The gene(s) responsible for natural killer (NK)-cell lymphoma/leukemia have not been identified. In the present study, we found that in NK-cell lymphoma lines (n ‫؍‬ 10) and specimens of primary lymphoma (n ‫؍‬ 10), levels of miR-21 and miR-155 expression were inversely related and were significantly greater than those found in normal natural killer (CD3 ؊ CD56 ؉ ) cells (n ‫؍‬ 8). To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) tar- IntroductionNatural killer (NK)-cell lymphomas/leukemias are characterized groups of highly aggressive lymphoid malignancies, which are composed of "extranodal NK/T-cell lymphoma, nasal type" and "aggressive NK-cell leukemia." 1 Notably, these 2 subtypes show many similarities in their morphologic features, immunophenotypes, and genotypes and are invariably associated with EpsteinBarr virus (EBV), which suggests they may share the same genetic alterations. To assign a classification, the World Health Organization classification uses cytogenetic and molecular features to characterize lymphoma subtypes. 1 For example, it is known that various genomic translocations and genetic alterations, including BCL2, CCDN1, and c-MYC, occur in B-cell lymphomas. These disease-specific genetic translocations characterize lymphoma subtypes, such as follicular lymphoma characterized by BCL2 rearrangement, mantle-cell lymphoma characterized by CCDN1 rearrangement, and Burkitt lymphoma characterized by c-MYC rearrangement. However, although the World Health Organization classification recognizes NK-cell lymphomas/leukemias as distinct clinicopathologic entities, disease-specific translocations and the gene(s) affected in the 2 subtypes have not yet been identified. It was previously reported that a 6q deletion occurs in approximately 10% to 20% of NK-cell lymphomas/leukemias 2-7 ; however, this loss may not be disease specific because it has been observed in a variety of cancers, including solid tumors and hematologic malignancies. It is currently unclear whether the loss is a primary or progression-associated event.It was recently discovered that some microRNAs (miRNAs) are oncogenic in B-cell lymphomas. For example, aberrant overexpression of 2 miRNAs, miR-17-92 and miR-155, is closely associated with B-cell lymphomagenesis. 8 With respect to miR-17-92, we recently demonstrated that the polycistron can down-regulate CDKN1A/p21 in B-cell lymphomagenesis and promote cell-cycle regulation. 8 Furthermore, it is unlikely that aberrant expression of miRNAs is restricted to B-cell lymphomas, and it may occur in other lymphoma subtypes, including T/NK-cell lymphomas. In the present study, therefore, we used Northern and quantitative polymerase chain reaction (PCR) analyses to screen for and quantitatively assess miRNA expression in NK-cell lymphomas/leukemias and found that miR-21 and miR-155 were overexpressed in NK-cell lymphoma/leukemia. Moreover, the effects of antisense oligonucleotides (ASOs) revealed that miR-21 and miR-15...

The present data suggest that the sustained increase of glyceraldehyde-derived AGE could at least in part contribute to the pathogenesis of NASH. The serum glyceraldehyde-derived AGE level may be a useful biomarker for discriminating NASH from simple steatosis.

No abstract

MicroRNA (miRNA; miR) is a class of small regulatory RNA molecules, the aberrant expression of which can lead to the development of cancer. We recently reported that overexpression of miR-21 and/or miR-155 leads to activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway in malignant lymphomas expressing CD3 À CD56þ natural killer (NK) cell antigen. Through expression analysis, we show in this study that in both NK/T-cell lymphoma lines and samples of primary lymphoma, levels of miR-150 expression are significantly lower than in normal NK cells. To examine its role in lymphomagenesis, we transduced miR-150 into NK/T-cell lymphoma cells, which increased the incidence of apoptosis and reduced cell proliferation. Moreover, the miR-150 transductants appeared senescent and showed lower telomerase activity, resulting in shortened telomeric DNA. We also found that miR-150 directly downregulated expression of DKC1 and AKT2, reduced levels of phosphorylated AKT ser473/4 and increased levels of tumor suppressors such as Bim and p53. Collectively, these results suggest that miR-150 functions as a tumor suppressor, and that its aberrant downregulation induces continuous activation of the PI3K-AKT pathway, leading to telomerase activation and immortalization of cancer cells. These findings provide new insight into the pathogenesis of malignant lymphoma.

SummaryRecent studies in animal models for systemic lupus erythematosus (SLE) have shown that Toll-like receptors (TLR-7 and TLR-9) and interferon (IFN)-a are involved in the pathogenesis of murine lupus. Recent studies using flow cytometry have also shown increased expression of TLR-9 in peripheral blood mononuclear cells (PBMCs) from SLE patients. In this study, we performed quantitative real-time reverse transcription-polymerase chain reaction analyses of PBMCs from 21 SLE patients and 21 healthy subjects, to estimate TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, IFN-a and LY6E (a type I IFNinducible gene) mRNA expression levels. Expression levels of TLR2, TLR7, TLR9, IFN-a and LY6E mRNAs in SLE patients were significantly higher than those in healthy controls. Expression levels of TLR7 and TLR9 mRNAs correlated with that of IFN-a mRNA in SLE patients. These results suggest that up-regulated expression of TLR7 and TLR9 mRNAs together with increased expression of IFN-a mRNA in PBMCs may also contribute to the pathogenesis of human lupus.