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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    • "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.
    RNA 07/2014; 20(9). DOI:10.1261/rna.045757.114 · 4.94 Impact Factor
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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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    Bioscience Reports 06/2014; 34(4). DOI:10.1042/BSR20140084 · 2.64 Impact Factor
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    • "However, the only up-regulated validated microRNA identified in our signature that could discriminate between colonic hepatic metastasis and primary hepatocellular carcinoma was hsa-miR-103. The relevance of this miRNA in cancer has been assessed in pancreatic, bladder, esophageal, gastric and breast tumors [29], [90]–[93]. High levels of hsa-miR-103 were correlated to poor survival in esophageal cancer and are associated to metastatic disease in breast and gastric cancer. Particularly, hsa-miR-103 upregulation was detected in gastric cancer patients bearing positive lymph nodes. "
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    ABSTRACT: MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor.
    PLoS ONE 06/2014; 9(6):e96670. DOI:10.1371/journal.pone.0096670 · 3.23 Impact Factor
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