Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients

Division of Biomedicine, Systems Biology Research Centre, School of Life Sciences, Skövde University, SE-541 28, Skövde, Sweden.
BMC Cancer (Impact Factor: 3.36). 08/2011; 11(1):345. DOI: 10.1186/1471-2407-11-345
Source: PubMed


Dicer is aberrantly expressed in several types of cancers. Applying real-time PCR, we detected the expression of Dicer mRNA in normal mucosa (n = 162), primary colorectal cancer (CRC) (n = 162) and liver metastasis (n = 37), and analysed the relationship between Dicer expression and clinicopathological features. We also correlated the expression of Dicer mRNA to the miRNA expression of miR-141, miR-200a, miR-200b, mir-200c and miR-429 in liver metastases.
RT-PCR and qPCR were used to analyse the Dicer expression in normal mucosa, primary tumour and liver metastasis by using the High Capacity cDNA Reverse Transcription Kit and TaqMan™® Gene Expression assays for Dicer and GAPDH. RT-PCR and qPCR were used to detect miRNA expression in liver metastases by utilizing TaqMan® MicroRNA Reverse Transcription Kit and TaqMan® miRNA Assays. Statistical analyses were performed with STATISTICA.
Dicer expression in rectal cancer (3.146 ± 0.953) was higher than in colon cancer (2.703 ± 1.204, P = 0.018). Furthermore the Dicer expression was increased in primary tumours (3.146 ± 0.952) in comparison to that in normal mucosa from rectal cancer patients (2.816 ± 1.009, P = 0.034) but this is not evident in colon cancer patients. Dicer expression in liver metastases was decreased in comparison to that of either normal mucosa or primary tumour in both colon and rectal cancers (P < 0.05). Patients with a high Dicer expression in normal mucosa had a worse prognosis compared to those with a low Dicer expression, independently of gender, age, tumour site, stage and differentiation (P < 0.001, RR 3.682, 95% CI 1.749 - 7.750). In liver metastases, Dicer was positively related to miR-141 (R = 0.419, P = 0.015).
Dicer is up-regulated in the early development of rectal cancers. An increased expression of Dicer mRNA in normal mucosa from CRC patients is significantly related to poor survival independently of gender, age, tumour site, stage and differentiation.

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Available from: Sebastian Gnosa
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    • "We identified indels in the pre-miRNA sequences of several miRNAs that have been linked to cancers. For example, the precursor of miR-558, which has been previously linked with aggressive neuroblastoma [33], contained 5 indels, and an indel (rs34385807) is located the pre-miRNA sequence of miR-141, which is involved in cancer proliferation [34], [35], [36], [37] and has been shown to target the tumor suppressor PTEN [38]. Additional precursor sequences of miRNAs containing indels include miR-520h [39], [40], [41], miR-486 [42], miR-489 [43], miR-223 [44], miR-373 [45], miR-630 [46] and miR-1233 [17], which have been shown to be involved in cancer development, and miR-631, which is associated with risk of coronary artery disease [47]. "
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    ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNA that play an important role in posttranscriptional regulation of mRNA. Genetic variations in miRNAs or their target sites have been shown to alter miRNA function and have been associated with risk for several diseases. Previous studies have focused on the most abundant type of genetic variations, single nucleotide polymorphisms (SNPs) that affect miRNA-mRNA interactions. Here, we systematically identified small insertions and deletions (indels) in miRNAs and their target sites, and investigated the effects of indels on miRNA targeting. We studied the distribution of indels in miRNAs and their target sites and found that indels in mature miRNAs, experimentally supported miRNA target sites and PAR-CLIP footprints have significantly lower density compared to flanking regions. We identified over 20 indels in the seed regions of miRNAs, which may disrupt the interactions between these miRNAs and their target genes. We also identified hundreds of indels that alter experimentally supported miRNA target sites. We mapped these genes to human disease pathways to identify indels that affect miRNA targeting in these pathways. We also used the results of genome-wide association studies (GWAS) to identify potential links between miRNA-related indels and diseases.
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    • "Table 1 summarizes these alterations based on experimental data from patients. MiRNome signatures revealed that miRNA affected many tumor-suppressive and oncogenic pathways implicated in CRC pathobiology, including β-catenin/Wnt signaling (miR-135a, -135b, -139, -145) [38•, 39, 40], apoptosis (miR-34a, -133b, -195) [38•, 41], differentiation (miR-141, -200c) [42–44], p53 signaling (miR-34b/c) [45], proliferation (K-RAS signaling: let7 family, miR-18a, -143, -200c) [38•, 41, 46], cell cycle control (miR-34a, -192, -215, -675) [38•, 41, 47], and migration, invasion, and metastasis (miR-126, -143, -196a, -200a, -200b, -200c, -373, -520c) [38•, 41, 44]. MiRNA pathway may also modulate DNA methylation (miR-143, -342) [48, 49]. "
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    ABSTRACT: Dicer is aberrantly expressed in several types of malignancies. Cleaved by Dicer, the small noncoding microRNAs (miRNAs) are considered potential tools for the diagnosis and prognosis of cancer. This study investigated the expression of miRNAs thought to target Dicer. Expression of 1,205 human miRNAs and miRNA*s were examined in four patients with prostate cancer (PCa) by miRNA array in which the threshold was set as two-fold. Seventy-three miRNAs and miRNA*s were significantly down-regulated while 10 were up-regulated in PCa tissues compared with matched histologically normal glands. Of these, miR-29b-1, miR-200a, miR-370, and miR-31, which were the most down/up-regulated and closely potentially target to the Dicer 3' UTR, were investigated further. Tissues of primary tumors and matched normal prostate glands from 185 patients with PCa were collected for further investigation. Dicer mRNA levels were negatively correlated with miR-29b-1 (ρs = -0.177, p = 0.017), miR-200a (ρs = -0.489, p < 0.0001) and miR-31 (ρs = -0.314, p < 0.0001) expression. Compared with adjacent normal glands, PCa tissues showed significantly lower miR-200a and miR-31 expression levels. Furthermore, in metastatic PCa, the expression levels of miR-200a, miR-370, and miR-31 were dramatically higher than in localized PCa. Additionally, elevated expression levels of miR-200a and miR-31 appeared to be associated with castration-resistant PCa. These findings suggest possibilities that miR-200a and miR-31 target Dicer and are involved in the carcinogenesis, migration, and behavior of castration-resistant PCa, indicating that they could be potential biomarkers for monitoring PCa progression.
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