MicroRNA expression profiling in classic Hodgkin lymphoma

Abstract

IntroductionMature microRNAs (miRNAs) are naturally occurring small noncoding RNAs that act as negative regulators of gene expression through messenger RNA interference. These molecules were described for the first time in 1993 by Ambros and colleagues in Caenorhabditis elegans (Lee et al 1 ), and to date, hundreds of miRNAs have been identified in other species, including viruses. 2,3 miRNAs are encoded by intronic or intergenic DNA regions, primarily as large molecules that can exceed 1 Kb, and are cleaved by an RNase complex into fragments with characteristic stem-loop structures. In the cytoplasm, a RNase called Dicer further cleaves miRNA to generate a duplex molecule of 21 to 25 nucleotides in length. 4 One of the 2 chains is the mature miRNA that binds a protein complex called the RNA-induced silencing complex (RISC). When a miRNA and a messenger RNA exhibit total complementarities, RISC is capable of degrading target messenger RNA, 4 whereas if an incomplete base pairing complementarity takes place, translational silencing of the target occurs. Through these mechanisms, miRNAs decrease translation of human genes. 5,6 miRNAs play an important role in cellular proliferation and differentiation and embryonic development, and they also act as oncogenes or tumor suppressor genes. 7-10 Notably, the majority of miRNAs are found in cancer-associated genomic regions or in chromosome-fragile sites, 11 suggesting an important role for miRNAs in human tumorigenesis. There is also evidence that the influence of miRNAs in oncogenesis might be indirectly driven. For example, the presence of some viruses in a cell may change the host miRNA pattern. 12 Viruses may participate in the origin of some tumors, such as the Epstein-Barr virus (EBV) in Hodgkin lymphoma (HL).HL is a neoplasm characterized by the presence of relatively few tumoral cells (Hodgkin and Reed-Sternberg cells) in a nonneoplastic microenvironment. 13 Hodgkin and Reed-Sternberg cells arise from germinal center B cells. 14 Classic HL (cHL) is subclassified according to the morphology of Reed-Sternberg cells and the composition of the cellular background into nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte depletion. 15 The 2 former subtypes are the most frequent forms of cHL and contain a variable proportion of neoplastic cells.EBV is present in the malignant cells of 40% to 60% of cHL patients. However, the precise role of the EBV in the pathogenesis of cHL is unknown. It has been reported that viruses have their own miRNA set, 16 and that there is an interaction between the host miRNAs and virus miRNAs. 17,18 The interaction between the virus and the malignant cells in cHL might be mediated in part by miRNAs.To investigate whether a specific expression signature of miRNAs is associated with cHL, we assessed the expression of 156 miRNAs, the majority of which are related to hematopoiesis or tumorigenesis, 7,8,11 in lymph nodes from patients with nodular sclerosis and mixed cellularity cHL and compared the expression patterns with tho...

Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization

“…miR-27a, mapped to chromosome 19p13, which was gained in seven of ten primary cHL cases in the present study, was shown to be one of the most strongly upregulated microRNA in cHL cell lines. 46 Collectively, the data from the present study show that array CGH of primary HRS cells enables the detection of new genomic imbalances and the delineation of known ones. Furthermore, our findings suggest that genomic aberrations in HRS cells may contribute to the typical cHL-specific phenotype with constitutive expression of several signaling pathways via gene dosage effects.…”

Everything you wanted to know about small RNA but were afraid to ask

“…111 On the more clinical end of the research spectrum, profiling of microRNAs in many other kinds of cancers is proceeding rapidly, with recent examples from cervical, prostate, pancreatic, and germ cell tumors, among many others. 92,94,[113][114][115][116][117][118] Characteristic microRNA patterns offer new information that could yield advances in tumor classification and prognosis determination, although the clinical validation of such efforts will require some time.…”

MicroRNAs and lymphomagenesis: a functional review

“…Indeed, MIR21 was the only consistently up-regulated miRNA in a study that profiled 540 clinical samples from cancer patients . Overexpression of this miRNA has been documented in both Hodgkin and non-Hodgkin lymphoma (Lawrie et al, 2007;Navarro et al, 2008). MIR21 has been shown to target many tumour suppressor genes including tropomyosin 1 (TPM1), programmed cell death 4 (PDCD4) and maspin (SERPINB5) in breast cancer and lymphoma (Zhu et al, 2008;Schramedei et al, 2011), PTEN in hepatocellular cancer and NK/T cell lymphoma (Meng et al, 2007;Yamanaka et al, 2009), tissue inhibitor of metalloproteinase-3 (TIMP3) in glioma (Gabriely et al, 2008), tumour suppressor genes ANP32A and SMAR-CA4 in B-cell lymphoma (Schramedei et al, 2011), and multiple components of the TP53, transforming growth factor-b (TGFB1), and mitochondrial apoptosis tumour-suppressive pathways (Papagiannakopoulos et al, 2008).…”