Abstract
The tumor suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumors. APC stimulates the activity of the Cdc42- and Rac1-specific guanine nucleotide exchange factor Asef and promotes the migration and invasion of colorectal tumor cells. Furthermore, Asef is overexpressed in colorectal tumors and is required for colorectal tumorigenesis. It is also known that NOTCH signaling plays critical roles in colorectal tumorigenesis and fate determination of intestinal progenitor cells. Here we show that NOTCH3 up-regulates Asef expression by activating the Asef promoter in colorectal tumor cells. Moreover, we demonstrate that microRNA-1 (miR-1) is down-regulated in colorectal tumors and that miR-1 has the potential to suppress NOTCH3 expression through direct binding to its 3’-UTR region. These results suggest that the miR-1-NOTCH3-Asef pathway is important for colorectal tumor cell migration and may be a promising molecular target for the treatment of colorectal tumors.
Highlights
Mutations in adenomatous polyposis coli (APC) are responsible for sporadic and familial colorectal cancer [1,2]
Consistent with this result, overexpression of NOTCH3 ICD (N3ICD-HA) resulted in the upregulation of Asef mRNA and protein expression (Figure 1 E). These results suggest that NOTCH3 signaling regulates Asef expression in colorectal cancer cells
We have previously reported that activation of Asef by truncated mutant APCs present in colorectal tumor cells contributes to their aberrant migratory properties, and that Asef deficiency results in the suppression of intestinal adenoma formation in APCMin/+ mice
Summary
APC normally induces the degradation of β–catenin and negatively regulates Wnt signaling [3,4,5,6]. The truncated mutant APCs commonly found in colorectal tumors are defective in this activity. Wnt signaling is constitutively activated in colorectal tumor cells. Mutant APCs aberrantly activate Asef and induce c-Jun amino-terminal kinase (JNK)mediated transactivation of matrix metalloproteinase (MMP) 9, which is required for tumor invasion [11]. Asef expression is aberrantly enhanced in most human colorectal tumors [11]. Consistent with these findings, we have recently shown that Asef and Asef are required for adenoma formation in ApcMin/+ mice [11]
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