HB-EGF's Role in Atrophic Gastritis and Gastric Cancer

我们发现胃泌素对结肠的生长很重要，胃泌素缺乏会导致结肠增殖减少，而甘氨酸延伸的胃泌素过度表达会导致结肠增殖和结肠粘膜肥大。我们进一步证明，胃泌素似乎是β-连环素/Tcf-4信号通路的下游靶点，该信号通路介导肠息肉的生长。胃泌素在胃的发育过程中也很重要。胃泌素缺乏会导致壁细胞数量明显减少，短期的胃泌素输注可以挽救壁细胞的数量。然而，如果长期输液，就会发生壁细胞萎缩。我们已经证明，过度表达酰胺化胃泌素的转基因小鼠也会出现最初的增生，随后是壁细胞萎缩、小凹增生，最后是浸润性胃癌。在壁细胞萎缩的过程中，肝素结合的表皮样生长因子(HB-EGF)表达上调。我们已经证明胃泌素可以通过PKC依赖的途径直接上调HB-EGF的表达。根据这些发现，我们推测胃泌素可以直接影响胃干细胞向壁细胞分化，但随着时间的推移，它会导致壁细胞HB-EGF的上调，从而在负反馈循环中抑制向壁细胞的分化，促进向凹陷细胞的分化。目的是验证这一假说：1.确定胃泌素调节HB-EGF启动子的顺式作用调控元件。2.建立高表达HB-EGF的转基因小鼠，研究HB-EGF在胃壁细胞中的表达在胃粘膜分化中的作用。

We have found that gastrin is important in the growth of the colon, with gastrin deficiency resulting in decreased colonic proliferation, and over- expression of glycine-extended gastrin resulting in increased colonic proliferation and colonic mucosal hypertrophy. We have further demonstrated that gastrin appears to be a downstream target of the beta- catenin/Tcf-4 signaling pathway that mediates growth of intestinal polyps. Gastrin is also important in the development of the stomach. Gastrin deficiency results in a marked decreased in parietal cell number which can be rescued by short-term infusions of gastrin. With long term infusion however, parietal cell atrophy occurs. We have shown that transgenic mice that overexpress amidated gastrin also have initial hyperplasia, followed by parietal cell atrophy, foveolar hyperplasia, and eventually invasive gastric cancer. At the time when parietal cell atrophy develops, there is an up-regulation of heparin binding epidermal-like growth factor (HB-EGF). We have shown that gastrin can directly up- regulate HB-EGF expression through a PKC-dependent pathway. From these findings we hypothesize that gastrin can directly influence the gastric stem cell to differentiate towards the parietal cell partway, but with time it causes up-regulation of HB-EGF in parietal cells which in a negative feedback loop inhibits differentiation towards parietal cells and promotes differentiation into pit cells. The aims are to test this hypothesis: 1. Determine the cis-acting regulatory elements involved in gastrin's regulation of the HB-EGF promoter. 2. Determine the role of HB-EGF expression in gastric parietal cells on gastric mucosal differentiation by creating transgenic mice that over-expression HB-EGF in parietal cells.