DGCR8

Gene Summary

Gene:DGCR8; DGCR8 microprocessor complex subunit
Aliases: Gy1, pasha, DGCRK6, C22orf12
Location:22q11.2
Summary:This gene encodes a subunit of the microprocessor complex which mediates the biogenesis of microRNAs from the primary microRNA transcript. The encoded protein is a double-stranded RNA binding protein that functions as the non-catalytic subunit of the microprocessor complex. This protein is required for binding the double-stranded RNA substrate and facilitates cleavage of the RNA by the ribonuclease III protein, Drosha. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:microprocessor complex subunit DGCR8
HPRD
Source:NCBIAccessed: 21 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: DGCR8 (cancer-related)

González-Duarte RJ, Cázares-Ordoñez V, Ávila-Chávez E
The microRNA biogenesis machinery: regulation by steroid hormones and alterations in cancer.
Rev Invest Clin. 2014 Sep-Oct; 66(5):460-4 [PubMed] Related Publications
MicroRNAs are a class of non-coding RNAs that regulate gene expression at the post-transcriptional level. The major proteins of the canonical microRNA biogenesis pathway in human are: Drosha, DGCR8, DDX5, DDX17, Exportin 5, Dicer and Argonaute 2. Recent studies suggest that gene expression of some canonical microRNA biogenesis components could be regulated by steroid hormones. Furthermore, various alterations in microRNA biogenesis have been associated with diseases like cancer. Due to the importance of microRNAs in cell physiology, the study of the factors that regulate or affect their biogenesis is critical.

Wegert J, Ishaque N, Vardapour R, et al.
Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors.
Cancer Cell. 2015; 27(2):298-311 [PubMed] Related Publications
Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.

Walz AL, Ooms A, Gadd S, et al.
Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors.
Cancer Cell. 2015; 27(2):286-97 [PubMed] Related Publications
We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.

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.

Hagrass HA, Pasha HF, Ali AM
Estrogen receptor alpha (ERα) promoter methylation status in tumor and serum DNA in Egyptian breast cancer patients.
Gene. 2014; 552(1):81-6 [PubMed] Related Publications
BACKGROUND: Status of DNA methylation is one of the most common molecular alterations in human neoplasia. Because it is possible to detect these epigenetic alterations in the bloodstream of patients, we investigated the aberrant DNA methylation status of estrogen receptor alpha (ERα) in patient pretherapeutic sera and tissue.
MATERIALS AND METHODS: In this case control study the patient series consisted of 120 sporadic primary breast cancer cases and 100 patients with benign breast lesion. ER3, ER4, and ER5 primers were used for methylation-specific polymerase chain reaction (MSP) to analyze the CpG methylation of promoter region of ERα gene. Correlation between ER3, ER4, and ER5 methylation and clinicopathological characteristics of the patients was investigated.
RESULT: The methylation status of ER3, ER4 and ER5 was 65%, 26.7% and 61.7% in tissue respectively and 57.5%, 21.7% and 55.8% in serum respectively. The concordance between tumor and serum DNA methylation was 80%, 72% and 92% for ER3, ER4 and ER5 respectively.
CONCLUSIONS: This study demonstrated the potential utility of serum DNA methylation of ERα gene promoter as a non-invasive diagnostic and/or prognostic marker in patients with breast cancer.

Han C, Liu Y, Wan G, et al.
The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression.
Cell Rep. 2014; 8(5):1447-60 [PubMed] Article available free on PMC after 11/09/2015 Related Publications
Posttranscriptional maturation is a critical step in microRNA (miRNA) biogenesis that determines mature miRNA levels. In addition to core components (Drosha and DGCR8 [DiGeorge syndrome critical region gene 8]) in the microprocessor, regulatory RNA-binding proteins may confer the specificity for recruiting and processing of individual primary miRNAs (pri-miRNAs). Here, we identify DDX1 as a regulatory protein that promotes the expression of a subset of miRNAs, including five members in the microRNA-200 (miR-200) family and four miRNAs in an eight-miRNA signature of a mesenchymal ovarian cancer subtype. A majority of DDX1-dependent miRNAs are induced after DNA damage. This induction is facilitated by the ataxia telangiectasia mutated (ATM)-mediated phosphorylation of DDX1. Inhibiting DDX1 promotes ovarian tumor growth and metastasis in a syngeneic mouse model. Analysis of The Cancer Genome Atlas (TCGA) reveals that low DDX1 levels are associated with poor clinical outcome in patients with serous ovarian cancer. These findings suggest that DDX1 is a key modulator in miRNA maturation and ovarian tumor suppression.

Gutierrez-Camino A, Lopez-Lopez E, Martin-Guerrero I, et al.
Noncoding RNA-related polymorphisms in pediatric acute lymphoblastic leukemia susceptibility.
Pediatr Res. 2014; 75(6):767-73 [PubMed] Related Publications
BACKGROUND: Evidence for an inherited genetic risk for pediatric acute lymphoblastic leukemia has been provided in several studies. Most of them focused on coding regions. However, those regions represent only 1.5% of the entire genome. In acute lymphoblastic leukemia (ALL), it has been suggested that the expression of microRNAs (miRNAs) is dysregulated, which suggests that they may have a role in ALL risk. Changes in miRNA function may occur through single-nucleotide polymorphisms (SNPs). Therefore, the aim of this study was to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA-processing genes, contribute to a predisposition for childhood ALL.
METHODS: In this study, we analyzed 118 SNPs in pre-miRNAs and miRNA-processing genes in 213 B-cell ALL patients and 387 controls.
RESULTS: We found 11 SNPs significantly associated with ALL susceptibility. These included three SNPs present in miRNA genes (miR-612, miR-499, and miR-449b) and eight SNPs present in six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1, CNOT1, and CNOT6). Among the 118 SNPs analyzed, rs12803915 in mir-612 and rs3746444 in mir-499 exhibited a more significant association, with a P value <0.01.
CONCLUSION: The results of this study indicate that SNP rs12803915 located in pre-mir-612, and SNP rs3746444 located in pre-mir-499, may represent novel markers of B-cell ALL susceptibility.

Hussein AG, Pasha HF, El-Shahat HM, et al.
CYP1A1 gene polymorphisms and smoking status as modifier factors for lung cancer risk.
Gene. 2014; 541(1):26-30 [PubMed] Related Publications
OBJECTIVE: Lung cancer remains the most prevalent malignancy worldwide. Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes. Several metabolic enzymes are currently under investigation for their possible role in lung cancer susceptibility, including members of the cytochrome P450 (CYP) superfamily. The aim of this work was to identify the correlation between CYP1A1 m1 and m2 polymorphisms and lung cancer risk and figure its interactions with smoking as genetic modifiers in the etiology of lung cancer in the Egyptian population.
MATERIALS AND METHODS: One hundred and ten patients with lung cancer and one hundred and ten controls were enrolled in the study. CYP1A1 m1 and m2 polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism.
RESULTS: Subjects carrying TC and CC genotypes of CYP1A1 m1 and AG and GG genotypes of CYP1A1 m2 were significantly more likely to develop lung cancer especially squamous cell carcinoma. The proportion of lung cancer attributable to the interaction of smoking and CYP1A1 m1 and CYP1A1 m2 polymorphisms was 32% and 52% respectively.
CONCLUSION: Our results revealed that CYP1A1 m1 and m2 polymorphisms contribute to smoking related lung cancer risk in the Egyptian population.

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.

Puppin C, Durante C, Sponziello M, et al.
Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation.
Endocrine. 2014; 47(2):528-36 [PubMed] Related Publications
Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC. Among them, 33 and 13 harbored RET and RAS mutations, respectively. DICER, DGCR8, and XPO5 mRNA levels were significantly overexpressed in MTC harboring RET mutations, in particular, in the presence of RET634 mutation. When MTCs with RET and RAS mutations were compared, only DGCR8 displayed a significant difference, while MTCs with RAS mutations did not show significant differences with respect to non-mutated tumors. We then attempted to correlate expression of miRNA biogenesis genes with tumor aggressiveness. According to the TNM status, MTCs were divided in two groups and compared (N0 M0 vs. N1 and/or M1): for all four genes no significant difference was detected. Cell line experiments, in which expression of a RET mutation is silenced by siRNA, suggest the existence of a causal relationship between RET mutation and overexpression of DICER, DGCR8, and XPO5 genes. These findings demonstrate that RET- but not RAS-driven tumorigenic alterations include abnormalities in the expression of some important genes involved in miRNA biogenesis that could represent new potential markers for targeted therapies in the treatment of RET-mutated MTCs aimed to restore the normal miRNA expression profile.

Hagrass HA, Pasha HF, Shaheen MA, et al.
Methylation status and protein expression of RASSF1A in breast cancer patients.
Mol Biol Rep. 2014; 41(1):57-65 [PubMed] Related Publications
Recently genetics and epigenetics alterations have been found to be characteristic of malignancy and hence can be used as targets for detection of neoplasia. RAS association domain family protein 1A (RASSF1A) gene hypermethylation has been a subject of interest in recent researches on cancer breast patients. The aim of the present study was to evaluate whether RASSF1A methylation status and RASSF1A protein expression are associated with the major clinico-pathological parameters. One hundred and twenty breast cancer Egyptian patients and 100-control subjects diagnosed with benign lesions of the breast were enrolled in this study. We evaluated RASSF1A methylation status in tissue and serum samples using Methyl specific PCR together with RASSF1A protein expression in tissues by immunohistochemistry. Results were studied in relation to known prognostic clinicopathological features in breast cancer. Frequency of RASSF1A methylation in tissues and serum were 70 and 63.3 % respectively and RASSF1A protein expression showed frequency of 46.7 %. There was an association between RASSF1A methylation in tissues, serum and loss of protein expression in tissues with invasive carcinoma, advanced stage breast cancer, L.N. metastasis, ER/PR and HER2 negativity. RASSF1A methylation in serum showed high degree of concordance with methylation in tissues (Kappa = 0.851, P < 0.001). RASSF1A hypermethylation in tissues and serum and its protein expression may be a valid, reliable and sensitive tool for detection and follow up of breast cancer patients.

Haselmann V, Kurz A, Bertsch U, et al.
Nuclear death receptor TRAIL-R2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells.
Gastroenterology. 2014; 146(1):278-90 [PubMed] Related Publications
BACKGROUND & AIMS: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL-R1) (TNFRSF10A) and TRAIL-R2 (TNFRSF10B) on the plasma membrane bind ligands that activate apoptotic and other signaling pathways. Cancer cells also might have TRAIL-R2 in the cytoplasm or nucleus, although little is known about its activities in these locations. We investigated the functions of nuclear TRAIL-R2 in cancer cell lines.
METHODS: Proteins that interact with TRAIL-R2 initially were identified in pancreatic cancer cells by immunoprecipitation, mass spectrometry, and immunofluorescence analyses. Findings were validated in colon, renal, lung, and breast cancer cells. Functions of TRAIL-R2 were determined from small interfering RNA knockdown, real-time polymerase chain reaction, Drosha-activity, microRNA array, proliferation, differentiation, and immunoblot experiments. We assessed the effects of TRAIL-R2 overexpression or knockdown in human pancreatic ductal adenocarcinoma (PDAC) cells and their ability to form tumors in mice. We also analyzed levels of TRAIL-R2 in sections of PDACs and non-neoplastic peritumoral ducts from patients.
RESULTS: TRAIL-R2 was found to interact with the core microprocessor components Drosha and DGCR8 and the associated regulatory proteins p68, hnRNPA1, NF45, and NF90 in nuclei of PDAC and other tumor cells. Knockdown of TRAIL-R2 increased Drosha-mediated processing of the let-7 microRNA precursor primary let-7 (resulting in increased levels of mature let-7), reduced levels of the let-7 targets (LIN28B and HMGA2), and inhibited cell proliferation. PDAC tissues from patients had higher levels of nuclear TRAIL-R2 than non-neoplastic pancreatic tissue, which correlated with increased nuclear levels of HMGA2 and poor outcomes. Knockdown of TRAIL-R2 in PDAC cells slowed their growth as orthotopic tumors in mice. Reduced nuclear levels of TRAIL-R2 in cultured pancreatic epithelial cells promoted their differentiation.
CONCLUSIONS: Nuclear TRAIL-R2 inhibits maturation of the microRNA let-7 in pancreatic cancer cell lines and increases their proliferation. Pancreatic tumor samples have increased levels of nuclear TRAIL-R2, which correlate with poor outcome of patients. These findings indicate that in the nucleus, death receptors can function as tumor promoters and might be therapeutic targets.

Di Carlo V, Grossi E, Laneve P, et al.
TDP-43 regulates the microprocessor complex activity during in vitro neuronal differentiation.
Mol Neurobiol. 2013; 48(3):952-63 [PubMed] Related Publications
TDP-43 (TAR DNA-binding protein 43) is an RNA-binding protein implicated in RNA metabolism at several levels. Even if ubiquitously expressed, it is considered as a neuronal activity-responsive factor and a major signature for neurological pathologies, making the comprehension of its activity in the nervous system a very challenging issue. TDP-43 has also been described as an accessory component of the Drosha-DGCR8 (DiGeorge syndrome critical region gene 8) microprocessor complex, which is crucially involved in basal and tissue-specific RNA processing events. In the present study, we exploited in vitro neuronal differentiation systems to investigate the TDP-43 demand for the microprocessor function, focusing on both its canonical microRNA biosynthetic activity and its alternative role as a post-transcriptional regulator of gene expression. Our findings reveal a novel role for TDP-43 as an essential factor that controls the stability of Drosha protein during neuronal differentiation, thus globally affecting the production of microRNAs. We also demonstrate that TDP-43 is required for the Drosha-mediated regulation of Neurogenin 2, a master gene orchestrating neurogenesis, whereas post-transcriptional control of Dgcr8, another Drosha target, resulted to be TDP-43-independent. These results implicate a previously uncovered contribution of TDP-43 in regulating the abundance and the substrate specificity of the microprocessor complex and provide new insights into TDP-43 as a key player in neuronal differentiation.

Sakai NS, Samia-Aly E, Barbera M, Fitzgerald RC
A review of the current understanding and clinical utility of miRNAs in esophageal cancer.
Semin Cancer Biol. 2013; 23(6 Pt B):512-21 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) are a class of small, well-conserved, non-coding RNAs that regulate the translation of RNAs. They have a role in biological and pathological process including cell differentiation, apoptosis, proliferation and metabolism. Since their discovery, they have been shown to have a potential role in cancer pathogenesis through their function as oncogenes or tumor suppressors. A substantial number of miRNAs show differential expression in esophageal cancer tissues, and so have been investigated for possible use in diagnosis. Furthermore, there is increasing interest in their use as prognostic markers and determining treatment response, as well as identifying their downstream targets and understanding their mode of action.
METHODS: We analyzed the most recent studies on miRNAs in esophageal cancer and/or Barrett's esophagus (BE). The publications were identified by searching in PuBMed for the following terms: Barrett's esophagus and microRNA; esophageal cancer and microRNA.
RESULTS: Four miRNAs (mi-R-25, -99a, -133a and -133b) showed good potential as diagnostic markers and interestingly five (mi-R-21, -27b, -126, - 143 and -145) appeared to be useful both as diagnostic and prognostic/predictive markers.
CONCLUSION: The data so far on miRNAs in esophageal carcinogenesis is promising but further work is required to determine whether miRNAs can be used as biomarkers, not only in the clinical setting or added to individualized treatment regimes but also in non-invasive test by making use of miRNAs identified in blood.

Han SJ, Marshall V, Barsov E, et al.
Kaposi's sarcoma-associated herpesvirus microRNA single-nucleotide polymorphisms identified in clinical samples can affect microRNA processing, level of expression, and silencing activity.
J Virol. 2013; 87(22):12237-48 [PubMed] Article available free on PMC after 11/09/2015 Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs that can produce 25 KSHV mature microRNAs. We previously reported single-nucleotide polymorphisms (SNPs) in KSHV-encoded pre-microRNA and mature microRNA sequences from clinical samples (V. Marshall et al., J. Infect. Dis., 195:645-659, 2007). To determine whether microRNA SNPs affect pre-microRNA processing and, ultimately, mature microRNA expression levels, we performed a detailed comparative analysis of (i) mature microRNA expression levels, (ii) in vitro Drosha/Dicer processing, and (iii) RNA-induced silencing complex-dependent targeting of wild-type (wt) and variant microRNA genes. Expression of pairs of wt and variant pre-microRNAs from retroviral vectors and measurement of KSHV mature microRNA expression by real-time reverse transcription-PCR (RT-PCR) revealed differential expression levels that correlated with the presence of specific sequence polymorphisms. Measurement of KSHV mature microRNA expression in a panel of primary effusion lymphoma cell lines by real-time RT-PCR recapitulated some observed expression differences but suggested a more complex relationship between sequence differences and expression of mature microRNA. Furthermore, in vitro maturation assays demonstrated significant SNP-associated changes in Drosha/DGCR8 and/or Dicer processing. These data demonstrate that SNPs within KSHV-encoded pre-microRNAs are associated with differential microRNA expression levels. Given the multiple reports on the involvement of microRNAs in cancer, the biological significance of these phenotypic and genotypic variants merits further studies in patients with KSHV-associated malignancies.

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 11/09/2015 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 11/09/2015 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.

Nemlich Y, Greenberg E, Ortenberg R, et al.
MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth.
J Clin Invest. 2013; 123(6):2703-18 [PubMed] Article available free on PMC after 11/09/2015 Related Publications
Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding–dependent, yet RNA editing–independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.

Caramuta S, Lee L, Ozata DM, et al.
Clinical and functional impact of TARBP2 over-expression in adrenocortical carcinoma.
Endocr Relat Cancer. 2013; 20(4):551-64 [PubMed] Article available free on PMC after 11/09/2015 Related Publications
Deregulation of microRNA (miRNA) expression in adrenocortical carcinomas (ACCs) has been documented to have diagnostic, prognostic, as well as functional implications. Here, we evaluated the mRNA expression of DROSHA, DGCR8, DICER (DICER1), TARBP2, and PRKRA, the core components in the miRNA biogenesis pathway, in a cohort of 73 adrenocortical tumors (including 43 adenomas and 30 carcinomas) and nine normal adrenal cortices using a RT-qPCR approach. Our results show a significant over-expression of TARBP2, DICER, and DROSHA in the carcinomas compared with adenomas or adrenal cortices (P<0.001 for all comparisons). Using western blot and immunohistochemistry analyses, we confirmed the higher expression of TARBP2, DICER, and DROSHA at the protein level in carcinoma cases. Furthermore, we demonstrate that mRNA expression of TARBP2, but not DICER or DROSHA, is a strong molecular predictor to discriminate between adenomas and carcinomas. Functionally, we showed that inhibition of TARBP2 expression in human NCI-H295R ACC cells resulted in a decreased cell proliferation and induction of apoptosis. TARBP2 over-expression was not related to gene mutations; however, copy number gain of the TARBP2 gene was observed in 57% of the carcinomas analyzed. In addition, we identified that miR-195 and miR-497 could directly regulate TARBP2 and DICER expression in ACC cells. This is the first study to demonstrate the deregulation of miRNA-processing factors in adrenocortical tumors and to show the clinical and biological impact of TARBP2 over-expression in this tumor type.

Jiang Y, Chen J, Wu J, et al.
Evaluation of genetic variants in microRNA biosynthesis genes and risk of breast cancer in Chinese women.
Int J Cancer. 2013; 133(9):2216-24 [PubMed] Related Publications
MicroRNAs (miRNA) are a class of small, noncoding RNA molecules involved in a diversity of cellular functions. Single nucleotide polymorphisms (SNPs) in miRNA biosynthesis genes may affect the biogenesis of miRNAs and consequently affect the miRNAs regulation. In this study, we systematically selected 24 functional SNPs located in eight key biosynthesis genes of miRNA (DROSHA, DGCR8, RAN, DICER, AGO2, GEMIN3, GEMIN4 and HIWI) and investigated the association between these SNPs and the risk of breast cancer in a Chinese population. All 24 SNPs were firstly genotyped in stage 1 (878 cases and 900 controls) and three promising SNPs (DROSHA rs2291109, RAN rs7301722 and DGCR8 rs417309) were selected for further validation in stage 2 (914 cases and 967 controls). We found that only one SNP (rs417309) located in the 3'-UTR of DGCR8 was consistently associated with an increased breast cancer risk in two stages with a combined odds ratio (OR) of 1.50 [95% confidence interval (CI) = 1.16-1.93]. Based on the bioinformatics prediction, rs417309 is located at the binding sites of miR-106b and miR-579 in the 3'-UTR of DGCR8. To evaluate whether rs417309 variant affects the binding capacity of miRNAs, we cotransfected luciferase reporter plasmids of DGCR8 3'-UTR and miR-106b/miR-579 in three cell lines. Luciferase activity assay showed a higher expression level with rs417309 A allele compared with G allele in MCF-7 cell lines (p = 3.31 × 10(-7) , 9.29 × 10(-7) for miR-106b and miR-579, respectively). Our findings suggested that DGCR8 rs417309 G > A might affect breast cancer risk through the interruption of miRNA binding.

Márquez J, Kohli M, Arteta B, et al.
Identification of hepatic microvascular adhesion-related genes of human colon cancer cells using random homozygous gene perturbation.
Int J Cancer. 2013; 133(9):2113-22 [PubMed] Related Publications
Random homozygous gene perturbation (RHGP), in combination with liver sinusoidal endothelial cell (LSEC) adhesion screening of clonal colon cancer cells with perturbed genes, was used to identify genes contributing to the hepatic microvascular adhesion of colon cancer cells. Plasmid vector encoding transactivator and gene search vector were transfected into HT-29 human colorectal cancer cells to create a HT-29 RHGP cell library; the adhesion of these library cells to primary cultured mouse LSEC significantly decreased in the presence of RSL1 ligand (inducer), indicating that most of the genes contributing to HT-29 adhesion to LSEC were altered. Next, HT-29 RHGP cell library fractions with upregulated or silenced LSEC adhesion-related genes were isolated. Around 160 clones having altered expression in LSEC adhesion-related genes were obtained, and nine relevant protein-coding genes were identified. Some were proadhesive genes detected because of their overexpression in adherent HT-29 cells (DGCR8 and EFEMP1 genes) and their silenced status in nonadherent HT-29 cells (DGKE, DPY19L1, KIAA0753, PVR and USP11 genes). Others were antiadhesive genes detected because of their overexpression in nonadherent HT-29 cells (ITPKC gene) and their silenced status in adherent HT-29 cells (PPP6R2 gene). Silencing of PVR, DGCR8 and EFEMP1 genes decreased adhesion to LSEC and hepatic microvascular retention of HT-29 cells. The results conclude that RHGP was a valuable strategy for the discovery of mechanisms regulating microvascular adhesion of circulating colon cancer cells before hepatic metastasis formation. Identified genes may contribute to understand the metastatic process of colon cancer and to discovering molecular targets for hepatic metastasis therapeutics.

Kitagawa N, Ojima H, Shirakihara T, et al.
Downregulation of the microRNA biogenesis components and its association with poor prognosis in hepatocellular carcinoma.
Cancer Sci. 2013; 104(5):543-51 [PubMed] Related Publications
Genetic alterations and deregulation of the miRNA biogenesis pathway components have been reported in human tumors. Tissue-specific deletion of the Dicer gene, which encodes an essential miRNA processing enzyme, promotes carcinogenesis in animal models. These features indicate that aberrant miRNA biogenesis components are directly associated with cancer. For the present study, we conducted quantitative RT-PCR of 14 genes that are related to the miRNA biogenesis pathway in 47 paired samples of primary hepatocellular carcinoma (HCC) and matched non-cancerous liver. Expression of seven genes (Dgcr8, p68, p72, Dicer, Ago3, Ago4 and Piwil4) was significantly decreased in primary HCC, especially in non-viral HCC subtypes, compared to the non-cancerous liver. Combinations of decreased expression of the miRNA biogenesis components in non-cancerous liver were related to cigarette smoking, alcohol intake and diabetes, which are known to be risk factors for HCC, and were also associated with the occurrence of multicentric tumors. Reduction of two of these genes (Dicer and p68) in HCC was associated with poor prognosis. Trimethylation of histone H3 lysine 27 in the promoters is implicated in the deregulation of these miRNA-biogenesis-related genes in non-HBV genome integrated HCC cell lines. In conclusion, deregulation of the miRNA biogenesis pathway components is frequently observed in non-viral-associated HCC and is linked to etiological risk factors and poor prognosis. Our study further showed that epigenetic regulation could be implicated in the deregulation of these genes during hepatocarcinogenesis.

Ke HL, Chen M, Ye Y, et al.
Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer.
Carcinogenesis. 2013; 34(5):1006-11 [PubMed] Article available free on PMC after 11/09/2015 Related Publications
Micro-RNAs (miRNAs) are small non-coding RNA molecules, which can act as either oncogenes or tumor suppressors. Dysregulated expression of miRNA genes have been implicated in the development of many different cancers. We hypothesize that genetic variations in miRNA biogenesis genes may be associated with the prognosis of bladder cancer. We genotyped 76 single nucleotide polymorphisms (SNPs) in eight miRNA biogenesis genes in 421 patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed the associations of SNPs with recurrence and progression in all patients as well as stratified by treatment: transurethral resection (TUR) alone or TUR plus intravesical bacillus Calmette-Guérin (BCG) instillation. Two SNPs were significantly associated with tumor recurrence in TUR only subgroup after adjustment for multiple comparisons (Q < 0.1). The most significant SNP was rs197412 in DDX20: the variant allele conferred a decreased risk of recurrence [hazard ratio (HR) = 0.58, 95% confidence interval (95% CI) = 0.40-0.82]. This SNP was validated in a separate group of 586 NMIBC patients and the pooled HR was 0.62 (95% CI = 0.48-0.81, P < 0.001). Two linked SNPs (rs2073778 and rs720012) in DGCR8 showed significant association with tumor progression (HR = 4.00, 95% CI = 1.53-10.46, P = 0.005). A strong gene-dosage effect was observed with higher risk for tumor recurrence and progression with increasing number of unfavorable genotypes. Haplotype and survival tree analyses further characterized the association of miRNA-related SNPs with tumor recurrence and progression. Taken together, our results indicate that genetic variants in miRNA biogenesis pathway may influence bladder cancer clinical outcome in NMIBC patients.

Elton TS, Selemon H, Elton SM, Parinandi NL
Regulation of the MIR155 host gene in physiological and pathological processes.
Gene. 2013; 532(1):1-12 [PubMed] Related Publications
MicroRNAs (miRNAs), a family of small nonprotein-coding RNAs, play a critical role in posttranscriptional gene regulation by acting as adaptors for the miRNA-induced silencing complex to inhibit gene expression by targeting mRNAs for translational repression and/or cleavage. miR-155-5p and miR-155-3p are processed from the B-cell Integration Cluster (BIC) gene (now designated, MIR155 host gene or MIR155HG). MiR-155-5p is highly expressed in both activated B- and T-cells and in monocytes/macrophages. MiR-155-5p is one of the best characterized miRNAs and recent data indicate that miR-155-5p plays a critical role in various physiological and pathological processes such as hematopoietic lineage differentiation, immunity, inflammation, viral infections, cancer, cardiovascular disease, and Down syndrome. In this review we summarize the mechanisms by which MIR155HG expression can be regulated. Given that the pathologies mediated by miR-155-5p result from the over-expression of this miRNA it may be possible to therapeutically attenuate miR-155-5p levels in the treatment of several pathological processes.

Shaikhibrahim Z, Lindstrot A, Ochsenfahrt J, et al.
Epigenetics-related genes in prostate cancer: expression profile in prostate cancer tissues, androgen-sensitive and -insensitive cell lines.
Int J Mol Med. 2013; 31(1):21-5 [PubMed] Article available free on PMC after 11/09/2015 Related Publications
Epigenetic changes have been suggested to drive prostate cancer (PCa) development and progression. Therefore, in this study, we aimed to identify novel epigenetics-related genes in PCa tissues, and to examine their expression in metastatic PCa cell lines. We analyzed the expression of epigenetics-related genes via a clustering analysis based on gene function in moderately and poorly differentiated PCa glands compared to normal glands of the peripheral zone (prostate proper) from PCa patients using Whole Human Genome Oligo Microarrays. Our analysis identified 12 epigenetics-related genes with a more than 2-fold increase or decrease in expression and a p-value <0.01. In modera-tely differentiated tumors compared to normal glands of the peripheral zone, we found the genes, TDRD1, IGF2, DICER1, ADARB1, HILS1, GLMN and TRIM27, to be upregulated, whereas TNRC6A and DGCR8 were found to be downregulated. In poorly differentiated tumors, we found TDRD1, ADARB and RBM3 to be upregulated, whereas DGCR8, PIWIL2 and BC069781 were downregulated. Our analysis of the expression level for each gene in the metastatic androgen-sensitive VCaP and LNCaP, and -insensitive PC3 and DU-145 PCa cell lines revealed differences in expression among the cell lines which may reflect the different biological properties of each cell line, and the potential role of each gene at different metastatic sites. The novel epigenetics-related genes that we identified in primary PCa tissues may provide further insight into the role that epigenetic changes play in PCa. Moreover, some of the genes that we identified may play important roles in primary PCa and metastasis, in primary PCa only, or in metastasis only. Follow-up studies are required to investigate the functional role and the role that the expression of these genes play in the outcome and progression of PCa using tissue microarrays.

Pushpavalli SN, Ramaiah MJ, Lavanya A, et al.
Imidazo-benzothiazoles a potent microRNA modulator involved in cell proliferation.
Bioorg Med Chem Lett. 2012; 22(20):6418-24 [PubMed] Related Publications
MicroRNAs are endogenously expressed tiny non-coding RNAs that control gene expression at the post-transcriptional level and regulate processes of cell growth, differentiation, proliferation and apoptosis. Aberrant expression of microRNAs correlates with various cancers. Our experiments demonstrated that imidazo-benzothiazole conjugates caused apoptosis in colon cancer cells by modulating the expression of microRNAs. In vivo study in Drosophila melanogaster has exhibited inhibitory action on bantam microRNA, the homolog of human miR-542-5p that is involved in deciding the cellular cues that regulate the balance between proliferation and apoptosis. The expression of direct targets of bantam such as Hid and HDAC-6 were affected upon compound treatment. Interestingly, these conjugates downregulate the genes involved in microRNA biogenesis such as Drosha, Pasha and Dicer-1. Our findings have elucidated the microRNA inhibitory role of imidazo-benzothiazole conjugates.

Sohn EJ, Park J, Kang SI, Wu YP
Accumulation of pre-let-7g and downregulation of mature let-7g with the depletion of EWS.
Biochem Biophys Res Commun. 2012; 426(1):89-93 [PubMed] Related Publications
EWS functions in RNA splicing and transcription by encoding an RNA binding protein, which results in the chromosomal translocation t(11;22)(q24;q12) found in Ewing sarcoma. EWS interacts with the microprocessor complex involving Drosha and DGCR8, which play roles as the cofactors of primary microRNA processing. However, the role of EWS in microRNA biogenesis has not been investigated. Here, we show that endogenous EWS interacts with endogenous Drosha by IP-western blotting. In addition, EWS knockout mouse decreased the expression of Drosha. The depletion of EWS results in the accumulation of precursor let-7g but down-regulates mature let-7g in U2OS cells. Consistently, mature let 7g was suppressed in both Ewing sarcoma cell and primary Ewing sarcoma. Also, expression levels of Dicer and CCND1 (Cyclin D1), which are known target genes of the let-7 family were upregulated. Our findings suggest that EWS mediates generation of mature let-7g from pre-let-7g.

Sand M, Skrygan M, Georgas D, et al.
The miRNA machinery in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases and benign melanocytic nevi.
Cell Tissue Res. 2012; 350(1):119-26 [PubMed] Related Publications
Although several studies have shown a dysregulation of microRNA (miRNA) expression profiles in cutaneous melanoma, there has been little research on the miRNA machinery itself. In this study, we investigated the mRNA expression profiles of different miRNA machinery components in primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM) and benign melanocytic nevi (BMN). Patients with PCMM (n = 7), CMMM (n = 6) and BMN (n = 7) were included in the study. Punch biopsies were harvested from the centers of tumors (lesional) and from BMN (control). In contrast to previous reports exploring specific clusters of miRNAs in PCMM, the present study investigates mRNA expression levels of Dicer, Drosha, Exp5, DGCR8 and the RISC components PACT, argonaute-1, argonaute-2, TARBP1, TARBP2, MTDH and SND1, which were detected by TaqMan real-time reverse transcription polymerase chain reaction (RT-PCR). Argonaute-1, TARBP2 and SND1 expression levels were significantly higher in BMN compared to PCMM (p < 0.05). TARBP2 expression levels were significantly higher in CMMM compared to PCMM (p < 0.05). SND1 expression levels were significantly higher in CMMM compared to PCMM and BMN (p < 0.05). Dicer, Drosha, DGCR8, Exp5, argonaute-2, PACT, TARBP1 and MTDH expression levels showed no significant differences within groups (p > 0.05). The results of this study show that the miRNA machinery components argonaute-1, TARBP2 and SND1 are dysregulated in PCMM and CMMM compared to BMN and may play a role in the process of malignant transformation.

Radwan MI, Pasha HF, Mohamed RH, et al.
Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients.
Cytokine. 2012; 60(1):271-6 [PubMed] Related Publications
BACKGROUND: Host genetic factors may affect clinical outcomes of hepatitis C virus (HCV) infection; however, the possible mechanisms remain largely unknown. This study aimed to evaluate transforming growth factor-β1 (TGF-β1)-509 and tumor necrosis factor-α (TNF-α)-308 genes polymorphisms as a risk factors for cirrhosis and hepatocellular carcinoma (HCC) in chronic hepatitis C patients.
MATERIALS AND METHODS: Two hundred and eighty HCV patients (152 patients with cirrhosis, 128 patients with HCC) and 160 controls were enrolled in the study. Polymorphisms of TGF-β1-509 and TNF-α-308 gene were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum TGF-β1 and TNF-α were determined using ELISA.
RESULTS: TGF-β1-509 TT, TNF-α-308 AA and GA genotypes frequencies were significantly increased in cirrhotic and HCC groups. Serum TGF-β1 and TNF-α level were significantly increased in TGF-β1-509 TT and TNF-α-308 AA genotypes respectively.
CONCLUSION: TGF-β1-509 and TNF-α-308 genes polymorphisms are associated with risk of liver cirrhosis and HCC in patients with chronic HCV infection.

Sung H, Jeon S, Lee KM, et al.
Common genetic polymorphisms of microRNA biogenesis pathway genes and breast cancer survival.
BMC Cancer. 2012; 12:195 [PubMed] Article available free on PMC after 11/09/2015 Related Publications
BACKGROUND: Although the role of microRNA's (miRNA's) biogenesis pathway genes in cancer development and progression has been well established, the association between genetic variants of this pathway genes and breast cancer survival is still unknown.
METHODS: We used genotype data available from a previously conducted case-control study to investigate association between common genetic variations in miRNA biogenesis pathway genes and breast cancer survival. We investigated the possible associations between 41 germ-line single-nucleotide polymorphisms (SNPs) and both disease free survival (DFS) and overall survival (OS) among 488 breast cancer patients. During the median follow-up of 6.24 years, 90 cases developed disease progression and 48 cases died.
RESULTS: Seven SNPs were significantly associated with breast cancer survival. Two SNPs in AGO2 (rs11786030 and rs2292779) and DICER1 rs1057035 were associated with both DFS and OS. Two SNPs in HIWI (rs4759659 and rs11060845) and DGCR8 rs9606250 were associated with DFS, while DROSHA rs874332 and GEMIN4 rs4968104 were associated with only OS. The most significant association was observed in variant allele of AGO2 rs11786030 with 2.62-fold increased risk of disease progression (95% confidence interval (CI), 1.41-4.88) and in minor allele homozygote of AGO2 rs2292779 with 2.94-fold increased risk of death (95% CI, 1.52-5.69). We also found cumulative effects of SNPs on DFS and OS. Compared to the subjects carrying 0 to 2 high-risk genotypes, those carrying 3 or 4-6 high-risk genotypes had an increased risk of disease progression with a hazard ratio of 2.16 (95% CI, 1.18- 3.93) and 4.47 (95% CI, 2.45- 8.14), respectively (P for trend, 6.11E-07).
CONCLUSIONS: Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer survival. Further studies in larger sample size and functional characterizations are warranted to validate these results.

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