MicroRNA Expression Abnormalities in Pancreatic Endocrine and Acinar Tumors Are Associated With Distinctive Pathologic Features and Clinical Behavior

Department of Surgical and Gastroenterological Sciences, University of Verona, Verona, Veneto, Italy
Journal of Clinical Oncology (Impact Factor: 18.43). 11/2006; 24(29):4677-84. DOI: 10.1200/JCO.2005.05.5194
Source: PubMed


We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies.
Using a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas.
Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis.
These results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.

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    • "Highly accurate biomarkers for early detection are thus expected to significantly impact patient's prognosis; a five-year survival approaching 70% has been reported after incidental diagnosis of Stage I tumors, when they were still confined to the pancreas and smaller than 2 cm[1]. MicroRNAs (miRNAs), small noncoding evolutionarily conserved RNAs, are critically implicated in the regulation of a whole host of cellular processes[2], and their aberrant expression is associated with cancer in a variety of tissues[3], including pancreas[4,5]. Recently, it has been shown that cell-free circulating miRNAs are highly stable (i.e. "
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    ABSTRACT: Currently, the majority of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) present with locally invasive and/or metastatic disease, resulting in five-year survival of less than 5%. The development of an early diagnostic test is, therefore, expected to significantly impact the patient's prognosis. In this study, we successfully evaluated the feasibility of identifying diagnostic cell free microRNAs (miRNAs) for early stage PDAC, through the analysis of urine samples. Using Affymetrix microarrays, we established a global miRNA profile of 13 PDAC, six chronic pancreatitis (CP), and seven healthy (H) urine specimens. Selected differentially expressed miRNAs were subsequently investigated using an independent technique (RT-PCR) on 101 urine samples including 46 PDAC, 29 CP and 26 H. Receiver operating characteristic (ROC) and logistic regression analyses were applied to determine the discriminatory potential of the candidate miRNA biomarkers. Three miRNAs (miR-143, miR-223, and miR-30e) were significantly over-expressed in patients with Stage I cancer when compared with age-matched healthy individuals (P=0.022, 0.035 and 0.04, respectively); miR-143, miR-223 and miR-204 were also shown to be expressed at higher levels in Stage I compared to Stages II-IV PDAC (P=0.025, 0.013 and 0.008, respectively). Furthermore, miR-223 and miR-204 were able to distinguish patients with early stage cancer from patients with CP (P=0.037 and 0.036). Among the three biomarkers, miR-143 was best able to differentiate Stage I (n=6) from healthy (n=26) with area under the curve (AUC) of 0.862 (95% CI 0.695-1.000), with sensitivity (SN) of 83.3% (95% CI 50.0-100.0), and specificity (SP) of 88.5% (95% CI 73.1-100.0). The combination of miR-143 with miR-30e was significantly better at discriminating between these two groups, achieving an AUC of 0.923 (95% CI 0.793-1.000), with SN of 83.3% (95% CI 50.0-100.0) and SP of 96.2% (95% CI 88.5-100.0). In this feasibility study, we demonstrate for the first time the utility of miRNA biomarkers for non-invasive, early detection of PDAC in urine specimens.
    Full-text · Article · Jan 2016 · American Journal of Cancer Research
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    • "These findings have the following important ramification. MiR-103a-3p has been shown to play important roles in cellular processes such as DNA repair, metabolism, cell cycle progression, and cell differentiation (Liu et al. 2009; Yang et al. 2009; Finnerty et al. 2010; Liao and Lonnerdal 2010; Polster et al. 2010) and to be dysregulated in multiple diseases (e.g., cancers) and conditions (e.g., diabetes, Alzheimer's disease, etc.) (Roldo et al. 2006; Xie et al. 2009; Yao et al. 2010). To date only a few targets are known for miR-103a-3p. "
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    ABSTRACT: MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of their targets in a sequence-dependent manner. For protein-coding transcripts, miRNAs regulate expression levels through binding sites in either the 3' untranslated region (3' UTR) or the amino acid coding sequence (CDS) of the targeted messenger RNA (mRNA). Currently, for the 5' untranslated region (5' UTR) of mRNAs, very few naturally occurring examples exist whereby the targeting miRNA down-regulates the expression of the corresponding mRNA in a seed-dependent manner. Here we describe and characterize two miR-103a-3p target sites in the 5' UTR of GPRC5A, a gene that acts as a tumor suppressor in some cancer contexts and as an ongocene in other cancer contexts. In particular, we show that the interaction of miR-103a-3p with each of these two 5' UTR targets reduces the expression levels of both GPRC5A mRNA and GPRC5A protein in one normal epithelial and two pancreatic cancer cell lines. By ectopically expressing "sponges" that contain instances of the wild-type 5' UTR targets we also show that we can reduce miR-103a-3p levels and increase GPRC5A mRNA and protein levels. These findings provide some first knowledge on the post-transcriptional regulation of this tumor suppressor/oncogene and present additional evidence for the participation of 5' UTRs in miRNA driven post-transcriptional regulatory control.
    Preview · Article · Jul 2014 · RNA
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    • "To date, every type of cancers analysed by miRNA profiling has shown significantly different miRNA profiles compared with normal cells from the same tissues. Several other genome-wide profiling studies have been performed on various cancer types, including chronic lymphocytic leukemia [7], breast cancer [8], glioblastoma [9], hepatocellular carcinoma [10], lung cancer [11], colon cancer and endocrine pancreatic tumours [12]. "
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    ABSTRACT: MicroRNAs (MiRNAs) are small non-coding RNAs (18-25nt) that regulate gene expression mainly through affecting post-transcriptional modification. Osteosarcoma is an aggressive sarcoma of the bone characterized by a high level of genetic instability and recurrent DNA deletions and amplifications. microRNAs (miRNAs) play an important role in cancer cell growth and migration, however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. In this paper, miR-199a and miR-34a were discussed the mechanisms of apoptosis using micrRNA mimics in human osteosarcoma cells. The results demonstrated that miR-199a and miR-34a could induce the apoptosis of human osteosarcoma cells via p53 signaling pathway.
    Full-text · Article · Jun 2014 · Bioscience Reports
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