Farnesoid X receptor represses matrix metalloproteinase 7 expression, revealing this regulatory axis as a promising therapeutic target in colon cancer

Abstract

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of bile acid-activated transcription factors and an important regulator of cell proliferation, apoptosis, and Wnt signaling. Down-regulated expression of FXR plays an important role in some malignancies such as colon cancer, and in rodent models of intestinal neoplasia, FXR knockout increases the size and number of colon tumors. These previous observations implicate FXR as a tumor suppressor, but the underlying molecular mechanisms are unclear. Employing complementary experimental approaches and using human colon cancer specimens, human and murine colon cancer cell lines, and FXR transgenic mice, here we identified an additional, potentially important role for FXR. We observed an inverse relationship between the expression of FXR and matrix metalloproteinase-7 (MMP7), a collagenase and signaling molecule consistently associated with colon cancer progression. We noted that <i>FXR</i> gene ablation increases MMP7 expression. Consistent with this finding, FXR overexpression and a dominant-negative FXR mutation reduced and augmented, respectively, MMP7 expression. Of note, <i>MMP7</i> was the only <i>MMP</i> gene family member whose expression was down-regulated after FXR activation. FXR-mediated regulation of <i>MMP7</i> transcription did not require heterodimerization with the retinoid X receptor (RXR), indicating that FXR represses <i>MMP7</i> expression independently of RXR. Last, we uncovered that FXR suppresses <i>MMP7</i> transcription by binding to a negative FXR-responsive element in the 5' <i>MMP7</i> promoter, an event that inhibited colon cancer cell proliferation and invasion. These findings identify the <i>FXR-MMP7</i> axis as a potential therapeutic target for managing colon cancer.