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 FXR 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, MMP7 was the only MMP gene family member whose expression was down-regulated after FXR activation. FXR-mediated regulation of MMP7 transcription did not require heterodimerization with the retinoid X receptor (RXR), indicating that FXR represses MMP7 expression independently of RXR. Last, we uncovered that FXR suppresses MMP7 transcription by binding to a negative FXR-responsive element in the 5' MMP7 promoter, an event that inhibited colon cancer cell proliferation and invasion. These findings identify the FXR-MMP7 axis as a potential therapeutic target for managing colon cancer.
Highlights
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
In human colon cancer cells, we found that matrix metalloproteinase-7 (MMP7) mediates transactivation of epidermal growth factor receptors (EGFRs) by catalyzing the release of heparinbinding EGF-like growth factor, one of seven known EGFR ligands [21]
To fill these gaps in knowledge and pursue this interesting observation, we examined the correlation between FXR and MMP7 expression in paired, fresh-frozen surgical specimens of colon cancer and adjacent normal colon tissues obtained from the same persons
Summary
Correlation between reduced levels of FXR and increased MMP7 expression in colon cancer. MMP7 protein levels were increased significantly in primary and metastatic tumors (Fig. 2, A and C) These findings provide further evidence of an inverse relationship between FXR and MMP7 expression, consistent with a role for FXR as a potential regulator of MMP7 gene transcription. Tukey’s HSD post hoc tests showed significant differences (p Ͻ 0.05) between any two groups except 1 M versus 10 M, 1 M versus 50 M, and 10 M versus 50 M. colon cancer cells that lack FXR expression (Fig. S1B), treating cells with CDCA and GW4064 did not alter MMP7 mRNA or protein levels (Fig. 5, E–H). Reduced-length sequences from this 30-bp element (16-bp oligonucleotide (5Ј-ATTGTGTGCTTCCTGC), 20-bp oligonucleotide (5Ј-ATTGTGTGCTTCCTGCCAAT, or 21-bp oligonucleotide 5Ј-TTCCTGCCAATAACGATGTAA)) failed to cause gel shifts with either recombinant human FXR or HT-29 nuclear extracts (data not shown) These results indicate that the entire 30-bp MMP7 FXRE is required for FXR binding. These results are consistent with our previous conclusions from the luciferase assays and EMSAs that the 30-bp sequence from 141 to 171 bp represents the negative FXRE in the MMP7 promoter
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