| Summary: | 碩士 === 國立中山大學 === 生物醫學研究所 === 104 === Gastric cancer (GC) is an aggressive disease with the highest rate of mortality among cancers and is the second leading cause of cancer death worldwide. Recent molecular pathology studies have elucidated a detailed profile of genetic lesions associated with GC initiation and progression—activation KRAS and inactivation or loss of E-cadherin, P53, APC and PTEN—providing a foundation for investigation of the biological and biochemical basis for this malignancy. LKB1, also known as Serine/threonine kinase 11 (STK11), encodes a serine/threonine kinase that directly phosphorylates and activates AMPK, a cellular metabolic kinase. LKB1-AMPK pathway function also includes the maintenance of epithelial junction stability by regulating E-cadherin expression. In addition, LKB1 mutations are associated with the Peutz-Jeghers syndrome (PJS) consisting of intestinal polyposis and other gastrointestinal malignancies. PTEN, a tyrosine phosphatase, which regulates the activation of AKT pathway, is frequently mutated in many types of human cancer. This study seeks to use the H+/K+ ATPase Cre transgene mice, developed in our lab, directs Cre recombinase to the stomach commencing to both abrogate LKB1 and PTEN function in a stomach-specific manor to induce the development and metastatic progression of gastric adenocarcinomas, with similarities to human gastric adenocarcinoma. We also determine how these alterations contributes to gastric tumor histopathologic progression, invasive and metastatic potential, angiogenic and tumor stromal microenvironment. Meanwhile, information about responses in a bona fide GC model will likely contribute to interpreting those clinical results, are they positive or negative, and potentially might help guide further trial designs to combat stomach cancer.
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