| Summary: | 碩士 === 國立陽明大學 === 生物藥學研究所 === 91 === Gastric cancer (GC) is highly prevalent. It represents the second leading cause of cancer death worldwide. However, the pathogenic mechanism leading to this malignancy still remains largely unknown. Our lab has taken various approaches of representational difference analysis to identify the genetic events that are involved in gastric tumorigenesis. By suppression subtractive hybridization, PIGPC1 gene, a recently cloned p53 downstream target gene, was identified as one of the overexpressed genes in human gastric cancer. An important role of PIGPC1 was further demonstrated by gene knock-down approach that inhibition of the expression of zebrafish ortholog at early stage of embryogenesis by antisense oligonucleotide led to abnormal phenotypes. We therefore, in the present study, examined the role of PIGPC1 in the pathogenic development of GC. We first examined the possibility of PIGPC1 as a tumor suppressor by assessing loss of heterozygosity (LOH) of PIGPC1 gene in GC. High percentage (44.8﹪, 13 of 29) of LOH of chromosome 6q24, the PIGPC1 locus, was found in various subtypes of gastric cancer. However, no mutation was identified in the PIGPC1 gene in different gastric as well as colorectal cancer cell lines. To further explore the role of PIGPC1 involved in gastric tumorigenesis, we examined whether overexpression of PIGPC1 would affect cellular regulatory mechanisms by disrupting signaling pathways. By reporter assay, we showed that PIGPC1 negatively regulates MAP kinase-mediated AP1 activity, with concomitant inhibition of c-Fos expression in a dose-dependent manner. In addition, expression of PIGPC1 also affects the expression and phosphorylation of focal adhesion kinase (FAK). Taken together, our findings suggest that PIGPC1 is overexpressed in human gastric cancer and it may contribute to gastric cancer formation by affecting various cellular events.
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