Regulatory interaction of HNF1-alpha to microRNA-194 gene during intestinal epithelial cell differentiation
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Bunkyoku, Tokyo, Japan. Nucleic Acids Symposium Series
02/2007; 51(51):415-6. DOI: 10.1093/nass/nrm208
Maintenance of intestinal epithelium is based on well-balanced molecular mechanisms that confer the stable and continuous supply of specialized epithelial cell lineages from multipotent progenitors. Lineage commitment decisions in intestinal epithelium system involve multiple regulatory systems that interplay each other to establish the cellular identities. Here, we demonstrate that the microRNA system could be involved in intestinal epithelial cell differentiation and that microRNA-194 (miR194) is highly induced during this process and controlled by a transcription factor, HNF-alpha, that is well known to regulate gene expression in intestinal epithelial cells. Thus, the 5' conserved genomic region of miR-1942 gene, the inducible class of miR-194 parental gene, contains a binding motif for HNF1-alpha. This consensus region is required for the transcription of miR-1942 and active in intestinal epithelial cell line, Caco-2, in-vivo. Our observations indicate that microRNA genes could be targets of lineage specific transcription factors and that microRNAs are regulated in intestinal epithelial cells in a tissue specific manner. Given that role of microRNA in fine tuning of gene expression patterns, our results suggest that HNF1-alpha regulates the gene expression program by not only direct activation of genes but also modulation through induction of microRNAs such as miR-194, in intestinal epithelial cells. This represents a novel molecular machinery that might specify the fates of intestinal epithelial cell lineages during their differentiation.
Available from: George A Calin
- "High levels of miR-194 are expressed in the intestines and liver , . Hepatocyte nuclear factor (HNF) can induce miR-194 expression during intestinal epithelial cell differentiation , . miR-194 suppresses invasion and migration of liver mesenchymal-like cancer cells . "
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ABSTRACT: Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3'-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.
Available from: Jonathan Schug
- "(Supplementary Table S1). We confirmed high-level expression of previously known abundant microRNAs in the respective tissue, such as mir-122 and mir-192 in the liver, miR-215 and miR-192 in the intestine, and miR-375 and miR-152 in the pancreas (Supplementary Table S1) (16–20). The let-7 family was highly expressed in all tissues. "
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ABSTRACT: MicroRNAs fine-tune the activity of hundreds of protein-coding genes. The identification of tissue-specific microRNAs and
their promoters has been constrained by the limited sensitivity of prior microRNA quantification methods. Here, we determine
the entire microRNAome of three endoderm-derived tissues, liver, jejunum and pancreas, using ultra-high throughput sequencing.
Although many microRNA genes are expressed at comparable levels, 162 microRNAs exhibited striking tissue-specificity. After
mapping the putative promoters for these microRNA genes using H3K4me3 histone occupancy, we analyzed the regulatory modules
of 63 microRNAs differentially expressed between liver and jejunum or pancreas. We determined that the same transcriptional
regulatory mechanisms govern tissue-specific gene expression of both mRNA and microRNA encoding genes in mammals.
Available from: Bo Lonnerdal
- "There are some limited reports on intestinal epithelial miRNA expression. Takada et al.  showed high abundance of miR-143 and miR-194 in mouse small intestine and Hino et al. ,  further showed induction of miR-194 by HNF-1 during differentiation of intestinal epithelial Caco-2 cells. We used a sensitive model for stimulating intestinal crypt cell proliferation by a growth factor, and obtained not only the first extensive mouse intestinal crypt cell miRNA profiles, but also the differentially expressed miRNA species during cell proliferation. "
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ABSTRACT: MicroRNAs play extensive roles in cellular development. Analysis of the microRNA expression pattern during intestinal cell proliferation in early life is likely to unravel molecular mechanisms behind intestinal development and have implications for therapeutic intervention. In this study, we isolated mouse intestinal crypt cells, examined the differences in microRNA expression upon IGF-1 stimulated proliferation and identified miR-103 as a one of the key regulators. Mouse intestinal crypt cells were cultured and treated with IGF-1 for 24 h. MicroRNA microarray showed that multiple microRNAs are regulated by IGF-1, and miR-103 was the most sharply down-regulated. Expression of miR-103 in mouse intestinal crypt cells was confirmed by real-time Q-PCR. Sequence analyses showed that, among the 1040 predicted miR-103 target genes, CCNE1, CDK2, and CREB1 contain complementary sequences to the miR-103 seed region that are conserved between human and mouse. We further demonstrated that miR-103 controls the expression level of these three genes in mouse crypt cells by luciferase assay and immunoblotting assay. Taken together, our data suggest that in mouse intestinal crypt cells, miR-103 is part of the G1/S transition regulatory network, which targets CCNE1, CDK2, and CREB1 during IGF-1 stimulated proliferation.
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