Gene Summary

Gene:TARBP2; TARBP2 subunit of RISC loading complex
Summary:HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene binds between the bulge and the loop of the HIV-1 TAR RNA regulatory element and activates HIV-1 gene expression in synergy with the viral Tat protein. Alternative splicing results in multiple transcript variants encoding different isoforms. This gene also has a pseudogene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:RISC-loading complex subunit TARBP2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

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Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: TARBP2 (cancer-related)

Huang SQ, Zhou ZX, Zheng SL, et al.
Association of variants of miRNA processing genes with cervical precancerous lesion risk in a southern Chinese population.
Biosci Rep. 2018; 38(3) [PubMed] Free Access to Full Article Related Publications
The miRNA processing genes play essential roles in the biosynthesis of mammalian miRNAs, and their genetic variants are involved in the development of various cancers. Our study aimed to determine the potential association between miRNA processing gene polymorphisms and cervical precancerous lesions. Five single nucleotide polymorphisms (SNPs), including Ran-GTP (

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.

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] Free Access to Full Article 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.

Lee HC, Wang H, Baladandayuthapani V, et al.
RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma.
Br J Haematol. 2017; 177(1):80-94 [PubMed] Free Access to Full Article Related Publications
Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.

Nikolić Z, Savić Pavićević D, Vučić N, et al.
Genetic variants in RNA-induced silencing complex genes and prostate cancer.
World J Urol. 2017; 35(4):613-624 [PubMed] Related Publications
PURPOSE: The purpose of this study is to evaluate the potential association between genetic variants in genes encoding the components of RNA-induced silencing complex and prostate cancer (PCa) risk. Genetic variants chosen for this study are rs3742330 in DICER1, rs4961280 in AGO2, rs784567 in TARBP2, rs7813 in GEMIN4 and rs197414 in GEMIN3.
METHODS: The study involved 355 PCa patients, 360 patients with benign prostatic hyperplasia and 318 healthy controls. For individuals diagnosed with PCa, clinicopathological characteristics including serum prostate-specific antigen level at diagnosis, Gleason score (GS) and clinical stage were determined. Genotyping was performed using high-resolution melting analysis, PCR-RFLP, TaqMan SNP Genotyping Assay and real-time PCR-based genotyping assay using specific probes. Allelic and genotypic associations were evaluated by unconditional linear and logistic regression methods.
RESULTS: The study provided no evidence of association between the analyzed genetic variants and PCa risk. Nevertheless, allele A of rs784567 was found to confer the reduced risk of higher serum PSA level at diagnosis (P = 0.046; Difference = -66.64, 95 % CI -131.93 to 1.35, for log-additive model). Furthermore, rs4961280, as well as rs3742330, were shown to be associated with GS. These variants, together with rs7813, were found to be associated with the lower clinical stage of PCa. Also, rs3742330 minor allele G was found to be associated with lower PCa aggressiveness (P = 0.036; OR 0.14, 95 % CI 0.023-1.22, for recessive model).
CONCLUSIONS: According to our data, rs3742330, rs4961280 and rs7813 qualify for potentially protective genetic variants against PCa progression. These variants were not shown to be associated with PCa risk.

Triozzi PL, Achberger S, Aldrich W, et al.
Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma.
Clin Epigenetics. 2016; 8:80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma. The role of epigenetic events mediated by microRNA (miR) is less clear. Tumor and plasma miR expression was examined in patients with primary uveal melanoma with tumor monosomy-3, a predictor of metastasis.
RESULTS: miR profiling of tumors by microarray found six miRs over-expressed and 19 under-expressed in 33 tumors with monosomy-3 compared to 22 without. None of the miRs differentially expressed in tumors with and without monosomy-3 was differentially expressed in tumors with and without tumor infiltrating lymphocytes. Tumors manifesting monosomy-3 were also characterized by higher levels of TARBP2 and DDX17 and by lower levels of XPO5 and HIWI, miR biogenesis factors. miR profiling of plasma by a quantitative nuclease protection assay found elevated levels of 11 miRs and reduction in four in patients with tumor monosomy-3. Only three miRs differentially expressed in the tumor arrays were detectable in plasma. miRs implicated in uveal melanoma development were not differentially expressed. Elevated plasma levels in patients with tumor monosomy-3 of miR-92b, identified in the tumor array, and of miR-199-5p and miR-223, identified in the plasma array, were confirmed by quantitative real-time polymerase chain reaction. Levels were also higher in patients compared to normal controls.
CONCLUSIONS: These results support a role for epigenetic mechanisms in the development of metastasis in patients with uveal melanoma and the analysis of miRs as biomarkers of metastatic risk. They also suggest that potentially useful blood miRs may be derived from the host response as well as the tumor.

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] Free Access to Full Article 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] Free Access to Full Article 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.

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] Free Access to Full Article 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.

Yu X, Li Z
The role of TARBP2 in the development and progression of cancers.
Tumour Biol. 2016; 37(1):57-60 [PubMed] Related Publications
TARBP2 is a RNA-binding protein (RBP) involved in miRNA processing and maturation. TARBP2 plays significant roles in many biological and pathological conditions, including viral expression of HIV-1, microsatellite instability, cancer stem cell properties, and tumor progression. Overexpression of TARBP2 was observed in many cancers such as prostate cancer, cutaneous malignant melanoma, and adrenocortical carcinoma. In addition, TARBP2 was also found to be downregulated in some cancers including colorectal cancer, gastric cancer, Ewing sarcoma, and upper urinary tract urothelial carcinoma. Therefore, whether TARBP2 functions as the tumor suppressor or tumor promoter is conflicting. In the present review, we provide an overview of current knowledge concerning the role of TARBP2 in tumor development and progression.

Spitzwieser M, Holzweber E, Pfeiler G, et al.
Applicability of HIN-1, MGMT and RASSF1A promoter methylation as biomarkers for detecting field cancerization in breast cancer.
Breast Cancer Res. 2015; 17:125 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: It has been shown in some articles that genetic and epigenetic abnormalities cannot only be found in tumor tissues but also in adjacent regions that appear histologically normal. This phenomenon is metaphorically called field cancerization or field defect. Field cancerization is regarded as clinically significant because it is assumed to be an important factor in local recurrence of cancer. As the field showing these molecular abnormalities may not be removed completely by surgery, these changes might lead to neoplasms and subsequent transformation to a tumor. We aimed to investigate the applicability of the methylation status of six tumor suppressor genes as biomarkers for detecting field cancerization in breast cancer.
METHODS: The promoter methylation status of CCND2, DAPK1, GSTP1, HIN-1, MGMT and RASSF1A was determined by methylation-sensitive high-resolution melting (MS-HRM) analysis. MS-HRM methods for CCND2, MGMT and RASSF1A were developed in-house, primer sequences for DAPK1, GSTP1 and HIN-1 have already been published. Biopsy samples were taken from tumor, tumor-adjacent and tumor-distant tissue from 17 breast cancer patients. Normal breast tissues of four healthy women served as controls.
RESULTS: All MS-HRM methods proved to be very sensitive. LODs were in the range from 0.1 to 1.5 %, LOQs ranged from 0.3 to 5.3 %. A total of 94 %, 82 % and 65 % of the tumors showed methylation of RASSF1A, HIN-1 and MGMT promoters, respectively. The methylation status of these promoters was significantly lower in tumor-distant tissues than in tumor tissues. Tumor-adjacent tissues showed higher methylation status of RASSF1A, HIN-1 and MGMT promoters than tumor-distant tissues, indicating field cancerization. The methylation status of the HIN-1 promoter in tumor-adjacent tissues was found to correlate strongly with that in the corresponding tumors (r = 0.785, p < 0.001), but not with that in the corresponding tumor-distant tissues (r = 0.312, p = 0.239).
CONCLUSIONS: Among the gene promoters investigated, the methylation status of the HIN-1 promoter can be considered the best suitable biomarker for detecting field cancerization. Further investigation is needed to test whether it can be used for defining surgical margins in order to prevent future recurrence of breast cancer.

de Sousa GR, Ribeiro TC, Faria AM, et al.
Low DICER1 expression is associated with poor clinical outcome in adrenocortical carcinoma.
Oncotarget. 2015; 6(26):22724-33 [PubMed] Free Access to Full Article Related Publications
Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas.

Martin-Guerrero I, Gutierrez-Camino A, Lopez-Lopez E, et al.
Genetic variants in miRNA processing genes and pre-miRNAs are associated with the risk of chronic lymphocytic leukemia.
PLoS One. 2015; 10(3):e0118905 [PubMed] Free Access to Full Article Related Publications
Genome wide association studies (GWAS) have identified several low-penetrance susceptibility alleles in chronic lymphocytic leukemia (CLL). Nevertheless, these studies scarcely study regions that are implicated in non-coding molecules such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Genetic variations in miRNAs can affect levels of miRNA expression if present in pre-miRNAs and in miRNA biogenesis genes or alter miRNA function if present in both target mRNA and miRNA sequences. Therefore, the present study aimed to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes contribute to predisposition for CLL. A total of 91 SNPs in 107 CLL patients and 350 cancer-free controls were successfully analyzed using TaqMan Open Array technology. We found nine statistically significant associations with CLL risk after FDR correction, seven in miRNA processing genes (rs3805500 and rs6877842 in DROSHA, rs1057035 in DICER1, rs17676986 in SND1, rs9611280 in TNRC6B, rs784567 in TRBP and rs11866002 in CNOT1) and two in pre-miRNAs (rs11614913 in miR196a2 and rs2114358 in miR1206). These findings suggest that polymorphisms in genes involved in miRNAs biogenesis pathway as well as in pre-miRNAs contribute to the risk of CLL. Large-scale studies are needed to validate the current findings.

Yamamoto H, Imai K
Microsatellite instability: an update.
Arch Toxicol. 2015; 89(6):899-921 [PubMed] Related Publications
Deficient DNA mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability (MSI), which is a hallmark of Lynch syndrome-associated cancers. MSI is characterized by length alterations within simple repeated sequences that are called microsatellites. Lynch syndrome is primarily caused by mutations in the MMR genes, mainly MLH1 and MSH2, and less frequently in MSH6, and rarely PMS2, and large genomic rearrangements account for 5-20 % of all mutations. Germ line hemiallelic methylations of MLH1 or MSH2 are termed as epimutations and have been identified as causative of Lynch syndrome. Moreover, germ line 3' deletions of EPCAM gene is involved in MSH2 methylation. MSI is also observed in about 15 % of sporadic colorectal cancer (CRC), gastric cancer (GC), and endometrial cancer (EC), and at lower frequencies in other cancers, often in association with hypermethylation of the MLH1 gene. Trimethylation of histone H3 on Lys36 (H3K36 me3) is an epigenetic histone mark that was required for DNA MMR in vivo. Thus, mutations in the H3K36 trimethyltransferase SETD2 have been reported as a potential cause of MSI. Genetic, epigenetic, and transcriptomic differences have been identified between cancers with and without MSI. Recent comprehensive molecular characterizations of CRC, EC, and GC by The Cancer Genome Atlas indicate that MSI+ cancers are distinct biological entities. The BRAF V600E mutation is specifically associated with sporadic MSI+ CRCs with methylated MLH1, but is not associated with Lynch syndrome-related CRCs. Accumulating evidence indicates a role of interactions between MSI and microRNA (miRNA) in the pathogenesis of MSI-positive (MSI+) cancer. As another new mechanism underlying MSI, overexpression of miR-155 or miR-21 has been shown to downregulate the expression of the MMR genes. Gene targets of frameshift mutations caused by MSI are involved in various cellular functions, including DNA repair (MSH3 and MSH6), cell signaling (TGFBR2 and ACVR2A), apoptosis (BAX), epigenetic regulation (HDAC2 and ARID1A), and miRNA processing (TARBP2 and XPO5), and a subset of MSI+ CRCs reportedly shows the mutated miRNA machinery phenotype. Moreover, microsatellite repeats in miRNA genes, such as hsa-miR-1273c, may be novel MSI targets for CRC, and mutations in noncoding regulatory regions of MRE11, BAX (BaxΔ2), and HSP110 (HSP110ΔE9) may affect the efficiency of chemotherapy. Thus, analyses of MSI and its related molecular alterations in cancers are increasingly relevant in clinical settings, and MSI is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. In this review, we summarize recent advances in the pathogenesis of MSI and focus on genome-wide analyses that indicate the potential use of MSI and related alterations as biomarkers and novel therapeutic targets.

Shi J
Regulatory networks between neurotrophins and miRNAs in brain diseases and cancers.
Acta Pharmacol Sin. 2015; 36(2):149-57 [PubMed] Free Access to Full Article Related Publications
Neurotrophins are involved in many physiological and pathological processes in the nervous system. They regulate and modify signal transduction, transcription and translation in neurons. It is recently demonstrated that the neurotrophin expression is regulated by microRNAs (miRNAs), changing our views on neurotrophins and miRNAs. Generally, miRNAs regulate neurotrophins and their receptors in at least two ways: (1) miRNAs bind directly to the 3' untranslated region (UTR) of isoform-specific mRNAs and post-transcriptionally regulate their expression; (2) miRNAs bind to the 3' UTR of the regulatory factors of neurotrophins and regulate their expression. On the other hand, neurotrophins can regulate miRNAs. The results of BNDF research show that neurotrophins regulate miRNAs in at least three ways: (1) ERK stimulation enhances the activation of TRBP (HIV-1 TAR RNA-binding protein) and Dicer, leading to the upregulation of miRNA biogenesis; (2) ERK-dependent upregulation of Lin28a (RNA-binding proteins) blocks select miRNA biogenesis; (3) transcriptional regulation of miRNA expression through activation of transcription factors, including CREB and NF-κB. These regulatory processes integrate positive and negative regulatory loops in neurotrophin and miRNA signaling pathways, and also expand the function of neurotrophins and miRNAs. In this review, we summarize the current knowledge of the regulatory networks between neurotrophins and miRNAs in brain diseases and cancers, for which novel cutting edge therapeutic, delivery and diagnostic approaches are emerging.

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] Free Access to Full Article Related Publications
microRNAs (miRNAs) are non coding RNAs with different biological functions and pathological implications. Given their role as post-transcriptional gene expression regulators, they are involved in several important physiological processes like development, cell differentiation and cell signaling. miRNAs act as modulators of gene expression programs in different diseases, particularly in cancer, where they act through the repression of genes which are critical for carcinogenesis. The expression level of mature miRNAs is the result of a fine mechanism of biogenesis, carried out by different enzymatic complexes that exert their function at transcriptional and post-transcriptional levels. In this review, we will focus our discussion on the alterations in the miRNA biogenesis machinery, and its impact on the establishment and development of cancer programs.

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

Bandara V, Michael MZ, Gleadle JM
Hypoxia represses microRNA biogenesis proteins in breast cancer cells.
BMC Cancer. 2014; 14:533 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancers are commonly characterised by hypoxia and also by global reductions in the levels of mature microRNAs. We have examined the hypothesis that hypoxia might mediate this reduction through repressive effects on microRNA biogenesis proteins.
METHODS: Breast cancer cell lines were exposed to hypoxia and manipulations of hypoxia inducible factor (HIF) and HIF hydroxylase activity. The effects of hypoxia on the mRNA and protein levels of enzymes involved in microRNA biogenesis (Dicer, Drosha, TARPB2, DCGR8, XPO5) was determined by RT PCR and immunoblotting. The effect of hypoxia on microRNAs was determined with microarray studies, RT PCR and reporter assays.
RESULTS: In breast cancer lines there was significant reduction of Dicer mRNA and protein levels in cells exposed to hypoxia. This effect was independent of HIF but dependent on the HIF hydroxylase PHD2 and was partly mediated by feedback effects via microRNAs. Furthermore, several other proteins with critical roles in microRNA biogenesis (Drosha, TARBP2 and DCGR8) also showed significant and co-ordinated repression under hypoxic conditions. Despite these substantial alterations no, or modest, changes were observed in mature microRNA production.
CONCLUSION: These observations provide further and important interfaces between oxygen availability and gene expression and a potential mechanistic explanation for the reduced levels of microRNAs observed in some cancers. They provide further support for the existence of feedback mechanisms in the regulation of the microRNA biogenesis pathway and the relative stability of microRNAs.

Goodarzi H, Zhang S, Buss CG, et al.
Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins.
Nature. 2014; 513(7517):256-60 [PubMed] Free Access to Full Article Related Publications
Aberrant regulation of RNA stability has an important role in many disease states. Deregulated post-transcriptional modulation, such as that governed by microRNAs targeting linear sequence elements in messenger RNAs, has been implicated in the progression of many cancer types. A defining feature of RNA is its ability to fold into structures. However, the roles of structural mRNA elements in cancer progression remain unexplored. Here we performed an unbiased search for post-transcriptional modulators of mRNA stability in breast cancer by conducting whole-genome transcript stability measurements in poorly and highly metastatic isogenic human breast cancer lines. Using a computational framework that searches RNA sequence and structure space, we discovered a family of GC-rich structural cis-regulatory RNA elements, termed sRSEs for structural RNA stability elements, which are significantly overrepresented in transcripts displaying reduced stability in highly metastatic cells. By integrating computational and biochemical approaches, we identified TARBP2, a double-stranded RNA-binding protein implicated in microRNA processing, as the trans factor that binds the sRSE family and similar structural elements--collectively termed TARBP2-binding structural elements (TBSEs)--in transcripts. TARBP2 is overexpressed in metastatic cells and metastatic human breast tumours and destabilizes transcripts containing TBSEs. Endogenous TARBP2 promotes metastatic cell invasion and colonization by destabilizing amyloid precursor protein (APP) and ZNF395 transcripts, two genes previously associated with Alzheimer's and Huntington's disease, respectively. We reveal these genes to be novel metastasis suppressor genes in breast cancer. The cleavage product of APP, extracellular amyloid-α peptide, directly suppresses invasion while ZNF395 transcriptionally represses a pro-metastatic gene expression program. The expression levels of TARBP2, APP and ZNF395 in human breast carcinomas support their experimentally uncovered roles in metastasis. Our findings establish a non-canonical and direct role for TARBP2 in mammalian gene expression regulation and reveal that regulated RNA destabilization through protein-mediated binding of mRNA structural elements can govern cancer progression.

Torrezan GT, Ferreira EN, Nakahata AM, et al.
Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour.
Nat Commun. 2014; 5:4039 [PubMed] Free Access to Full Article Related Publications
Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in 81% of the DROSHA-mutated tumours. In addition, we identify non-recurrent mutations in other genes of this pathway (DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the DROSHA-E1147K-mutated tumours and cell lines expressing this mutation, we determine that this variant leads to a predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA-processing gene DROSHA.

Lin X, Wu M, Liu P, et al.
Up-regulation and worse prognostic marker of cytoplasmic TARBP2 expression in obstinate breast cancer.
Med Oncol. 2014; 31(4):868 [PubMed] Related Publications
Expression of trans-activation-responsive-RNA-binding protein 2 (TARBP2) varied from normal cell lines to various cancer cell lines. The discussion of TARBP2 serve as tumor suppressor or tumor promotor goes on. However, its expression in breast cancer remains unknown. The aim of present study was to assess the expression of cytoplasm TARBP2 as potential prognostic marker in breast cancer. We further investigated cytoplasm TARBP2 could be a novel target in treatment for late-stage breast cancer and triple-negative breast cancer (TNBC). A total of patients with breast cancer were involved in our cohort. Immunohistochemical staining for TARBP2 on tissue microarray and western blot were used. Immunohistochemistry showed that cytoplasm TARBP2 was frequently up-regulated in breast carcinoma. This finding was in line with the result of western blot analysis. Further investigation showed that cytoplasm TARBP2 expression in non-TNBC was higher than that of their adjacent normal breast tissues (NBT), and TNBC was the highest of the three groups. The positive expression of cytoplasm TARBP2 in stage III breast cancer, stage I-II breast cancer, and NBT decreased gradually. In addition, univariate and multivariate survival analysis revealed cytoplasm TARBP2 was an independent prognostic factor for breast cancer. Breast cancer patients with cytoplasm TARBP2 expression had poorer disease-free survival and overall survival, and similar results were obtained in TNBC group and stage III breast cancer group. Our results provide convincing evidence for the first time that the expression of cytoplasm TARBP2 is up-regulated in breast cancer. Breast cancer patients with TARBP2 cytoplasm expression have unfavorable prognosis. Patients of TNBC and late-stage breast cancer with higher cytoplasm TARBP2 expression have an unfavorable prognosis.

Navarro A, Muñoz C, Gaya A, et al.
MiR-SNPs as markers of toxicity and clinical outcome in Hodgkin lymphoma patients.
PLoS One. 2013; 8(5):e64716 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways.
DESIGN AND METHODS: We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS).
RESULTS: The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P = 0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P = 0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P = 0.036). XPO5 (P = 0.039) and TRBP (rs784567) (P = 0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P = 0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P = 0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P = 0.008) and OS (P = 0.008).
CONCLUSION: miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse.

Bai S, Nunez AL, Wei S, et al.
Microsatellite instability and TARBP2 mutation study in upper urinary tract urothelial carcinoma.
Am J Clin Pathol. 2013; 139(6):765-70 [PubMed] Related Publications
Microsatellite instability (MSI) contributes to the tumorigenesis of upper urinary tract urothelial carcinomas (UUT-UCs). In this study, we first used MLH1 and MSH2 immunohistochemistry to identify patients with loss of expression of either or both of these proteins in 132 UUT-UCs. We found a total loss of MSH2 expression in 4 patients. MSI was evaluated using 5 markers in these 4 cases. All of the tumors had high MSI (MSI-H) status. Trans-activation responsive RNA-binding protein 2, an integral component of DICER1-containing complex, was a putative target of DNA mismatch repair deficiency. Truncating mutation has been identified in gastrointestinal cancers with MSI. No previous study has evaluated the mutation status of this gene in MSI UUT-UCs. In this study, we analyze the mutation of TARBP2 in MSI-H UUT-UCs with reverse transcription polymerase chain reaction. No truncating mutations were identified in the MSI-H UUT-UCs.

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] Free Access to Full Article 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.

Sousa E, Graça I, Baptista T, et al.
Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processing.
Epigenetics. 2013; 8(5):548-58 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is one of the most incident malignancies worldwide. Although efficient therapy is available for early-stage PCa, treatment of advanced disease is mainly ineffective and remains a clinical challenge. microRNA (miRNA) dysregulation is associated with PCa development and progression. In fact, several studies have reported a widespread downregulation of miRNAs in PCa, which highlights the importance of studying compounds capable of restoring the global miRNA expression. The main aim of this study was to define the usefulness of enoxacin as an anti-tumoral agent in PCa, due to its ability to induce miRNA biogenesis in a TRBP-mediated manner. Using a panel of five PCa cell lines, we observed that all of them were wild type for the TARBP2 gene and expressed TRBP protein. Furthermore, primary prostate carcinomas displayed normal levels of TRBP protein. Remarkably, enoxacin was able to decrease cell viability, induce apoptosis, cause cell cycle arrest, and inhibit the invasiveness of cell lines. Enoxacin was also effective in restoring the global expression of miRNAs. This study is the first to show that PCa cells are highly responsive to the anti-tumoral effects of enoxacin. Therefore, enoxacin constitutes a promising therapeutic agent for PCa.

Pouliot LM, Shen DW, Suzuki T, et al.
Contributions of microRNA dysregulation to cisplatin resistance in adenocarcinoma cells.
Exp Cell Res. 2013; 319(4):566-74 [PubMed] Free Access to Full Article Related Publications
Cisplatin resistance in cancer cells is due to a pleiotropic phenotype transition that allows cells to resist cell death. miRNAs have been shown to be reliable markers of phenotype, critical in cell differentiation, and dysregulated in cancer and other pathologies. Here we investigate the influence of miRNA on cisplatin resistance in KB adenocarcinoma cells. Silencing both DICER and TRBP2 in the miRNA biosynthesis pathway in KB-3-1 (sensitive parental), KB-CP.5 (cisplatin-resistant), and KB-CP20 (highly cisplatin-resistant) cells resulted in the reversal of cisplatin resistance, with no effect on cell viability in the absence of cisplatin. We found miR-181 expression differences in the cell lines using RT-PCR, with several members of the miR-181 family overexpressed in two KB cisplatin-resistant lines and in two cisplatin-resistant lung cancer lines, compared to their respective parental cells. Functional assays showed minimal effects of miR-181 on cisplatin resistance. We conclude that the miRNA biosynthesis pathway is critical for maintaining the cisplatin-resistant phenotype, but that it is difficult to determine the precise miRNAs involved in cisplatin resistance simply using expression profiles of individual miRNA species. Functional assays are needed to determine the influence of a specific miRNA and different members of the same miRNA family may have opposite effects.

Daniels SM, Gatignol A
The multiple functions of TRBP, at the hub of cell responses to viruses, stress, and cancer.
Microbiol Mol Biol Rev. 2012; 76(3):652-66 [PubMed] Free Access to Full Article Related Publications
The TAR RNA binding protein (TRBP) has emerged as a key player in many cellular processes. First identified as a cellular protein that facilitates the replication of human immunodeficiency virus, TRBP has since been shown to inhibit the activation of protein kinase R (PKR), a protein involved in innate immune responses and the cellular response to stress. It also binds to the PKR activator PACT and regulates its function. TRBP also contributes to RNA interference as an integral part of the minimal RNA-induced silencing complex with Dicer and Argonaute proteins. Due to its multiple functions in the cell, TRBP is involved in oncogenesis when its sequence is mutated or its expression is deregulated. The depletion or overexpression of TRBP results in malignancy, suggesting that the balance of TRBP expression is key to normal cellular function. These studies show that TRBP is multifunctional and mediates cross talk between different pathways. Its activities at the molecular level impact the cellular function from normal development to cancer and the response to infections.

Yamamoto H, Adachi Y, Taniguchi H, et al.
Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer.
World J Gastroenterol. 2012; 18(22):2745-55 [PubMed] Free Access to Full Article Related Publications
There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI- cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.

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.

De Vito C, Riggi N, Cornaz S, et al.
A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma.
Cancer Cell. 2012; 21(6):807-21 [PubMed] Related Publications
We have recently demonstrated that human pediatric mesenchymal stem cells can be reprogrammed toward a Ewing sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSCs is shared by embryonic stem cells and CSCs from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSCs is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor maintenance may depend on deregulation of TARBP2-dependent miRNA expression.

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