The major theme of my research is to explore the signal transduction pathways of gastrointestinal tumorigenesis in order to identify potential molecular markers and therapeutic targets of this disease. Specifically, my research is focused on genetic risk factors of gastrointestinal malignancies, such as the Adenomatous Polyposis Coli (APC) tumor suppressor gene and K-RAS and c-MYC proto-oncogenes. My current research interests include the following areas: I. Role of kallikrein 6 in colon cancer progression and metastasis formation. Emerging experimental data suggest a causal role of kallikrein family members in tumorigenesis. Our published data show that: 1. KLK6 gene transcription and protein secretion is elevated in colon cancer cell lines expressing the K-RAS oncogene and is associated with the invasive phenotype 2. Caveolin-1 (CAV-1), a membrane-associated protein and a putative regulator of cell transformation and protein trafficking, facilitates KLK6 transcription and secretion in colon cancer cells; 3. Inhibition of KLK6 in colon cancer cells in vitro using small interference RNA treatment or a specific KLK6 antibody resulted in suppression of cell migration. Our preliminary data demonstrate that KLK6 can be detected in colonic adenomas using a fluorescent antibody, and that knockdown of KLK6 gene increases animal survival rates in the SCID mouse orthotopic colon cancer model. Currently we are working on defining the role of KLK6 in colon cancer progression and metastasis and exploring the clinical utility of KLK6 as a biomarker and a therapeutic target. II. Role of PPARγ (peroxisomal proliferator-activated receptor &gamma and the Pparγ target gene SAT1 (spermidine/spermine N1-acetyltransferase) in colon carcinogenesis in mouse models. The PPARg is a ligand-activated transcription factor that plays an important role in the regulation of expression of genes controlling cell proliferation and differentiation. The polyamine catabolic gene SAT1 has a functional PPARg response element (PPRE) in the promoter region to activate expression of this gene. PPARg is an important regulator of adipogenesis.The long-term goal of our research efforts in the ongoing collaborative studies is to better understand the role of Pparγ andthe Pparγ target gene Sat1 in colon carcinogenesis using mouse models.