecular mechanism of proton pump- and pH-dependent Wnt-signaling activation and cancer initiation/progression. Moreover, the role of pH and proton pumps in mouse development and gastrointestinal maturation will be analyzed. The results will help to understand the mechanism of Wnt-signaling activation and carcinogenesis in gastrointestinal tissues, which may ultimately lead to the development of new cancer therapies.