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.
Despite advances in colorectal cancer (CRC) screening, including colonoscopy and fecal occult blood testing, CRC is still a leading cause of cancer death in the United States including in Veterans due to patient non-compliance with screening tests, suboptimal test sensitivity and 'miss' rate on colonoscopy and other factors. The majority of the colon cancer death is caused by metastatic disease for which there is no effective treatment. In this proposed study, we will pursue our finding that FXR activation inhibits colon cancer progression through a novel FXR target gene: matrix metalloproteinase 7. We anticipate that this work will shed new light into FXR's key role as a tumor suppressor for advanced colon cancer and to identify new therapeutic targets for treating Veterans with advanced colon cancer.
| Said, Anan H; Hu, Shien; Abutaleb, Ameer et al. (2017) Interacting post-muscarinic receptor signaling pathways potentiate matrix metalloproteinase-1 expression and invasion of human colon cancer cells. Biochem J 474:647-665 |
