Transcriptional Repression of MMP7 by FXR in Intestinal Epithelial Cells

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 DESCRIPTION (provided by applicant): Colon cancer remains a leading cause of morbidity and mortality in Veterans because therapy for metastatic disease has limited efficacy. Our long-term goal is to develop innovative, effective, and safe therapies by targeting pivotal signal transduction molecules underlying colon cancer progression. The Farnesoid X Receptor (FXR), a member of the nuclear receptor superfamily of bile acid-activated transcription factors, appears to be such a pivotal molecule. FXR is a tumor suppressor whose expression is strikingly reduced in colon cancer; in rodent models of intestinal neoplasia FXR deficiency increases adenoma size and number. FXR regulates cell proliferation, apoptosis, and Wnt signaling but the molecular mechanisms underlying its tumor-suppressive actions are incompletely understood. Our short-term goal is to fill this gap in knowledge. Recently, we made the seminal observation that matrix metalloproteinase 7 (MMP7) is an FXR target gene. MMP7, a collagenase that degrades extracellular matrix, is over-expressed in most colon tumors and enhances cell proliferation, tumor invasion, and metastasis. Our preliminary data show that FXR is a transcriptional repressor for MMP7; decreased FXR levels correlate with increased MMP7 expression in normal intestine and colon cancer. Also, we found that activating FXR in human colon cancer cells attenuates MMP7 expression, as well as xenograft growth and invasion. Based on these novel findings we propose the paradigm-shifting central hypothesis that FXR activation inhibits colon cancer progression by repressing MMP7 gene transcription. To test this hypothesis we propose three Specific Aims: Aim 1. Test the hypothesis that FXR is a direct transcriptional repressor of MMP7 and identify the MMP7 FXR responsive element. Aim 2. Test the hypothesis that activating intestinal FXR selectively down-regulates MMP7 expression, thereby inhibiting tumor growth in vivo. Aim 3. Test the hypothesis that neutralizing anti-MMP7 antibody attenuates colon cancer progression in vivo. Overall impact: We will reveal a novel role for FXR as a transcriptional repressor of MMP7 and identify a new mechanism whereby FXR suppresses colon cancer cell proliferation and disease progression. Moreover, we will demonstrate the clinical potential of using fexaramine, an intestine-selective FXR agonist, for chemo- prevention and anti-MMP7 antibody for advanced disease.