MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1)

Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 06/2007; 282(19):14328-36. DOI: 10.1074/jbc.M611393200
Source: PubMed

ABSTRACT MicroRNAs are small noncoding RNA molecules that control expression of target genes. Our previous studies show that mir-21 is overexpressed in tumor tissues compared with the matched normal tissues. Moreover, suppression of mir-21 by antisense oligonucleotides inhibits tumor cell growth both in vitro and in vivo. However, it remains largely unclear as to how mir-21 affects tumor growth, because our understanding of mir-21 targets is limited. In this study, we performed two-dimensional differentiation in-gel electrophoresis of tumors treated
with anti-mir-21 and identified the tumor suppressor tropomyosin 1 (TPM1) as a potential mir-21 target. In agreement with this, there is a putative mir-21 binding site at the 3′-untranslated region (3′-UTR) of TPM1 variants V1 and V5. Thus, we cloned the 3′-UTR of TPM1 into a
luciferase reporter and found that although mir-21 down-regulated the luciferase activity, anti-mir-21 up-regulated it. Moreover, deletion of the mir-21 binding site abolished the effect of mir-21 on the luciferase activity, suggesting that this mir-21 binding site is critical. Western blot with the cloned TPM1-V1 plus the 3′-UTR indicated that TPM1 protein level was also
regulated by mir-21, whereas real-time quantitative reverse transcription-PCR revealed no difference at the mRNA level, suggesting translational
regulation. Finally, overexpression of TPM1 in breast cancer MCF-7 cells suppressed anchorage-independent growth. Thus, down-regulation
of TPM1 by mir-21 may explain, at least in part, why suppression of mir-21 can inhibit tumor growth, further supporting the notion that mir-21 functions as an oncogene.

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    • "TPM1 í µí»¾ and í µí»¿ proteins (also known as í µí»¼-tropomyosins) are known to be incorporated into epithelial cell stress fibers. It has been suggested that their expression may be downmodulated in human breast cancers [14] [15] [16] [17] [18] [19] [20] [21]. However, because some novel tropomyosin 1 gene isoforms have been predicted (GenBank accession numbers: XP 005254697, XP 005254698, and XP 006720730) and identified in rat tissues, we decided to explore this issue further [22]. "
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    ABSTRACT: Nine malignant breast epithelial cell lines and 3 normal breast cell lines were examined for stress fiber formation and expression of TPM1 isoform-specific RNAs and proteins. Stress fiber formation was strong (++++) in the normal cell lines and varied among the malignant cell lines (negative to +++). Although TPM1γ and TPM1δ were the dominant transcripts of TPM1, there was no clear evidence for TPM1δ protein expression. Four novel human TPM1 gene RNA isoforms were discovered (λ, μ, ν, and ξ), which were not identified in adult and fetal human cardiac tissues. TPM1λ was the most frequent isoform expressed in the malignant breast cell lines, and it was absent in normal breast epithelial cell lines. By western blotting, we were unable to distinguish between TPM1γ, λ, and ν protein expression, which were the only TPM1 gene protein isoforms potentially expressed. Some malignant cell lines demonstrated increased or decreased expression of these isoforms relative to the normal breast cell lines. Stress fiber formation did not correlate with TPM1γ RNA expression but significantly and inversely correlated with TPM1δ and TPM1λ expression, respectively. The exact differences in expression of these novel isoforms and their functional properties in breast epithelial cells will require further study.
    01/2015; 2015:1-11. DOI:10.1155/2015/859427
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    • "Regarding the two miRNAs we found highly expressed in plasma from CRC patients , miR - 21 is an oncogenic miRNA altered in many tumours that regulates the expression of multiple cancer - related target genes such as PTEN and TPM1 ( Meng et al , 2007 ; Zhu et al , 2007 ) . Several studies have highlighted the potential of miR - 21 as a highly promising prognostic marker . "
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    ABSTRACT: Background:Plasma circulating tumour-specific microRNAs (miRNAs) are promising biomarkers of tumour presence and recurrence, especially for diseases whose best chance of successful treatment requires early diagnosis and timely surgery of an already malignant but not yet invasive tumour, such as colorectal cancer (CRC).Methods:Expression levels of miRNAs previously found to be differently expressed in tumour vs normal colon tissues were investigated by quantitative real-time PCR in plasma from CRC patients and from healthy donors and confirmed in independent case control series. The validated miRNAs were also measured after surgery. Analyses were repeated on the subsets of haemolysis-free samples.Results:We identified four miRNAs differently expressed between the compared groups, two (miR-21 and miR-378) of which were validated. miR-378 expression decreased in non-relapsed patients 4-6 months after surgery and miR-378 ability to discriminate CRC patients from healthy individuals was not influenced by haemolysis levels of plasma samples.Conclusion:The miRNA analysis on plasma samples represents a useful non-invasive tool to assess CRC presence as well as tumour-free status at follow-up. Plasma levels of miR-378 could be used to discriminate CRC patients from healthy individuals, irrespective of the level of haemoglobin of plasma samples.British Journal of Cancer advance online publication, 14 January 2014; doi:10.1038/bjc.2013.819
    British Journal of Cancer 01/2014; 110(4). DOI:10.1038/bjc.2013.819 · 4.82 Impact Factor
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    • "Its oncogenic activity also includes targeting the 3 0 UTR region of another tumour suppressor, the protein programmed cell death-4 (PDCD4), and it has been reported that the loss of PDCD4 function correlates with tumour aggressiveness and a poor prognosis. It is likely that the deregulation of these proteins eventually leads to the deregulation of the p53 tumour suppressor pathway (Zhu et al., 2007). Finally, miRNA-21 drives tumourigenesis by inhibiting negative regulators of the RAS/MEK/ERK pathway and inhibiting apoptosis (Hatley et al., 2010). "
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    ABSTRACT: Abstract Lung cancer is a major cause of death in Western countries. Current screening methods are invasive and still lead to a high percentage of false positives. There is, therefore, a need to find biomarkers that increase the probability of detecting lung cancer early. MicroRNAs (miRNAs) are stable molecules in blood plasma and exhaled breath condensate (EBC). We quantified miRNA-21 and miRNA-486 expression from plasma and EBC samples from patients with a diagnosis of non-small-cell lung cancer (NSCLC) and controls. miRNA-21 was significantly higher in plasma and in EBC of the NSCLC patients and miRNA-486 was significantly lower. This difference indicates a significantly improved diagnostic value, and suggests that these miRNAs could be clinically used as a first-line screening test in high-risk subjects.
    Biomarkers 10/2013; 18(8). DOI:10.3109/1354750X.2013.845610 · 2.52 Impact Factor
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