Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer–cell lymphoma/leukemia

Abstract

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...

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

“…We hypothesized that the loss of SHIP-1 might also be due to translational repression by miRs. miR-155 has recently been shown to suppress SHIP-1 expression by binding to its 3 0 untranslated region (UTR) (Costinean et al, 2009;O'Connell et al, 2009;Pedersen et al, 2009;Yamanaka et al, 2009). Three different internet-based miR prediction programs (http://www.microrna.org, http://www.targetscan.org, and http://mirnamap.mbc.nctu.edu.tw) predicted that SHIP-1 could be targeted not only by miR-155 but also by miR-210.…”

“…Downregulation of SHIP-1 expression by miR-155 activates the PI 3 0 kinase/Akt pathway (Costinean et al, 2009;Pedersen et al, 2009 (Rosenfeld and List, 2000). Aberrant expression of miR-155 has recently been found in natural killer leukemia/lymphoma cells that display increased level of phospho-Akt (Yamanaka et al, 2009). In addition, miR-155 may stimulate the proliferation of MDS cells by inducing granulocyte colony-stimulating factor expression.…”

MicroRNA-155 Expression has Prognostic Value in Patients with Non-small Cell Lung Cancer and Digestive System Carcinomas

“…Oncogenic properties of miR-155 are attributed to its anti-apoptotic function through a blockade of caspase-3 activity or suppressing proapoptotic genes such as TP53BP1 (Gironella et al, 2007;Ovcharenko et al, 2007), and promote cell proliferation by downregulating the SOCS1 gene (Jiang et al, 2010), or activate AKT signaling via down-regulation of tumor suppressors including PTEN, PDCD4 and SHIP1 (Yamanaka et al, 2009). Besides, miR-155 is regulated by the transforming growth factor-beta (TGF-β)/Smad4 pathway and plays a role in cell invasion by targeting RhoA (Kong et al, 2008).…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…PTEN is an important tumor suppressor that antagonizes PI3K activity by inhibiting the transformation of PIP2 to PIP3. In cancers, the expression of PTEN is repressed by many oncogenic miRNAs, including miR-21 [80,81] , miR-221/2 [82] , miR-301 [83] , miR-144 [84] , miR-136 [84] , and miR-19 [85] . SHIP is another lipid phosphatase that inhibits the generation of PIP3.…”