MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas

MicroRNAs (miRNA, miR) are negative regulators of gene expression that play an important role in diverse biological processes such as development, cell growth, apoptosis and haematopoiesis, suggesting their association with cancer. Here we analysed the expression signatures of 157 miRNAs in 58 diffuse large B-cell lymphoma (DLBCL), 46 follicular lymphoma (FL) and seven non-neoplastic lymph nodes (LN). Comparison of the possible combinations of DLBCL-, FL- and LN resulted in specific DLBCL- and FL-signatures, which include miRNAs with previously published function in haematopoiesis ( MIRN150 and MIRN155 ) or tumour development ( MIRN210 , MIRN10A , MIRN17-5P and MIRN145 ). As compared to LN, some miRNAs are differentially regulated in both lymphoma types ( MIRN155 , MIRN210 , MIRN106A , MIRN149 and MIRN139 ). Conversely, some miRNAs show lymphoma-specific aberrant expression, such as MIRN9/9* , MIRN301 , MIRN338 and MIRN213 in FL and MIRN150 , MIRN17-5P , MIRN145 , MIRN328 and others in DLBCL. A classification tree was computed using four miRNAs ( MIRN330 , MIRN17-5P , MIRN106a and MIRN210 ) to correctly identify 98% of all 111 cases that were analysed in this study. Finally, eight miRNAs were found to correlate with event-free and overall survival in DLBCL including known tumour suppressors ( MIRN21 , MIRN127 and MIRN34a ) and oncogenes ( MIRN195 and MIRNLET7G ).     

miR-106b-25/miR-17-92 clusters: Polycistrons with oncogenic roles in hepatocellular carcinoma

MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation. The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis. It has two other paralogs in the human genome, the miR-106b-25 cluster and the miR-106a-363 cluster. Collectively, the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families, namely the miR-17, the miR-92, the miR-18 and the miR-19 families. Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma. Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses. Various targets of these microRNAs have been identified, and these targets are involved in tumor growth, cell survival and metastasis. In this review, we first describe the regulation of these clusters by c-Myc and E2F1, and how the members of these clusters in turn regulate E2F1 expression forming an auto-regulatory loop. In addition, the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.     

Temporal expression of microRNA cluster miR-17-92 regulates effector and memory CD8+ T-cell differentiation

MicroRNAs are important regulators of various developmental and physiological processes. However, their roles in the CD8(+) T-cell response are not well understood. Using an acute viral infection model, we show that microRNAs of the miR-17-92 cluster are strongly induced after T-cell activation, down-regulated after clonal expansion, and further silenced during memory development. miR-17-92 promotes cell-cycle progression of effector CD8(+) T cells, and its expression is critical to the rapid expansion of these cells. However, excessive miR-17-92 expression enhances mammalian target of rapamycin (mTOR) signaling and strongly skews the differentiation toward short-lived terminal effector cells. Failure to down-regulate miR-17-92 leads to a gradual loss of memory cells and defective central memory cell development. Therefore, our results reveal a temporal expression pattern of miR-17-92 by antigen-specific CD8(+) T cells during viral infection, the precise control of which is critical to the effector expansion and memory differentiation of CD8(+) T cells.     

microRNA expression in erythropoiesis and erythroid disorders

MicroRNAs are a recently discovered class of small (c. 22 nt) naturally occurring non‐coding RNA molecules that regulate gene expression through binding to the un‐translated region of target mRNA. MicroRNAs play key roles in many cellular pathways including haematopoiesis and aberrant expression is a common feature of haematological malignancies. Whilst other areas of haematopoiesis have been extensively reviewed the involvement of microRNAs in red cell production (erythropoiesis) and disorders of this pathway is lacking. In this review the rapidly accumulating evidence that points to the major role microRNAs play in both erythropoiesis and erythroid disorders is discussed.     

MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n = 49) and CD138+ bone marrow PCs from subjects with MM (n = 16), monoclonal gammopathy of undetermined significance (MGUS) (n = 6), and normal donors (n = 6). We identified overexpression of miR-21, miR-106b approximately 25 cluster, miR-181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17 approximately 92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17 approximately 92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR106b approximately 25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.     

MicroRNAs与心房颤动

心房颤动是临床上最常见的心律失常,其易感因素众多、发病机制主要为心房电重构和结构重构,但具体分子调控机制尚不明确。微小RNA（MicroRNAs）是一类长度为18-25个核苷酸的内源性非编码小RNA,可通过与靶基因mRNA 3’非翻译区的不完全互补结合,在转录后水平抑制靶基因的表达。近年来研究发现microRNAs在心房颤动的发生发展过程中起到了重要作用。房颤相关的microRNAs主要包括miR-1、miR-26和miR-101,miR-133,miR-328、miR-21、miR-30等,主要通过调控离子通道的表达影响心房电重构,或通过调控心肌纤维化及细胞外基质沉积参与心房结构重构。     

A microRNA expression signature of human solid tumors defines cancer gene targets

Small noncoding microRNAs (miRNAs) can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers. From a large-scale miRnome analysis on 540 samples including lung, breast, stomach, prostate, colon, and pancreatic tumors, we identified a solid cancer miRNA signature composed by a large portion of overexpressed miRNAs. Among these miRNAs are some with well characterized cancer association, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155. The predicted targets for the differentially expressed miRNAs are significantly enriched for protein-coding tumor suppressors and oncogenes (P < 0.0001). A number of the predicted targets, including the tumor suppressors RB1 (Retinoblastoma 1) and TGFBR2 (transforming growth factor, beta receptor II) genes were confirmed experimentally. Our results indicate that miRNAs are extensively involved in cancer pathogenesis of solid tumors and support their function as either dominant or recessive cancer genes.     

Ordered progression of stage-specific miRNA profiles in the mouse B2 B-cell lineage

Micro-RNAs (miRNAs) have been recognized as critical regulators of gene expression, and deregulation of miRNA expression has been implicated in a wide spectrum of diseases. To provide a framework for the role of miRNAs in B-cell development and malignancy, we deep-sequenced miRNAs from B1 cells and 10 developmental stages that can be identified within the mouse B2 B-cell lineage. The expression profiles of the 232 known miRNAs that are expressed during B-cell development display stage-specific induction patterns, yet hierarchical clustering analysis showed relationships that are in full agreement with the model of the B2 B-cell developmental pathway. Analysis of exemplary miRNA expression profiles (miR-150, miR-146a, miR-155, miR-181) confirmed that our data are in agreement with previous results. The high resolution of the expression data allowed for the identification of the sequential expression of oncomir-1/miR-17-92 and its paralogs miR-106a-363 and miR-106b-25 in subsequent developmental stages in the BM. Further, we have identified and validated 45 novel miRNAs and 6 novel miRNA candidates expressed in developing B cells.     

Distinct microRNA expression profiles in acute myeloid leukemia with common translocations

MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.     

miR-17-92 ameliorates renal ischemia reperfusion injury

There is limited information on the role of miR-17-92 in renal tubular pathophysiology. Therefore, the present study was performed to determine whether miR-17-92 plays a role in ischemia-reperfusion injury (IRI)-induced acute kidney injury. We originally demonstrated that miR-17-92 is up-regulated following IRI in vivo. To explore the roles of miR-17-92 in the IRI process, we first generated a renal proximal tubule-specific miR-17-92 deletion (PT-miR-17-92^?/?) knockout mouse model with Cre driven by the Kap promoter. We found that PT-deficient miR-17-92 mice had more severe renal dysfunction and renal structures than their littermates. Compared with sham-operated mice, both wide-type (WT) mice and PT-miR-17-92^?/? mice showed increased serum levels of creatinine and urea. However, the levels of serum urea and creatinine in PT-miR-17-92^?/? mice after the IRI operation were significantly higher than the levels in WT mice. In addition, PT-miR-17-92^?/? mice showed higher levels of serum potassium and phosphonium after the IRI operation. Histological analysis revealed that PT-miR-17-92^?/? mice had substantial histopathologic changes, such as tubular dilation and tubular necrosis. Overexpression of miR-17-92 could partially reverse the side-effects of IRI on the proximal tubules in vivo. Furthermore, we employed a quantitative proteomic strategy and identified 16 proteins as potential targets of miR-17-92. Taken together, our findings suggested that miR-17-92 may ameliorates IRI-induced acute kidney injury. Our results indicate that pharmacologic modulation of these miRNAs may have therapeutic potential for acute kidney injury.