Abstract
MicroRNAs have broad roles in tumorigenesis and cell differentiation through regulation of target genes. Notch signaling also controls cell differentiation and tumorigenesis. However, the mechanisms through which Notch mediates microRNA expression are still unclear. In this study, we aimed to identify microRNAs regulated by Notch signaling. Our analysis found that microRNA-449a (miR-449a) was indirectly regulated by Notch signaling. Although miR-449a-deficient mice did not show any Notch-dependent defects in immune cell development, treatment of miR-449a-deficient mice with azoxymethane (AOM) or dextran sodium sulfate (DSS) increased the numbers and sizes of colon tumors. These effects were associated with an increase in intestinal epithelial cell proliferation following AOM/DSS treatment. In patients with colon cancer, miR-449a expression was inversely correlated with disease-free survival and histological scores and was positively correlated with the expression of MLH1 for which loss-of function mutations have been shown to be involved in colon cancer. Colon tissues of miR-449a-deficient mice showed reduced Mlh1 expression compared with those of wild-type mice. Thus, these data suggested that miR-449a acted as a key regulator of colon tumorigenesis by controlling the proliferation of intestinal epithelial cells. Additionally, activation of miR-449a may represent an effective therapeutic strategy and prognostic marker in colon cancer.
Highlights
Mature microRNAs are noncoding RNAs of approximately 22 nucleotides that regulate gene expression by targeting the 3′-untranslated regions (UTRs) of mRNAs, resulting in inhibition of mRNA translation[1, 2]
Rbpj-deficient T cells from Rbpjflox/flox crossed with CD4-Cre transgenic mice showed substantially reduced expression of miR-449a compared with that in wild-type cells (Fig. 1c), miR-449a expression was still detected in Rbpj-deficient cells
We searched for miRNAs that were regulated by Notch signaling and found that miR-449a was indirectly upregulated by Notch signaling
Summary
Mature microRNAs (miRNAs) are noncoding RNAs of approximately 22 nucleotides that regulate gene expression by targeting the 3′-untranslated regions (UTRs) of mRNAs, resulting in inhibition of mRNA translation[1, 2]. MiRNAs regulate various aspects of cell physiology, including proliferation, differentiation, cell death, and development[1]. Aberrantly expressed miRNAs are involved in tumorigenesis, as either oncogenes or tumor suppressors[3,4,5]. Notch signaling has pleiotropic roles in cell differentiation, proliferation, and cell death, and dysregulation of Notch is involved in many types of malignant tumors, including T-cell acute lymphoblastic leukemia (T-ALL) and lymphoma[8,9,10]. (c) The expression of miR-449a in T cells from C57BL/6 mice crossed with CD4-Cre transgenic mice (control) or Rbpjflox/flox mice crossed with CD4-Cre transgenic (Rbpj−/−) mice,as analyzed by real-time PCR.
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