Gene Summary

Gene:DGCR8; DGCR8 microprocessor complex subunit
Aliases: Gy1, pasha, DGCRK6, C22orf12
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, HGNC, Ensembl, GeneCard, Gene
Protein:microprocessor complex subunit DGCR8
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: DGCR8 (cancer-related)

Zhang J, Bai R, Li M, et al.
Excessive miR-25-3p maturation via N
Nat Commun. 2019; 10(1):1858 [PubMed] Free Access to Full Article Related Publications

Pasha M, Sivaraman SK, Frantz R, et al.
Metformin Induces Different Responses in Clear Cell Renal Cell Carcinoma Caki Cell Lines.
Biomolecules. 2019; 9(3) [PubMed] Free Access to Full Article Related Publications
Clear cell renal cell carcinoma (ccRCC) is the most common and lethal form of urological cancer diagnosed globally. Mutations of the von Hippel-Lindau

Pradhan AK, Bhoopathi P, Talukdar S, et al.
MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF.
Proc Natl Acad Sci U S A. 2019; 116(12):5687-5692 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Melanoma differentiation-associated gene-7/interleukin-24 (

Pasha HF, Mohamed RH, Radwan MI
RASSF1A and SOCS1 genes methylation status as a noninvasive marker for hepatocellular carcinoma.
Cancer Biomark. 2019; 24(2):241-247 [PubMed] Related Publications
BACKGROUND: DNA methylation status is one of the most prevalent molecular alterations in human cancers. Identification of powerful diagnostic and prognostic biomarkers for hepatocellular carcinoma (HCC) without a biopsy is urgently required.
OBJECTIVE: The purpose of this study was to determine the methylation status of RASSF1A and SOCS-1genes as a non-invasive biomarker for HCC identification and prognosis.
METHODS: Methylation specific-PCR technique was performed to recognize the methylation status of RASSF1A and SOCS-1 genes in 100 patients with HCC, 100 patients with liver cirrhosis (LC) but without HCC were considered as cirrhotic liver control group and 100 healthy control.
RESULTS: Methylation of RASSF1A and SOCS-1 genes were detected in 40% and 38% of HCC patients respectively, 14% and 20% of LC patients respectively. Methylation of SOCS-1 gene in peripheral blood of healthy control was 23%. Methylation of RASSF1A gene was associated with age, tumor size, vascular invasion and α fetoprotein (AFP), while SOCS-1 gene methylation was significantly associated with tumor size and AFP. Furthermore, using RASSF1A/ SOCS-1/ AFP panel improve diagnostic sensitivity for HCC 86% and specificity of 75%.
CONCLUSION: RASSF1A and SOCS1 genes methylation status may play an important role in the process of hepatocarcinogenesis and may be used as diagnostic and prognostic noninvasive biomarkers for HCC when combined with serum AFP.

Riddell M, Nakayama A, Hikita T, et al.
aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability.
Nat Commun. 2018; 9(1):5357 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

Kruber P, Angay O, Winkler A, et al.
Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation.
Int J Cancer. 2019; 144(6):1391-1400 [PubMed] Related Publications
Wilms tumor (WT) is the most common kidney cancer in childhood. Mutations in the microprocessor genes DROSHA and DGCR8 have been identified as putative oncogenic drivers, indicating a critical role of aberrant miRNA processing in WT formation. To characterize the in vivo role of DROSHA mutations during kidney development and their oncogenic potential, we analyzed mouse lines with either a targeted deletion of Drosha or an inducible expression of human DROSHA carrying a tumor-specific E1147K mutation that acts in a dominant negative manner. Both types of mutation induce striking changes in miRNA patterns. Six2-cre mediated deletion of Drosha in nephron progenitors led to perinatal lethality with apoptotic loss of progenitor cells and early termination of nephrogenesis. Mosaic deletions via Wt1-cre

You L, Wang H, Yang G, et al.
Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207.
Mol Oncol. 2018; 12(12):2147-2164 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Gemcitabine serves as a first-line chemotherapy agent for advanced pancreatic cancer (PC). However, the molecular basis by which gemcitabine exerts its effects is not well-established, and the targeted genetic pathways remain unclear. Pvt1 oncogene (non-protein coding) (PVT1) has been reported to be an oncogenic long non-coding RNA in tumorigenesis. In the present study, we show that the expression of PVT1 is correlated with gemcitabine efficacy in PC therapy. Inhibition of PVT1 led to decreased cell growth in PC cells treated with gemcitabine. We also demonstrate that gemcitabine treatment decreases PVT1 levels and increases its encoded miRNAs, such as the miR-1207 pair (miR-1207-5p/3p). Overexpression of the miR-1207 pair enhanced the chemosensitivity of cells to gemcitabine, whereas silencing of miR-1207-5p/3p to prevent its induction by gemcitabine treatment led to increased cell growth. Mechanistic studies revealed that miR-1207-5p and miR-1207-3p target the SRC proto-oncogene (non-receptor tyrosine kinase) and ras homolog family member A in PC cells, respectively. In particular, we observed that gemcitabine induced Drosha ribonuclease III (Drosha) and DGCR8 microprocessor complex subunit (DGCR8) upregulation and then triggered PVT1 processing. Suppression of Drosha and DGCR8 contributed to a dampened efficacy of gemcitabine, indicating that gemcitabine decreased PVT1 expression by promoting its processing into miRNAs, which in turn resulted in blunted oncogenic signaling in PC cells. Moreover, we demonstrate that gemcitabine chemoresistance was a result of decreased expression of Drosha and DGCR8 in AsPC-1 cells and tumor cell-engrafted models. Overall, our findings define a novel mechanism for understanding the efficacy of gemcitabine chemotherapy in PC.

Wen J, Lv Z, Ding H, et al.
Association of miRNA biosynthesis genes
Biosci Rep. 2018; 38(3) [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Single nucleotide polymorphisms (SNPs) in miRNA biosynthesis genes

Kian R, Moradi S, Ghorbian S
Role of components of microRNA machinery in carcinogenesis.
Exp Oncol. 2018; 40(1):2-9 [PubMed] Related Publications
MicroRNAs (miRNAs) are a broad class of non-coding RNAs nearly 21 nucleotides length, which play crucial functions in post-transcriptional gene regulation. These molecules are associated with many developmental and cellular processes in eukaryotic organisms. Current investigation has reported major factors contributing to miRNA biogenesis and has constituted basic principles of miRNA function. More recently, it was confirmed that various miRNAs are clearly implicated in human malignancies, such as lung, breast, ovarian, bladder, colon cancer and other kinds of carcinoma. In addition, dysregulation in the miRNA machinery elements such as Dicer, Drosha, DGCR8, Argonaut, and TRBP could be involved in the progress of many tumor types. The purpose of the current review was to compile growing information besides how miRNA biogenesis and gene silencing are modified to develop cancer.

Wang D, Sun X, Wei Y, et al.
Nuclear miR-122 directly regulates the biogenesis of cell survival oncomiR miR-21 at the posttranscriptional level.
Nucleic Acids Res. 2018; 46(4):2012-2029 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Hepatic miR-122 can serve as a pro-apoptotic factor to suppress tumorigenesis. The underlying mechanism, however, remains incompletely understood. Here we present the first evidence that miR-122 promotes hepatocellular carcinoma cell apoptosis through directly silencing the biogenesis of cell survival oncomiR miR-21 at posttranscriptional level. We find that miR-122 is strongly expressed in primary liver cell nucleus but its nuclear localization is markedly decreased in transformed cells particularly in chemoresistant tumor cells. MiRNA profiling and RT-qPCR confirm an inverse correlation between miR-122 and miR-21 in hepatocellular carcinoma tissues/cells, and increasing or decreasing nuclear level of miR-122 respectively reduces or increases miR-21 expression. Mechanistically, nuclear miR-122 suppresses miR-21 maturation via binding to a 19-nt UG-containing recognition element in the basal region of pri-miR-21 and preventing the Drosha-DGCR8 microprocessor's conversion of pri-miR-21 into pre-miR-21. Furthermore, both in vitro and in vivo studies demonstrate that nuclear miR-122 participates in the regulation of HCC cell apoptosis through modulating the miR-21-targeted programmed cell death 4 (PDCD4) signal pathway.

Yuan H, Deng R, Zhao X, et al.
SUMO1 modification of KHSRP regulates tumorigenesis by preventing the TL-G-Rich miRNA biogenesis.
Mol Cancer. 2017; 16(1):157 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: MicroRNAs (miRNAs) are important regulators involved in diverse physiological and pathological processes including cancer. SUMO (small ubiquitin-like modifier) is a reversible protein modifier. We recently found that SUMOylation of TARBP2 and DGCR8 is involved in the regulation of the miRNA pathway. KHSRP is a single stranded nucleic acid binding protein with roles in transcription and mRNA decay, and it is also a component of the Drosha-DGCR8 complex promoting the miRNA biogenesis.
METHODS: The in vivo SUMOylation assay using the Ni
RESULTS: KHSRP is modified by SUMO1 at the major site K87, and this modification can be increased upon the microenvironmental hypoxia while reduced by the treatment with growth factors. SUMO1 modification of KHSRP inhibits its interaction with the pri-miRNA/Drosha-DGCR8 complex and probably increases its translocation from the nucleus to the cytoplasm. Consequently, SUMO1 modification of KHSRP impairs the processing step of pre-miRNAs from pri-miRNAs which especially harbor short G-rich stretches in their terminal loops (TL), resulting in the downregulation of a subset of TL-G-Rich miRNAs such as let-7 family and consequential tumorigenesis.
CONCLUSIONS: Our data demonstrate how the miRNA biogenesis pathway is connected to tumorigenesis and cancer progression through the reversible SUMO1 modification of KHSRP.

Gadd S, Huff V, Walz AL, et al.
A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.
Nat Genet. 2017; 49(10):1487-1494 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

Poursadegh Zonouzi AA, Shekari M, Nejatizadeh A, et al.
Impaired expression of Drosha in breast cancer.
Breast Dis. 2017; 37(2):55-62 [PubMed] Related Publications
BACKGROUND: Impaired miRNAs processing pathway is one interesting scenario for global downregulation of the miRNAome in various types of malignancy. We previously reported that DGCR8 and Dicer genes dysregulated in patients with breast cancer.
OBJECTIVE: To evaluate the expression pattern of Drosha in patients with breast cancer.
METHODS: We evaluated the mRNA expression level of Drosha in 70 fresh breast carcinomas and adjacent non-neoplastic tissue using quantitative real-time PCR and assessed the possible correlation between its expression and clinicopathological parameters.
RESULTS: Our results revealed that mRNA expression level of Drosha was decreased in tumors when compared to adjacent non-neoplastic tissue. However, this difference is not statistically significant (P > 0.05). Downregulation of Drosha is related to older age at diagnosis, higher histological grade, higher tumor size and metastasis. However, there was no significant correlation between Drosha expression level and clinicopathological parameters (P > 0.05). We found that Drosha expression negatively correlated with DGCR8 (P = 0.043), whereas dysregulated expression levels of Drosha and Dicer are positively correlated with to each other (P < 0.0001).
CONCLUSION: This study provides evidence that the expression of Drosha is impaired in breast cancer. However, the molecular basis of observed expression pattern have remained inexplicable and should be further investigated.

Wang Y, Chen F, Yang Z, et al.
The Fragment HMGA2-sh-3p20 from HMGA2 mRNA 3'UTR Promotes the Growth of Hepatoma Cells by Upregulating HMGA2.
Sci Rep. 2017; 7(1):2070 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
High mobility group A2 (HMGA2) plays a crucial role in the development of cancer. However, the mechanism by which HMGA2 promotes the growth of hepatocellular carcinoma (HCC) remains unclear. Here, we explore the hypothesis that HMGA2 may enhance the growth of hepatoma cells through a fragment based on the secondary structure of HMGA2 mRNA 3'-untranslated region (3'UTR). Bioinformatics analysis showed that HMGA2 mRNA displayed a hairpin structure within its 3'UTR, termed HMGA2-sh. Mechanistically, RNA immunoprecipitation assays showed that the microprocessor Drosha or DGCR8 interacted with HMGA2 mRNA in hepatoma cells. Then, Dicer contributes to the generation of the fragment HMGA2-sh-3p20 from the HMGA2-sh. HMGA2-sh-3p20 was screened by PCR analysis. Interestingly, HMGA2-sh-3p20 increased the expression of HMGA2 through antagonizing the tristetraprolin (TTP)-mediated degradation of HMGA2. HMGA2-sh-3p20 inhibited the expression of PTEN by targeting the 3'UTR of PTEN mRNA. In addition, the overexpression of PTEN could downregulate HMGA2 expression. Significantly, we documented the ability of HMGA2-sh-3p20 to promote the growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the fragment HMGA2-sh-3p20 from HMGA2 mRNA 3'UTR promotes the growth of hepatoma cells by upregulating HMGA2. Our finding provides new insights into the mechanism by which HMGA2 enhances hepatocarcinogenesis.

Suzuki HI, Young RA, Sharp PA
Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis.
Cell. 2017; 168(6):1000-1014.e15 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.

Bruzgielewicz A, Osuch-Wójcikiewicz E, Walczak A, et al.
Evaluation of polymorphisms in microRNA biosynthesis genes and risk of laryngeal cancer in the Polish population.
Pol J Pathol. 2016; 67(3):283-290 [PubMed] Related Publications
MicroRNAs are the largest group of short regulatory RNAs. They regulate genes participating in many physiological and pathological processes. The role of micro RNAs in cancer development is also considerable. Therefore, the aim of this study was to evaluate the relationship between DROSHA (rs6877842) and DGCR8 (rs417309, rs1640299) gene polymorphisms with risk of occurrence of laryngeal cancer. The study included 100 patients and 100 healthy subjects. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissues. Analysis of the gene polymorphisms was performed using TaqMan SNP Genotyping Assay. The rs417309 AA genotype was found to be correlated with increased risk of larynx cancer. The rs1640299 TG and rs6877842 CG heterozygotes were significantly inversely associated with the presence of larynx cancer. Additionally, rs417309 AA genotype increased the risk of larynx cancer in the T1 stage, and the rs1640299 TG heterozygote occurred more frequently in the control group than those in the T3 and T4 stage. The rs417309 and rs1640299 polymorphisms of the DGCR8 gene as well as rs6877842 of the DROSHA gene might be associated with a risk of laryngeal cancer occurrence in the Polish population.

Ma JZ, Yang F, Zhou CC, et al.
METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N
Hepatology. 2017; 65(2):529-543 [PubMed] Related Publications
CONCLUSION: These studies reveal an important role of METTL14 in tumor metastasis and provide a fresh view on m

Zhao L, Mao Y, Zhao Y, He Y
DDX3X promotes the biogenesis of a subset of miRNAs and the potential roles they played in cancer development.
Sci Rep. 2016; 6:32739 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
DDX3X, located on the X-chromosome, belongs to the DEAD-box RNA helicase family and acts as a key RNA-binding protein to exert its regulatory functions in various biological processes. In this paper, knock-down the expression of DDX3X can affect a subset of miRNA expression levels, especially for miR-1, miR-141, miR-145, miR-19b, miR-20a and miR-34a. Through adopting the immunoprecipitation (IP), RNA immunoprecipitation (RIP), dual luciferase reporter assays, we illustrate that DDX3X could interact with Drosha/DGCR8 complex, elevate the processing activity of Drosha/DGCR8 complex on pri-miRNAs, and increase mature miRNA expression levels. For the studies of potential roles and biological functions of DDX3X-dependent miRNAs and their downstream target genes in multiple cancers, we use the primary data from The Cancer Genome Atlas (TCGA), Ingenuity Pathway Analysis (IPA) and several miRNA target prediction databases, to systematically analyze the expression levels of DDX3X-dependent miRNAs in almost 14 kinds of cancers versus normal tissues, and the essential biological functions for their putative downstream target genes. All these findings will provide us novel insights and directions for thoroughly exploring the regulatory mechanisms of miRNA biogenesis, and shed light on effectively searching the clinical significances and biological roles of DDX3X-dependent miRNAs and their target genes in cancer development.

Chaleshi V, Tajali R, Savabkar S, et al.
Lack of Association between NOD2 rs3135500 and IL12B rs1368439 microRNA Binding Site SNPs and Colorectal Cancer Susceptibility in an Iranian Population.
Microrna. 2016; 5(2):152-156 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to evaluate the potential association between single nucleotide polymorphisms (SNPs) in microRNA (miRNA) binding sites in the NOD2 and IL12B gene 3.-untranslated regions and colorectal cancer (CRC) susceptibility in an Iranian population.
METHODS: We genotyped NOD2 rs3135500 [3. untranslated region (UTR) A/G] and IL12B rs1368439 (3.UTR G /T) in a hospital-based study of 92 colorectal cancer cases and 105 healthy controls. All samples were genotyped by TaqMan assay via an ABI 7500 Real Time PCR System (Applied Biosystems) with DNA from FFPE tissue and peripheral blood.
RESULTS: our results showed similar distribution of genotype and allelic frequencies of the NOD2 and IL12B polymorphisms between patients and controls. When the more common rs3135500 AA genotype was used as the reference, the rs3135500 AG and rs3135500 GG genotypes were not significantly associated with the risk of CRC (OR = 1.294, 95% CI: 0.524 -3.197; and OR = 2.230, 95% CI: 0.87 - 5.715, respectively), and The IL12B rs1368439 TG and IL12B rs1368439 GG genotypes were not significantly associated with the risk of CRC compared with the IL12B rs1368439 TT genotype (OR = 1.547 95% CI: 0.187- 12.771; and OR = 1.753, 95% CI: 0.217-14.157, respectively).
CONCLUSION: NOD2 rs3135500 and IL12B rs1368439 SNPs were not genetic risk factors for colorectal cancer in the studied Iranian population.

Napoli M, Venkatanarayan A, Raulji P, et al.
ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer.
Cancer Cell. 2016; 29(6):874-888 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
ΔNp63 is an oncogenic member of the p53 family and acts to inhibit the tumor-suppressive activities of the p53 family. By performing a chemical library screen, we identified histone deacetylase inhibitors (HDACi) as agents reducing ΔNp63 protein stability through the E3 ubiquitin ligase, Fbw7. ΔNp63 inhibition decreases the levels of its transcriptional target, DGCR8, and the maturation of let-7d and miR-128, which we found to be critical for HDACi function in vitro and in vivo. Our work identified Fbw7 as a predictive marker for HDACi response in squamous cell carcinomas and lymphomas, and unveiled let-7d and miR-128 as specific targets to bypass tumor resistance to HDACi treatment.

Mullany LE, Herrick JS, Wolff RK, et al.
Impact of polymorphisms in microRNA biogenesis genes on colon cancer risk and microRNA expression levels: a population-based, case-control study.
BMC Med Genomics. 2016; 9(1):21 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: MicroRNAs (miRNAs) have been implicated in the incidence and progression of cancer. It has been proposed that single nucleotide polymorphisms (SNPs) influence cancer risk due to their position within genes involved in miRNA synthesis and regulation.
METHODS: Genes directly and indirectly involved in miRNA biogenesis were identified from the literature. We then identified SNPs within these regions. Using genome-wide association study data we evaluated associations between biogenesis-related SNPs with colon cancer risk and their corresponding mRNA expression in normal colonic mucosa and carcinoma and difference in expression between the two tissues. SNPs that were associated with either altered colon cancer risk or with mRNA expression were evaluated for associations with altered miRNA expression.
RESULTS: Eleven SNPs were associated (P < 0.05) with colon cancer risk, and two of these variants remained significant after correction for multiple comparisons (PHolm < 0.05): rs1967327 (PRKRA) (ORdom = 0.78, 95 % CI 0.66-0.92) and rs4548444 (MAPKAP2) (ORrec = 1.67, 95 % CI 1.12-2.48). Of these two SNPs, rs4548444 (MAPKAP2), was associated with significantly altered miRNA expression levels in normal colonic mucosa, with nine miRNAs upregulated among individuals homozygous rare (GG) for rs4548444. One SNP associated with cancer prior to adjustment for multiple comparisons, rs11089328 (DGCR8), was associated with altered levels of hsa-miR-645 in differential tissue under the dominant model. Three SNPs, rs2740349 (GEMIN4) in carcinoma tissue, and rs235768 (BMP2) and rs2059691 (PRKRA) in normal mucosa, were significantly associated with altered mRNA expression levels across genotypes after multiple comparison adjustment. Rs2740349 (GEMIN4) and rs235768 (BMP2) were significantly associated with the upregulation of six and nine individual miRNAs in normal colonic mucosa, respectively.
CONCLUSION: Our data suggest that few of the SNPs in biogenesis genes we evaluated alter levels of mRNA transcription or colon cancer risk. As only one SNP both alters colon cancer risk and miRNA expression it is likely that SNPs influencing cancer do not do so through miRNAs. Because the significant SNPs were associated with downregulated mRNAs and upregulated miRNAs, and because each SNP was associated with unique miRNAs, it is possible that other mechanisms influence mature miRNA levels.

Li R, Pu X, Chang JY, et al.
MiRNA-Related Genetic Variations Associated with Radiotherapy-Induced Toxicities in Patients with Locally Advanced Non-Small Cell Lung Cancer.
PLoS One. 2016; 11(3):e0150467 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Severe radiation-induced toxicities limit treatment efficacy and compromise outcomes of lung cancer. We aimed to identify microRNA-related genetic variations as biomarkers for the prediction of radiotherapy-induced acute toxicities. We genotyped 233 SNPs (161 in microRNA binding site and 72 in processing gene) and analyzed their associations with pneumonitis and esophagitis in 167 stage III NSCLC patients received definitive radiation therapy. Sixteen and 11 SNPs were associated with esophagitis and pneumonitis, respectively. After multiple comparison correction, RPS6KB2:rs10274, SMO:rs1061280, SMO:rs1061285 remained significantly associated with esophagitis, while processing gene DGCR8:rs720014, DGCR8:rs3757, DGCR8:rs1633445 remained significantly associated with pneumonitis. Patients with the AA genotype of RPS6KB2:rs10274 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.51, p = 0.001, q = 0.06). Patients with the AG+GG genotype of SMO:rs1061280 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.53, p = 0.001, q = 0.06). Patients with the GG+GA genotype of DGCR8:rs720014 had a 3.54-fold increased risk of pneumonitis (OR: 3.54, 95% CI: 1.65-7.61, p <0.05, q <0.1). Significantly cumulative effects of the top SNPs were observed for both toxicities (P-trend <0.001). Using bioinformatics tools, we found that the genotype of rs10274 was associated with altered expression of the RPS6KB2 gene. Gene-based analysis showed DGCR8 (p = 0.010) and GEMIN4 (p = 0.039) were the top genes associated with the risk of developing pneumonitis. Our results provide strong evidence that microRNA-related genetic variations contribute to the development of radiotherapy-induced acute esophagitis and pneumonitis and could thus serve as biomarkers to help accurately predict radiotherapy-induced toxicity in NSCLC patients.

Liu F, Zhang S, Zhao Z, et al.
MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer.
Oncotarget. 2016; 7(15):19666-79 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
The infection with high-risk human papillomavirus is linked to cervical cancer, nevertheless, the role of miRNAs regulated by HPV oncogenes in cancer progression remain largely unknown. Here, we knocked down endogenous E6/E7 in HPV16-positive CaSki cell lines, screened differences in miRNA expression profile with control using miRNA array. 38 miRNAs were down-regulated and 6 miRNAs were up-regulated in the E6/E7 silenced CaSki cells (>2-fold changes with P <0.05). The levels of miR-27b, miR-20a, miR-24, miR-93, and miR-106b were verified by qPCR in E6/E7 silenced CaSki and SiHa cells. MiR-27b, up-regulated by E7, promoted CaSki and SiHa cell proliferation and invasion, inhibit paclitaxel-induced apoptosis. Dual-luciferase experiment confirmed miR-27b down-regulated its target gene PLK2 through the "seed regions". The tumor suppressor PLK2 inhibited SiHa cell proliferation, reduced cell viability, and promoted paclitaxel/cisplatin -induced apoptosis. Furthermore, DGCR8 was found to mediate the up-regulation of miR-27b by HPV16 E7. Our study demonstrated that HPV16 E7 could increase DGCR8 to promote the generation of miR-27b, which accelerated cell proliferation and inhibited paclitaxel-induced cell apoptosis through down-regulating PLK2. These findings provide an insight into the interaction network of viral oncogene, miR-27b and PLK2, and support the potential strategies using antisense nucleic acid of miR-27b for therapy of cervical cancer in the future.

Deng C, Dai R, Li X, Liu F
Genetic variation frequencies in Wilms' tumor: A meta-analysis and systematic review.
Cancer Sci. 2016; 107(5):690-9 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Over the last few decades, numerous biomarkers in Wilms' tumor have been confirmed and shown variations in prevalence. Most of these studies were based on small sample sizes. We carried out a meta-analysis of the research published from 1992 to 2015 to obtain more precise and comprehensive outcomes for genetic tests. In the present study, 70 out of 5175 published reports were eligible for the meta-analysis, which was carried out using Stata 12.0 software. Pooled prevalence for gene mutations WT1, WTX, CTNNB1, TP53, MYCN, DROSHA, and DGCR8 was 0.141 (0.104, 0.178), 0.147 (0.110, 0.184), 0.140 (0.100, 0.190), 0.410 (0.214, 0.605), 0.071 (0.041, 0.100), 0.082 (0.048, 0.116), and 0.036 (0.026, 0.046), respectively. Pooled prevalence of loss of heterozygosity at 1p, 11p, 11q, 16q, and 22q was 0.109 (0.084, 0.133), 0.334 (0.295, 0.373), 0.199 (0.146, 0.252), 0.151 (0.129, 0.172), and 0.148 (0.108, 0.189), respectively. Pooled prevalence of 1q and chromosome 12 gain was 0.218 (0.161, 0.275) and 0.273 (0.195, 0.350), respectively. The limited prevalence of currently known genetic alterations in Wilms' tumors indicates that significant drivers of initiation and progression remain to be discovered. Subgroup analyses indicated that ethnicity may be one of the sources of heterogeneity. However, in meta-regression analyses, no study-level characteristics of indicators were found to be significant. In addition, the findings of our sensitivity analysis and possible publication bias remind us to interpret results with caution.

Zhang X, Gee H, Rose B, et al.
Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers.
BMC Cancer. 2016; 16:86 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: The rates of oropharyngeal cancers such as tonsil cancers are increasing. The tumour suppressor protein Programmed Cell Death Protein 4 (PDCD4) has been implicated in the development of various human cancers and small RNAs such as microRNAs (miRNAs) can regulate its expression. However the exact regulation of PDCD4 by multiple miRNAs in oropharyngeal squamous cell carcinoma (SCC) is not well understood.
RESULTS: Using two independent oropharyngeal SCC cohorts with a focus on the tonsillar region, we identified a miRNA profile differentiating SCC tissue from normal. Both miR-21 and miR-499 were highly expressed in tonsil SCC tissues displaying a loss of PDCD4. Interestingly, expression of the miRNA machinery, Dicer1, Drosha, DDX5 (Dead Box Helicase 5) and DGCR8 (DiGeorge Syndrome Critical Region Gene 8) were all elevated by greater than 2 fold in the tonsil SCC tissue. The 3'UTR of PDCD4 contains three binding-sites for miR-499 and one for miR-21. Using a wild-type and truncated 3'UTR of PDCD4, we demonstrated that the initial suppression of PDCD4 was mediated by miR-21 whilst sustained suppression was mediated by miR-499. Moreover the single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites.
CONCLUSION: This study describes the regulation of PDCD4 specifically in tonsil SCC by miR-499 and miR-21 and has documented the loss of PDCD4 in tonsil SCCs. These findings highlight the complex interplay between miRNAs and tumour suppressor gene regulation and suggest that PDCD4 loss may be an important step in tonsillar carcinogenesis.

Fardmanesh H, Shekari M, Movafagh A, et al.
Upregulation of the double-stranded RNA binding protein DGCR8 in invasive ductal breast carcinoma.
Gene. 2016; 581(2):146-51 [PubMed] Related Publications
High-throughput experimental studies have indicated that the miRNAome is globally downregulated in various types of malignancy, and dysregulation of miRNAs processing component(s) is one possible mechanism for this phenomenon. Despite the progression in identifying cellular functions of Digeorge Syndrome Critical Region 8 (DGCR8) in miRNAs biogenesis, the role of altered expression of DGCR8 in the pathogenesis of invasive ductal breast carcinoma (IDC) has not yet been fully investigated. The objective of the present study was to evaluate DGCR8 mRNA expression in seventy fresh invasive ductal breast carcinomas and matched adjacent non-neoplastic tissues using quantitative real-time PCR and to assess the value of clinicopathological parameters on its expression. Our findings revealed that DGCR8 mRNA expression is upregulated in more than two-thirds of the cancerous specimens (68.66%) when compared to adjacent non-neoplastic tissue. This difference is statistically significant (P<0.05). We found that DGCR8 mRNA levels were increased in the high-grade and metastatic compared with those of both low-grade and non-metastatic. We demonstrated that there is not significant correlation between DGCR8 mRNA expression levels and clinicopathological parameters. In conclusion, our study suggested that upregulation of DGCR8 may be involved in tumorigenesis and aggressiveness of IDC and may serve as future therapeutic target.

Osuch-Wojcikiewicz E, Bruzgielewicz A, Niemczyk K, et al.
Association of Polymorphic Variants of miRNA Processing Genes with Larynx Cancer Risk in a Polish Population.
Biomed Res Int. 2015; 2015:298378 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Laryngeal cancer (LC) is one of the most prevalent types of head and neck cancer. An increasing interest has been focused on the role of microRNA (miRNAs) in LC development. The study group consisted of 135 larynx cancer patients and 170 cancer-free individuals. Nine polymorphisms of pre-miRNA processing genes, DROSHA (rs6877842), DGCR8 (rs3757, rs417309, and rs1640299), RAN (rs14035), XPO5 (rs11077), DICER1 (rs13078 and rs3742330) and TARBP2 (rs784567), were performed by TaqMan SNP Genotyping Assay. It was found that the frequency of the GT and the TT polymorphic variants of XPO5 gene were higher in LC patients than in controls (p < 0.0001 and p = 0.000183, resp.). In turn, the frequency of the CT genotype of RAN gene was higher in controls than in LC patients (p < 0.0001). The TT and the AG of DICER1 gene (p = 0.034697 for rs13078 and p = 0.0004 for rs3742330) as well as the AG and the GG genotypes of TARBP2 gene (p = 0.008335 and p < 0.0001, resp.) were associated with higher risk of LC occurrence. Our data suggested that polymorphisms of miRNA processing genes might be useful as predictive factors for the LC development.

Hata A, Kashima R
Dysregulation of microRNA biogenesis machinery in cancer.
Crit Rev Biochem Mol Biol. 2016 May-Jun; 51(3):121-34 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
MicroRNAs (miRNAs) are integral to the gene regulatory network. A single miRNA is capable of controlling the expression of hundreds of protein coding genes and modulate a wide spectrum of biological functions, such as proliferation, differentiation, stress responses, DNA repair, cell adhesion, motility, inflammation, cell survival, senescence and apoptosis, all of which are fundamental to tumorigenesis. Overexpression, genetic amplification, and gain-of-function mutation of oncogenic miRNAs ("onco-miRs") as well as genetic deletion and loss-of-function mutation of tumor suppressor miRNAs ("suppressor-miRs") are linked to human cancer. In addition to the dysregulation of a specific onco-miR or suppressor-miRs, changes in global miRNA levels resulting from a defective miRNA biogenesis pathway play a role in tumorigenesis. The function of individual onco-miRs and suppressor-miRs and their target genes in cancer has been described in many different articles elsewhere. In this review, we primarily focus on the recent development regarding the dysregulation of the miRNA biogenesis pathway and its contribution to cancer.

Zhu L, Gao J, Huang K, et al.
miR-34a screened by miRNA profiling negatively regulates Wnt/β-catenin signaling pathway in Aflatoxin B1 induced hepatotoxicity.
Sci Rep. 2015; 5:16732 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Aflatoxin-B1 (AFB1), a hepatocarcinogenic mycotoxin, was demonstrated to induce the high rate of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the regulation of several biological processes in HCC. However, the function of miRNAs in AFB1-induced HCC has received a little attention. Here, we applied Illumina deep sequencing technology for high-throughout profiling of microRNAs in HepG2 cells lines after treatment with AFB1. Analysis of the differential expression profile of miRNAs in two libraries, we identified 9 known miRNAs and 1 novel miRNA which exhibited abnormal expression. KEGG analysis indicated that predicted target genes of differentially expressed miRNAs are involved in cancer-related pathways. Down-regulated of Drosha, DGCR8 and Dicer 1 indicated an impairment of miRNA biogenesis in response to AFB1. miR-34a was up-regulated significantly, down-regulating the expression of Wnt/β-catenin signaling pathway by target gene β-catenin. Anti-miR-34a can significantly relieved the down-regulated β-catenin and its downstream genes, c-myc and Cyclin D1, and the S-phase arrest in cell cycle induced by AFB1 can also be relieved. These results suggested that AFB1 might down-regulate Wnt/β-catenin signaling pathway in HepG2 cells by up-regulating miR-34a, which may involve in the mechanism of liver tumorigenesis.

Rachagani S, Macha MA, Menning MS, et al.
Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.
Oncotarget. 2015; 6(37):40295-309 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets.

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