AGO2

Gene Summary

Gene:AGO2; argonaute RISC catalytic component 2
Aliases: Q10, EIF2C2
Location:8q24
Summary:This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, and contains a PAZ domain and a PIWI domain. It may interact with dicer1 and play a role in short-interfering-RNA-mediated gene silencing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein argonaute-2
HPRD
Source:NCBIAccessed: 08 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AGO2 (cancer-related)

Romero-Cordoba SL, Salido-Guadarrama I, Rodriguez-Dorantes M, Hidalgo-Miranda A
miRNA biogenesis: biological impact in the development of cancer.
Cancer Biol Ther. 2014; 15(11):1444-55 [PubMed] Related Publications
microRNAs (miRNAs) are non coding RNAs with different biological functions and pathological implications. Given their role as post-transcriptional gene expression regulators, they are involved in several important physiological processes like development, cell differentiation and cell signaling. miRNAs act as modulators of gene expression programs in different diseases, particularly in cancer, where they act through the repression of genes which are critical for carcinogenesis. The expression level of mature miRNAs is the result of a fine mechanism of biogenesis, carried out by different enzymatic complexes that exert their function at transcriptional and post-transcriptional levels. In this review, we will focus our discussion on the alterations in the miRNA biogenesis machinery, and its impact on the establishment and development of cancer programs.

Melo SA, Sugimoto H, O'Connell JT, et al.
Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis.
Cancer Cell. 2014; 26(5):707-21 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Exosomes are secreted by all cell types and contain proteins and nucleic acids. Here, we report that breast cancer associated exosomes contain microRNAs (miRNAs) associated with the RISC-Loading Complex (RLC) and display cell-independent capacity to process precursor microRNAs (pre-miRNAs) into mature miRNAs. Pre-miRNAs, along with Dicer, AGO2, and TRBP, are present in exosomes of cancer cells. CD43 mediates the accumulation of Dicer specifically in cancer exosomes. Cancer exosomes mediate an efficient and rapid silencing of mRNAs to reprogram the target cell transcriptome. Exosomes derived from cells and sera of patients with breast cancer instigate nontumorigenic epithelial cells to form tumors in a Dicer-dependent manner. These findings offer opportunities for the development of exosomes based biomarkers and therapies.

Sioud M
RNA interference: mechanisms, technical challenges, and therapeutic opportunities.
Methods Mol Biol. 2015; 1218:1-15 [PubMed] Related Publications
The ability to inhibit gene expression via RNA interference (RNAi) has a broad therapeutic potential for various human diseases such as infections and cancers. Recent advances in mechanistic understanding of RNAi have improved the design of functional small interfering (si) RNAs with superior potency and specificity. With respect to delivery, new developments in delivery strategies have facilitated preclinical and clinical siRNA applications. This review provides valuable insights to guide the design and delivery of therapeutic siRNAs.

Ostenfeld MS, Jeppesen DK, Laurberg JR, et al.
Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties.
Cancer Res. 2014; 74(20):5758-71 [PubMed] Related Publications
Exosomes are small secreted vesicles that can transfer their content to recipient cells. In cancer, exosome secretion has been implicated in tumor growth and metastatic spread. In this study, we explored the possibility that exosomal pathways might discard tumor-suppressor miRNA that restricts metastatic progression. Secreted miRNA characterized from isogenic bladder carcinoma cell lines with differing metastatic potential were uncoupled from binding to target transcripts or the AGO2-miRISC complex. In metastatic cells, we observed a relative increase in secretion of miRNA with tumor-suppressor functions, including miR23b, miR224, and miR921. Ectopic expression of miR23b inhibited invasion, anoikis, angiogenesis, and pulmonary metastasis. Silencing of the exocytotic RAB family members RAB27A or RAB27B halted miR23b and miR921 secretion and reduced cellular invasion. Clinically, elevated levels of RAB27B expression were linked to poor prognosis in two independent cohorts of patients with bladder cancer. Moreover, highly exocytosed miRNA from metastatic cells, such as miR23b, were reduced in lymph node metastases compared with patient-matched primary tumors and were correlated with increments in miRNA-targeted RNA. Taken together, our results suggested that exosome-mediated secretion of tumor-suppressor miRNA is selected during tumor progression as a mechanism to coordinate activation of a metastatic cascade.

Kanda M, Sugimoto H, Nomoto S, et al.
Clinical utility of PDSS2 expression to stratify patients at risk for recurrence of hepatocellular carcinoma.
Int J Oncol. 2014; 45(5):2005-12 [PubMed] Related Publications
Identification of novel genetic and epigenetic alterations is required for optimal stratification of patients with hepatocellular carcinoma (HCC) at risk for recurrence and adverse prognosis. Coenzyme Q10 (CoQ10), which mediates apoptosis, is synthesized by prenyl diphosphate synthase subunit 2 (PDSS2). In the present study we evaluated the clinical significance and regulatory mechanisms of PDSS2 expression in HCC. PDSS2 expression levels and those of genes encoding potentially interacting proteins as well as the methylation status of the PDSS2 promoter region were analyzed in HCC cell lines. PDSS2 mRNA levels in 151 pairs of resected specimens were determined to evaluate the association of PDSS2 expression and clinicopathological factors. The expression and distribution of PDSS2 were determined using immunohistochemistry. PDSS2 mRNA expression was decreased in six of nine HCC cell lines and significantly correlated with those of hepatocyte nuclear factor 4α. PDSS2 transcription in HCC cells with decreased PDSS2 expression accompanying hypermethylation was reactivated after treating these cells with a methylation inhibitor. Mean expression levels of PDSS2 mRNA relative to that of uninvolved liver diminished gradually in the order of chronic hepatitis to cirrhosis, and each was significantly higher than those of HCCs. PDSS2 and PDSS2 mRNA levels were consistent. Decreased PDSS2 mRNA levels were detected in HCC tissues of 56 patients, correlated with shorter disease-specific survival, and was identified as an independent prognostic factor. PDSS2 is a putative tumor suppressor, and promoter hypermethylation is a key regulatory mechanism in HCC. Decreased levels of PDSS2 mRNA expression may represent a novel biomarker of HCC.

Finalet Ferreiro J, Rouhigharabaei L, Urbankova H, et al.
Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma.
PLoS One. 2014; 9(7):e102977 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.

Hu X, Ai G, Meng X, et al.
An ider(17)(q10)t(15;17) with spliced long-type PML-RARA fusion transcripts in a case of acute promyelocytic leukemia.
Cancer Genet. 2014; 207(6):253-7 [PubMed] Related Publications
The ider(17)(q10)t(15;17) is a relatively rare chromosomal rearrangement in acute promyelocytic leukemia patients. We describe herein a case of APL with a poor prognosis and ider(17)(q10)t(15;17)(q22;q12), which was confirmed by fluorescence in situ hybridization. Reverse transcription polymerase chain reaction (RT-PCR) and sequencing of PCR products were used to detect the PML-RARA fusion gene and delineate the sequence of the fusion transcripts. We found that the PML-RARA fusion gene of this patient was the long isoform, which only generated transcripts of a splice variant lacking PML exon 5 and a splice variant lacking PML exons 5 and 6. Although the clinical and prognostic significance of patients with an ider(17)(q10)t(15;17) remains unclear, a combination of cytogenetics and molecular biology analysis should be performed to obtain further information about this chromosomal abnormality.

Wang T, Yuan J, Feng N, et al.
Hsa-miR-1 downregulates long non-coding RNA urothelial cancer associated 1 in bladder cancer.
Tumour Biol. 2014; 35(10):10075-84 [PubMed] Related Publications
MicroRNAs (miRNAs) are known to mainly target protein-coding genes at post-transcriptional level, resulting in mRNA destabilization and/or translational repression. Long non-coding RNAs (lncRNAs) are emerging as a novel set of targets for miRNAs. Here, we report that downregulated hsa-miR-1 and upregulated lncRNA urothelial cancer associated 1 (UCA1) were inversely expressed in bladder cancer. Hsa-miR-1 decreased the expression of UCA1 in bladder cancer cells in an Ago2-slicer-dependent manner. The binding site between UCA1 and hsa-miR-1 was confirmed. Overexpression of hsa-miR-1 inhibited bladder cancer cell growth, induced apoptosis, and decreased cell motility. Knockdown of UCA1 expression phenocopied the effects of upregulation of hsa-miR-1. Transfection of UCA1 expression vector partly reversed the changes caused by transfection of pre-miR-1 plasmids. This study provides evidence for hsa-miR-1 to play tumor suppressive roles via downregulating lncRNA UCA1 in bladder cancer, which may have potential therapeutic significance.

Masciarelli S, Quaranta R, Iosue I, et al.
A small-molecule targeting the microRNA binding domain of argonaute 2 improves the retinoic acid differentiation response of the acute promyelocytic leukemia cell line NB4.
ACS Chem Biol. 2014; 9(8):1674-9 [PubMed] Related Publications
Argonaute proteins are pivotal regulators of gene expression mediating miRNAs function. Modulating their activity would be extremely useful to elucidate the processes governing small-RNAs-guided gene silencing. We report the identification of a chemical compound able to compete with Argonaute 2 miRNAs binding, and we demonstrate that this functional inhibition determines effects similar to Argonaute 2 shRNA-mediated down-regulation, favoring granulocytic differentiation of the acute promyelocytic leukemia cell line NB4 in response to retinoic acid.

Wu S, Yu W, Qu X, et al.
Argonaute 2 promotes myeloma angiogenesis via microRNA dysregulation.
J Hematol Oncol. 2014; 7:40 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
BACKGROUND: Dysregulated microRNA (miRNA) expression contributes to cancer cell proliferation, apoptosis and angiogenesis. Angiogenesis is a hallmark of multiple myeloma (MM) development and progression. Argonaute 2 (AGO2) protein, a core component of the RNA-induced silencing complex (RISC), can directly bind to miRNAs and mediate target messenger RNA (mRNA) degradation. A previous study showed that AGO2 knockdown suppressed human umbilical vein endothelial cell (HUVEC) growth and tube formation. However, the roles and molecular mechanisms of AGO2-induced myeloma angiogenesis are not yet fully understood. The aim of this study was to characterize these roles and effects and their associated mechanisms.
RESULTS: Supernatants from AGO2-overexpressing MM lines induced HUVEC migration and accelerated tube formation. Conversely, supernatants from AGO2-knockdown MM lines suppressed HUVEC cell migration and tube formation. Moreover, a chick chorioallantoic membrane (CAM) assay was used to demonstrate that AGO2 could drive neovessel formation in MM lines in vivo. Using an miRNA microarray, we observed that 25 miRNAs were upregulated and 7 were downregulated in response to AGO2. Most let-7 family members and 2 miR-17/92 cluster members (miR-17a and miR-92-1), all known pro-angiogenic miRNAs, were positively regulated by AGO2 whereas anti-angiogenic miRNAs such as miR-145 and miR-361 were negatively regulated by AGO2.
CONCLUSIONS: We conclude that AGO2 can drive neovessel formation in vitro and in vivo by dysregulating the expression of some angiogenic miRNAs. The pro-angiogenic miRNAs of the let-7 family and the miR-17/92 cluster, along with the anti-angiogenic miRNA miR-145, play crucial roles in AGO2-mediated angiogenesis by targeting angiogenesis-related genes.

Unger GM, Kren BT, Korman VL, et al.
Mechanism and efficacy of sub-50-nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma.
Mol Cancer Ther. 2014; 13(8):2018-29 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Improved survival for patients with head and neck cancers (HNC) with recurrent and metastatic disease warrants that cancer therapy is specific, with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub-50-nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell-specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA-induced silencing complex pathway to target the CK2αα' mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft HNSCC models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise.

Rajgor D, Mellad JA, Soong D, et al.
Mammalian microtubule P-body dynamics are mediated by nesprin-1.
J Cell Biol. 2014; 205(4):457-75 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Nesprins are a multi-isomeric family of spectrin-repeat (SR) proteins, predominantly known as nuclear envelope scaffolds. However, isoforms that function beyond the nuclear envelope remain poorly examined. Here, we characterize p50(Nesp1), a 50-kD isoform that localizes to processing bodies (PBs), where it acts as a microtubule-associated protein capable of linking mRNP complexes to microtubules. Overexpression of dominant-negative p50(Nesp1) caused Rck/p54, but not GW182, displacement from microtubules, resulting in reduced PB movement and cross talk with stress granules (SGs). These cells disassembled canonical SGs induced by sodium arsenite, but not those induced by hydrogen peroxide, leading to cell death and revealing PB-microtubule attachment is required for hydrogen peroxide-induced SG anti-apoptotic functions. Furthermore, p50(Nesp1) was required for miRNA-mediated silencing and interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. These data identify p50(Nesp1) as a multi-functional PB component and microtubule scaffold necessary for RNA granule dynamics and provides evidence for PB and SG micro-heterogeneity.

Zhang K, Lin JW, Wang J, et al.
A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.
Genet Med. 2014; 16(10):787-92 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
PURPOSE: Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease.
METHODS: We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family.
RESULTS: We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells.
CONCLUSION: Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792.

Li Y, Schwab C, Ryan SL, et al.
Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.
Nature. 2014; 508(7494):98-102 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

Chiyomaru T, Fukuhara S, Saini S, et al.
Long non-coding RNA HOTAIR is targeted and regulated by miR-141 in human cancer cells.
J Biol Chem. 2014; 289(18):12550-65 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
HOTAIR is a long non-coding RNA that interacts with the polycomb repressive complex and suppresses its target genes. HOTAIR has also been demonstrated to promote malignancy. MicroRNA-141 (miR-141) has been reported to play a role in the epithelial to mesenchymal transition process, and the expression of miR-141 is inversely correlated with tumorigenicity and invasiveness in several human cancers. We found that HOTAIR expression is inversely correlated to miR-141 expression in renal carcinoma cells. HOTAIR promotes malignancy, including proliferation and invasion, whereas miR-141 suppresses malignancy in human cancer cells. miR-141 binds to HOTAIR in a sequence-specific manner and suppresses HOTAIR expression and functions, including proliferation and invasion. Both HOTAIR and miR-141 were associated with the immunoprecipitated Ago2 (Argonaute2) complex, and the Ago2 complex cleaved HOTAIR in the presence of miR-141. These results demonstrate that HOTAIR is suppressed by miR-141 in an Ago2-dependent manner.

Kwon SY, Lee JH, Kim B, et al.
Complexity in regulation of microRNA machinery components in invasive breast carcinoma.
Pathol Oncol Res. 2014; 20(3):697-705 [PubMed] Related Publications
Altered expression of microRNA (miRNA) machinery components may play an important role in breast cancer progression. The objective of the current study was to evaluate Drosha, the DiGeorge syndrome critical region gene 8 (DGCR8), Dicer, and Argonaute 2 (AGO2) mRNA expression in invasive breast carcinoma (IBC) and to assess the value of clinical parameters on their expression. By using quantitative real-time PCR, we examined the expression of the four miRNA machinery components in 52 breast tumor tissues which are diagnosed as invasive ductal carcinoma and adjacent non-neoplastic tissues. In the present study, decreased mRNA expression levels of major miRNA machinery components were observed in IBC. The altered mRNA expression levels of DGCR8 and AGO2 are positively correlated with to each other. This study revealed for the first time that expression alterations of DGCR8 are significantly associated with estrogen receptor and Ki-67 status in IBC. Moreover, AGO2 mRNA expression level was significantly correlated with N stage. These results provided evidences that down-regulated the four miRNA machinery components may play an important role in breast pathobiology and that DGCR8 and AGO2 might be associated with important clinical factors.

Yang FQ, Huang JH, Liu M, et al.
Argonaute 2 is up-regulated in tissues of urothelial carcinoma of bladder.
Int J Clin Exp Pathol. 2014; 7(1):340-7 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
UNLABELLED: Argonaute 2 proteins (Ago2) have been demonstrated to be widely expressed and involved in post-transcriptional gene silencing and play key roles in carcinogenesis. However, its expression profile and prognostic value in urothelial carcinoma of the bladder (UCB) have not been investigated.
METHODS: Real-time quantitative PCR (qRT-PCR) and Western blot were used to explore Ago2 expression in UCBs and normal bladder tissues. Moreover immunohistochemistry (ICH) was used to detect the expression of Ago2 in UCBs. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.
RESULTS: Up-regulated expression of Ago2 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blot when compared with their paired normal bladder tissues. Clinic pathological analysis was showed a significant correlation existed between the higher expression of Ago2 protein with the Histological grade, lymph node metastasis and Distant metastasis (P<0.05); Survival analysis by Kaplan-Meier survival curve and log-rank test demonstrated that elevated Ago2 expression in cancer tissue predicted poorer overall survival (OS) compared with group in lower expression (62.2% VS 86.3%, P<0.05). Notably, multivariate analyses by Cox's proportional hazard model revealed that expression of Ago2 was an independent prognostic factor in UCB.
CONCLUSIONS: These results suggest that the aberrant expression of Ago2 in human UCB is possibly involved with tumorigenesis and development, and the Ago2 protein could act as a potential biomarker for prognosis assessment of bladder cancer. Further studies on the cellular functions of Ago2 need to address these issues.

Kumar MS, Armenteros-Monterroso E, East P, et al.
HMGA2 functions as a competing endogenous RNA to promote lung cancer progression.
Nature. 2014; 505(7482):212-7 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Non-small-cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide. As the majority of patients present with invasive, metastatic disease, it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma, in which it contributes to cancer progression and metastasis. Here we show that Hmga2 promotes lung cancer progression in mouse and human cells by operating as a competing endogenous RNA (ceRNA) for the let-7 microRNA (miRNA) family. Hmga2 can promote the transformation of lung cancer cells independent of protein-coding function but dependent upon the presence of let-7 sites; this occurs without changes in the levels of let-7 isoforms, suggesting that Hmga2 affects let-7 activity by altering miRNA targeting. These effects are also observed in vivo, where Hmga2 ceRNA activity drives lung cancer growth, invasion and dissemination. Integrated analysis of miRNA target prediction algorithms and metastatic lung cancer gene expression data reveals the TGF-β co-receptor Tgfbr3 (ref. 12) as a putative target of Hmga2 ceRNA function. Tgfbr3 expression is regulated by the Hmga2 ceRNA through differential recruitment to Argonaute 2 (Ago2), and TGF-β signalling driven by Tgfbr3 is important for Hmga2 to promote lung cancer progression. Finally, analysis of NSCLC-patient gene-expression data reveals that HMGA2 and TGFBR3 are coordinately regulated in NSCLC-patient material, a vital corollary to ceRNA function. Taken together, these results suggest that Hmga2 promotes lung carcinogenesis both as a protein-coding gene and as a non-coding RNA; such dual-function regulation of gene-expression networks reflects a novel means by which oncogenes promote disease progression.

Iosue I, Quaranta R, Masciarelli S, et al.
Argonaute 2 sustains the gene expression program driving human monocytic differentiation of acute myeloid leukemia cells.
Cell Death Dis. 2013; 4:e926 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
MicroRNAs are key regulators of many biological processes, including cell differentiation. These small RNAs exert their function assembled in the RNA-induced silencing complexes (RISCs), where members of Argonaute (Ago) family of proteins provide a unique platform for target recognition and gene silencing. Here, by using myeloid cell lines and primary blasts, we show that Ago2 has a key role in human monocytic cell fate determination and in LPS-induced inflammatory response of 1,25-dihydroxyvitamin D3 (D3)-treated myeloid cells. The silencing of Ago2 impairs the D3-dependent miR-17-5p/20a/106a, miR-125b and miR-155 downregulation, the accumulation of their translational targets AML1, VDR and C/EBPβ and monocytic cell differentiation. Moreover, we show that Ago2 is recruited on miR-155 host gene promoter and on the upstream region of an overlapping antisense lncRNA, determining their epigenetic silencing, and miR-155 downregulation. These findings highlight Ago2 as a new factor in myeloid cell fate determination in acute myeloid leukemia cells.

Roug AS, Wendtland P, Bendix K, Kjeldsen E
Supernumerary isochromosome 1, idic(1)(p12), leading to tetrasomy 1q in Burkitt lymphoma.
Cytogenet Genome Res. 2014; 142(1):7-13 [PubMed] Related Publications
Burkitt lymphoma (BL) is an aggressive mature B-cell neoplasm. The cytogenetic hallmark are MYC-involving translocations, most frequently as t(8;14)(q24;q32). Additional cytogenetic abnormalities are seen in the majority of cases. The most frequent additional aberration involves the long arm of chromosome 1, either as partial or complete trisomy 1q. A very rare additional aberration is a supernumerary isochromosome 1q, i(1)(q10), resulting in tetrasomy 1q. The biological significance of this aberration is unclear. We present a highly aggressive case of BL in a child with immature B-cell immunophenotype (IP) and supernumerary i(1)(q10). Diagnostic karyotyping showed 47,XY,+i(1)(q10),t(8;14)(q24;q32)[2]/47,idem,del(15)(q24)[21]/46,XY[2]. aCGH analysis detected a gain of 1p12qter and a loss of 15q22q25. FISH analysis confirmed the isodicentric chromosome 1, which has not previously been reported in BL. In the literature, supernumerary i(1)(q10) was found in 11 cases of which >80% presented with immature B-cell IP and >60% relapsed or died. Tetrasomy 1q resulting from supernumerary idic(1)(p12) or i(1)(q10) is a rare genetic event in BL and probably associated with immature B-cell IP. We propose that high amplification of genes on chromosome 1p12qter may contribute to the BL IP and disease progression.

Völler D, Reinders J, Meister G, Bosserhoff AK
Strong reduction of AGO2 expression in melanoma and cellular consequences.
Br J Cancer. 2013; 109(12):3116-24 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
BACKGROUND: Processing of microRNAs (miRNAs) is a highly controlled process. Deregulation of miRNA expression was observed in several types of cancer but changes in the miRNA-processing enzymes have not been analysed until today. In this study, we analysed Argonaute2 (AGO2, EIF2C2), as one main factor of the miRNA processing ensemble, in the context of cancer development, especially in melanoma.
METHODS: We determined the AGO2 expression level in melanoma, as well as in other cancers, with biochemical approaches (qRT-PCR, western blot and immunofluorescence studies) and analysed the cell behaviour in migration assays.
RESULTS: Specifically in melanoma, we revealed a strong reduction of AGO2 expression compared with primary melanocytes. The reduction of AGO2 expression was only found on protein level, whereas the mRNA level stayed unchanged hinting to post-transcriptional regulation. We could show that re-expression of AGO2 in melanoma leads to a strong improvement of regulatory effects due to increased functionality of small-interfering RNAs and short hairpin RNAs.
CONCLUSION: We identified melanoma-specific downregulation of AGO2 and corresponding reduced RNAi efficiency. These findings will help to understand the molecular basis of malignant melanoma and can potentially lead to an improvement of therapeutic strategies.

Gadji M, Crous-Tsanaclis AM, Mathieu D, et al.
A new der(1;7)(q10;p10) leading to a singular 1p loss in a case of glioblastoma with oligodendroglioma component.
Neuropathology. 2014; 34(2):170-8 [PubMed] Related Publications
The combined 1p-/19q- deletions in oligodendrogliomas originate from translocation between both chromosomes. In the few cases of oligoastrocytomas and glioblastomas with an oligodendroglioma component (GBMO) where only 1p deletion was described, the origin remains unknown. We report the first case of GBMO, in which a single 1p deletion was detected and was linked to a translocation between chromosomes 1 and 7. Fresh surgical specimens were collected during surgery and the samples were used for cell culture, touch preparation smear slides (TP slides) and DNA extraction. Peripheral venous blood was also collected from the patient. G-banding using Trypsin and stained with Giemsa (GTG) banding and karyotyping were performed and 1p-/19q-, TP53, PTEN and c-MYC were analyzed by fluorescent in situ hybridization (FISH). Multicolor FISH (mFISH) and microsatellites analyses were also performed to complete the investigation. Three-dimensional quantitative FISH (3D-QFISH) of telomeres was performed on nuclei from TP slides and analyzed using TeloView(TM) to determine whether the 3D telomere profile as an assessment of telomere dysfunction and a characterization of genomic instability could predict the disease aggressiveness. An unbalanced chromosomal translocation was found in all metaphases and confirmed by mFISH. The karyotype of the case is: 50∼99,XXX, +der(1;7)(q10;p10),inc[47] The derivative chromosome was found in all 47 analyzed cells, but the number of derivatives varied from one to four. There was neither imbalance in copy number for genes TP53 and PTEN, nor amplification of c-MYC gene. We did not find loss of heterozygosity with analysis of microsatellite markers for chromosomes 1p and 19q in tumor cells. The 3D-telomere profile predicted a very poor prognostic and short-term survival of the patient and highlights the potential clinical power of telomere signatures as a solid biomarker of GBMO. Furthermore, this translocation between chromosomes 1 and 7 led to a singular 1p deletion in this GBMO and may generate the 1p and 7q deletions.

Huang V, Zheng J, Qi Z, et al.
Ago1 Interacts with RNA polymerase II and binds to the promoters of actively transcribed genes in human cancer cells.
PLoS Genet. 2013; 9(9):e1003821 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Argonaute proteins are often credited for their cytoplasmic activities in which they function as central mediators of the RNAi platform and microRNA (miRNA)-mediated processes. They also facilitate heterochromatin formation and establishment of repressive epigenetic marks in the nucleus of fission yeast and plants. However, the nuclear functions of Ago proteins in mammalian cells remain elusive. In the present study, we combine ChIP-seq (chromatin immunoprecipitation coupled with massively parallel sequencing) with biochemical assays to show that nuclear Ago1 directly interacts with RNA Polymerase II and is widely associated with chromosomal loci throughout the genome with preferential enrichment in promoters of transcriptionally active genes. Additional analyses show that nuclear Ago1 regulates the expression of Ago1-bound genes that are implicated in oncogenic pathways including cell cycle progression, growth, and survival. Our findings reveal the first landscape of human Ago1-chromosomal interactions, which may play a role in the oncogenic transcriptional program of cancer cells.

Kanematsu S, Tanimoto K, Suzuki Y, Sugano S
Screening for possible miRNA-mRNA associations in a colon cancer cell line.
Gene. 2014; 533(2):520-31 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs mediating the regulation of gene expression in various biological contexts, including carcinogenesis. Here, we screened putative associations between 34, 45, and 103 miRNAs and 164, 391, and 81 mRNAs via Argonaute1 (Ago1) or Ago2 immunoprecipitation (IP) experiments in a colon cancer cell line. We used a combination of RIP Seq analysis. RNAs that were co-immunoprecipitated with Ago1 or Ago2 were used for massively parallel small RNA and mRNA sequencing. The detected miRNAs and mRNAs were further associated with one another based on in silico target predictions. Analysis of the putative associations indicated that, although Ago1 and Ago2 shared a similar repertory of miRNAs, the mRNAs possibly regulated by those miRNAs seemed different. The mRNAs detected with Ago1 IP were indicated to be frequently associated with genes having constitutive cellular functions, regulated by a smaller number of miRNAs, and appeared to receive more stringent translational regulation. In contrast, putative miRNA-mRNA associations detected with Ago2 IP appeared to be related to signal transduction genes, which had a larger number of possible miRNA binding sites. We then conducted a similar analysis using the colon cancer cells cultured under hypoxia and identified potential hypoxia-induced miRNA-mRNA associations, which included several well-characterized cancer-related genes as novel putative miRNA targets.

Iio A, Takagi T, Miki K, et al.
DDX6 post-transcriptionally down-regulates miR-143/145 expression through host gene NCR143/145 in cancer cells.
Biochim Biophys Acta. 2013; 1829(10):1102-10 [PubMed] Related Publications
In various human malignancies, widespread dysregulation of microRNA (miRNA) expression is reported to occur and affects various cell growth programs. Recent studies suggest that the expression levels of miRNAs that act as tumor suppressors are frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription, and disturbances in miRNA processing. MiR-143 and -145 are well-recognized miRNAs that are highly expressed in several tissues, but down-regulated in most types of cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that DEAD-box RNA helicase 6, DDX6 (p54/RCK), post-transcriptionally down-regulated miR-143/145 expression by prompting the degradation of its host gene product, NCR143/145 RNA. In human gastric cancer cell line MKN45, DDX6 protein was abundantly expressed and accumulated in processing bodies (P-bodies). DDX6 preferentially increased the instability of non-coding RNA, NCR143/145, which encompasses the miR-143/145 cluster, and down-regulated the expression of mature miR-143/145. In human monocytic cell line THP-1, lipopolysaccharide treatment promoted the assembly of P-bodies and down-regulated the expression of NCR143/145 and its miR-143/145 rapidly. In these cells, cycloheximide treatment led to a loss of P-bodies and to an increase in NCR143/145 RNA stability, thus resulting in up-regulation of miR-143/145 expression. These data demonstrate that DDX6 contributed to the control of NCR143/145 RNA stability in P-bodies and post-transcriptionally regulated miR-143/145 expression in cancer cells.

Fan M, Krutilina R, Sun J, et al.
Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells.
J Biol Chem. 2013; 288(38):27480-93 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
MicroRNAs (miRNAs) regulate mRNA stability and translation through the action of the RNAi-induced silencing complex. In this study, we systematically identified endogenous miRNA target genes by using AGO2 immunoprecipitation (AGO2-IP) and microarray analyses in two breast cancer cell lines, MCF7 and MDA-MB-231, representing luminal and basal-like breast cancer, respectively. The expression levels of ∼70% of the AGO2-IP mRNAs were increased by DROSHA or DICER1 knockdown. In addition, integrated analysis of miRNA expression profiles, mRNA-AGO2 interaction, and the 3'-UTR of mRNAs revealed that >60% of the AGO2-IP mRNAs were putative targets of the 50 most abundantly expressed miRNAs. Together, these results suggested that the majority of the AGO2-associated mRNAs were bona fide miRNA targets. Functional enrichment analysis uncovered that the AGO2-IP mRNAs were involved in regulation of cell cycle, apoptosis, adhesion/migration/invasion, stress responses (e.g. DNA damage and endoplasmic reticulum stress and hypoxia), and cell-cell communication (e.g. Notch and Ephrin signaling pathways). A role of miRNAs in regulating cell migration/invasion and stress response was further defined by examining the impact of DROSHA knockdown on cell behaviors. We demonstrated that DROSHA knockdown enhanced cell migration and invasion, whereas it sensitized cells to cell death induced by suspension culture, glucose depletion, and unfolding protein stress. Data from an orthotopic xenograft model showed that DROSHA knockdown resulted in reduced growth of primary tumors but enhanced lung metastasis. Taken together, these results suggest that miRNAs collectively function to promote survival of tumor cells under stress but suppress cell migration/invasion in breast cancer cells.

Ortega M, Mallo M, Solé F, et al.
5q- syndrome and multiple myeloma diagnosed simultaneously and successful treated with lenalidomide.
Leuk Res. 2013; 37(10):1248-50 [PubMed] Related Publications
A 72-year-old woman was diagnosed with 5q- myelodysplastic syndrome in the course of an indolent multiple myeloma (MM). Bone marrow (BM) cytogenetics disclosed two unrelated clones: 46,XX,del(5)(q13q33), and [47,X,-X,der(1;21)(q10;q10),-4,-4,+5,del(5)(q13q31),+7,der(7)t(1;7)(p34.2;p22),add(8)(p23),-13,+15,der(16) t(1;16)(q23;q12.2),+19,-21,+mar1,+mar2]. The last complex karyotype belonged to malignant plasma cells. FISH and SKY techniques demonstrated different 5q deletions. EGR1 gene (on 5q31) lost in 5q- syndrome remained in 5q- plasma cells. Biclonal evolution was noted: myeloid 5q- cells added a deletion 13q and plasma cells showed monosomy 13. Patient achieved complete cytogenetic response of 5q- syndrome with low-dose of lenalidomide, and a partial remission of MM with high-dose of lenalidomide/dexamethasone combination.

Fernandez-Mercado M, Pellagatti A, Di Genua C, et al.
Mutations in SETBP1 are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression.
Br J Haematol. 2013; 163(2):235-9 [PubMed] Related Publications
Whole exome sequencing was performed in a patient with myelodysplastic syndrome before and after progression to acute myeloid leukaemia. Mutations in several genes, including SETBP1, were identified following leukaemic transformation. Screening of 328 patients with myeloid disorders revealed SETBP1 mutations in 14 patients (4·3%), 7 of whom had -7/del(7q) and 3 had i(17)(q10), cytogenetic markers associated with shortened overall survival and increased risk of leukaemic evolution. SETBP1 mutations were frequently acquired at the time of leukaemic evolution, coinciding with increase of leukaemic blasts. These data suggest that SETBP1 mutations may play a role in MDS and chronic myelomonocytic leukaemia disease progression.

Masliah-Planchon J, Pasmant E, Luscan A, et al.
MicroRNAome profiling in benign and malignant neurofibromatosis type 1-associated nerve sheath tumors: evidences of PTEN pathway alterations in early NF1 tumorigenesis.
BMC Genomics. 2013; 14:473 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
BACKGROUND: Neurofibromatosis type 1 (NF1) is a common dominant tumor predisposition syndrome affecting 1 in 3,500 individuals. The hallmarks of NF1 are the development of peripheral nerve sheath tumors either benign (dermal and plexiform neurofibromas) or malignant (MPNSTs).
RESULTS: To comprehensively characterize the role of microRNAs in NF1 tumorigenesis, we analyzed 377 miRNAs expression in a large panel of dermal and plexiform neurofibromas, and MPNSTs. The most significantly upregulated miRNA in plexiform neurofibromas was miR-486-3p that targets the major tumor suppressor gene, PTEN. We confirmed PTEN downregulation at mRNA level. In plexiform neurofibromas, we also report aberrant expression of four miRNAs involved in the RAS-MAPK pathway (miR-370, miR-143, miR-181a, and miR-145). In MPNSTs, significant deregulated miRNAs were involved in PTEN repression (miR-301a, miR-19a, and miR-106b), RAS-MAPK pathway regulation (Let-7b, miR-195, and miR-10b), mesenchymal transition (miR-200c, let-7b, miR-135a, miR-135b, and miR-9), HOX genes expression (miR-210, miR-196b, miR-10a, miR-10b, and miR-9), and cell cycle progression (miR-195, let-7b, miR-20a, miR-210, miR-129-3p, miR-449a, and miR-106b).
CONCLUSION: We confirmed the implication of PTEN in genesis of plexiform neurofibromas and MPNSTs in NF1. Markedly deregulated miRNAs might have potential diagnostic or prognostic value and could represent novel strategies for effective pharmacological therapies of NF1 tumors.

Kim B, Lee JH, Park JW, et al.
An essential microRNA maturing microprocessor complex component DGCR8 is up-regulated in colorectal carcinomas.
Clin Exp Med. 2014; 14(3):331-6 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
MicroRNAs (miRNAs) regulate gene expression through degradation and/or translational repression of target mRNAs. Dysregulations in the miRNA machinery may be involved in carcinogenesis of colorectal cancer (CRC). The purpose of the current study was to evaluate the DiGeorge syndrome critical region gene 8 (DGCR8) and argonaute 2 (AGO2) mRNA expression in CRC and to evaluate the value of clinical parameters on their expression. We investigated the mRNA expressions of DGCR8 and AGO2 in 60 CRC tissues and adjacent histologically non-neoplastic tissues by using quantitative real-time PCR. Our study revealed that the mRNA expression level of DGCR8 is up-regulated in CRC. However, AGO2 mRNA expression was not significantly altered in CRC tissues. Neither DGCR8 nor AGO2 mRNA expression level was not associated with any clinical parameters, including age, tumor stage, CEA titer, and BMI in CRC cases. However, the mRNA expression levels of DGCR8 and AGO2 were positively correlated to each other. This study demonstrated for the first time that the DGCR8 mRNA expression level was up-regulated in CRC, suggesting its important role in pathobiology of colorectal carcinogenesis.

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