ORCID Profile
0000-0001-8311-8845
Current Organisations
University of Newcastle Australia
,
The Ohio State University
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Publisher: Elsevier BV
Date: 10-2008
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432106
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432109
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: Oxford University Press (OUP)
Date: 13-03-2014
DOI: 10.1093/NAR/GKU202
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432097.V1
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2020
DOI: 10.1158/1538-7445.AM2020-2543
Abstract: MicroRNAs (miRs), a class of regulatory single-stranded small non-coding RNAs, are frequently deregulated in cancer and have been proposed as diagnostic and prognostic biomarkers in this fatal disease. Recent improvements in high-throughput sequencing (HTS) technologies have allowed the discovery of post-transcriptional modification phenomena involving miRs (e.g., isomiRs, A-to-I editing sites) able to alter the miR canonical sequence and thus their function. However, albeit earlier studies have proposed the exploitation of modified miRs as potential cancer biomarkers, their comprehensive and concurrent profiling, in cancer, still lacks. In light of this, we have applied the miRge2 pipeline (PubmedID:30153801) to more than 12K s les across 38 different cancer types from TCGA and TARGET, aiming at profiling the expression of all detectable canonical and modified miR isoforms in cancer. We identified over 29K unique miR isoforms (21 novel ones) expressed in at least one tumor type, whereby about 85% contains at least one modification (e.g., SNPs, RNA editing). According to our results, taking into account both canonical and modified miR isoforms throughout the analysis leads to an increase of about 20-fold in the identification of potential diagnostic and prognostic miRs with respect to conventional methods, which exclusively consider canonical miRs (miRBase v22). Then, leveraging on an independent cohort of 38 colorectal cancers and 21 adjacent healthy tissues (EGAS00001001127), we found that ~600 significantly deregulated miR isoforms were in common with the ones derived from the TCGA COAD dataset. Focusing on two miR isoforms, the canonical miR-151a-3p and its isoform (miR-151a-3p_-2|-2) with two left-shifted residues in both 5' and 3' end, which we found to be up-regulated in both cohorts, we performed a target prediction coupled with a miR rotein anti-correlation analysis. Interestingly, we found that the two miRs have a distinct set of targets. Finally, employing an Ingenuity(R) Pathway Analysis on their predicted targets, we observed that miR-151a-3p_-2|-2, in contrast to the canonical counterpart, is significantly involved in oncogenic pathways, such as PAK and CXCR4 signaling. This suggests that the final tumor phenotype could be substantially affected by modified miR isoforms. Here, we present one of the most in-depth and extensive miRNome profiling in cancer performed to date, revealing one magnitude of novel potential diagnostic and prognostic cancer biomarkers and enlightening the contribution of miR isoforms to the wider miRNome in cancer pathogenesis. Citation Format: Rosario Distefano, Luisa Tomasello, Gioacchino P. Marceca, Marina Bagnoli, Alessandro Lagana', Mario Acunzo, Chi Song, Pierluigi Gasparini, Giovanni Nigita, Carlo M. Croce. Concurrent profiling of canonical and modified miRNAomes from TCGA and TARGET cohorts leads to enhanced resolution in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR Cancer Res 2020 (16 Suppl):Abstract nr 2543.
Publisher: Cold Spring Harbor Laboratory
Date: 06-09-2020
DOI: 10.1101/2020.09.04.283689
Abstract: MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at iredibase .
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432100
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: Proceedings of the National Academy of Sciences
Date: 08-03-2021
Abstract: The mechanisms that promote the transition from chronic phase to blast crisis (BC) in chronic myeloid leukemia (CML) patients are not fully described. Given the loss of miR-15/16 loci is critical in the development of myeloid and lymphocytic leukemia, here we evaluated the correlation between the expression of miR-15a/16 and miR-15b/16 with the transition of CML from chronic phase to BC. A significant reduction of miR-15a, miR-15b, and miR-16 expression and an overexpression of their targets, such as Bmi-1, ROR1, and Bcl-2, can describe the progression from chronic phase to BC. This study suggests that targeting different oncogenes activated by the same genetic/epigenetic alteration could represent an important advancement in the treatment of BC CML.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432115.V1
Abstract: Supplementary Figure from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432103
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432109.V1
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-2010
DOI: 10.1158/1538-7445.AM10-4086
Abstract: Background: Non-coding RNAs (ncRNA) have recently been implicated in carcinogenesis. Highly conserved ncRNA expression across species suggests a biological function. A group of ncRNAs that are greater than 200 bp and highly conserved across species (ultraconserved regions) has been recently shown to be differentially expressed in human cancers but their role in hepatocarcinogenesis remains unclear. Our aim was to evaluate the expression and potential role of these ultraconserved RNA (ucRNA) in hepatocellular cancer (HCC). Methods: The global expression of 481 ucRNAs was analyzed in human non-malignant (HH) or malignant (HepG2) hepatocytes using a custom microarray. Expression of selected ucRNA was verified by real time PCR in HCC cell lines and by in situ hybridization in 30 human HCC tissues. Cells were transfected with siRNAs or plasmids over-expressing ucRNA to reduce or enhance their cellular expression. Anchorage dependent growth was evaluated using viable cell assay and anchorage independent growth was assessed by growth in soft agar using a fluorometric assay. Cell cycle progression was determined by flow cytometry. Results: 56 ucRNAs were aberrantly expressed with 33 increased and 23 decreased in HepG2 cells compared to HH (p& .05). Of these, uc.338 was the most up-regulated (6.9-fold). uc.338 was significantly increased in several HCC cell lines (HepG2, Huh-7, PLC/PRF-5, SK-Hep-1, SNU-182, and SNU-449) compared to HH by real-time PCR. uc.338 expression was also detected in 73% of human HCC. Although uc.338 is located within the PCBP2 gene, the expression of PCBP2 mRNA did not correlate with that of uc.338 and inhibition of uc.338 did not reduce PCBP2 mRNA, suggesting independent regulation of these genes. Over-expression of uc.338 increased growth rate of HH compared to cells transfected with an empty vector. Huh-7 and HepG2 cells transfected with anti-uc.338 had slower growth rate compared to cells transfected with control-siRNA. Growth in soft agar was decreased by 40% in HepG2 cells transfected with anti-uc.338 compared to controls. Transfection with anti-uc.338 also increased the number of cells in sub-G1 phase and decreased the number of cells in S phase by 30 ± 1.3 % (p& .001) compared to controls. To confirm the conservation of uc.338 in different species, we assessed its expression in murine BNL-CL2 cells (embryonic liver mouse cells) and BNL-SVA.8 cells (SV40-transformed BNL-CL2 cells with an increased growth potential). uc.338 was over-expressed by 2-fold in BNL-SVA.8 cells compared to BNL-CL2 cells (p:0.001). Inhibition of uc.338 by siRNA reduced anchorage-dependent growth by 65% at 72 hours in BNL-SVA.8 cells (p: 0.0001). Conclusion: These studies identify a novel non-coding RNA uc.338 that is increased in expression and modulates cell growth in HCC in a species-independent fashion. These studies indicate a functional role for ultraconserved RNA genes and expand the role of non-coding RNA in HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research 2010 Apr 17-21 Washington, DC. Philadelphia (PA): AACR Cancer Res 2010 (8 Suppl):Abstract nr 4086.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2019
DOI: 10.1038/S41419-019-2122-Z
Abstract: Colorectal cancer (CRC) is one of the leading cancer-related causes of death worldwide. Despite the improvement of surgical and chemotherapeutic treatments, as of yet, the disease has not been overcome due to metastasis to distant organs. Hence, it is of great relevance to understand the mechanisms responsible for metastasis initiation and progression and to identify novel metastatic markers for a higher chance of preventing the metastatic disease. The Death-associated protein kinase 1 (DAPK1), recently, has been shown to be a potential candidate for regulating metastasis in CRC. Hence, the aim of the study was to investigate the impact of DAPK1 protein on CRC aggressiveness. Using CRISPR/Cas9 technology, we generated DAPK1-deficient HCT116 monoclonal cell lines and characterized their knockout phenotype in vitro and in vivo. We show that loss of DAPK1 implemented changes in growth pattern and enhanced tumor budding in vivo in the chorioallantoic membrane (CAM) model. Further, we observed more tumor cell dissemination into chicken embryo organs and increased invasion capacity using rat brain 3D in vitro model. The novel identified DAPK1-loss gene expression signature showed a stroma typical pattern and was associated with a gained ability for remodeling the extracellular matrix. Finally, we suggest the DAPK1-ERK1 signaling axis being involved in metastatic progression of CRC. Our results highlight DAPK1 as an anti-metastatic player in CRC and suggest DAPK1 as a potential predictive biomarker for this cancer type.
Publisher: Cold Spring Harbor Laboratory
Date: 20-05-2021
DOI: 10.1101/2021.05.18.444694
Abstract: MiRNA Epitranscriptomics has placed a new layer of complexity in the cancer field. Despite the fast-growing interest in miRNA editing and shifted miRNA isoforms, a simultaneous study of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modifications, including A-to-I RNA editing and shifted miRNA isoforms, in K adult and pediatric tumor s les across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments datasets. We investigated the differences among canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint. The combination of canonical miRNAs/miRNA isoforms boosted the quality of clustering results, outlining unique cohorts’ clinical-pathological features. We described modified miRNAs showing opposite dysregulation with respect to their canonical counterparts in cancer, potentially impacting their targetome and function. The abundance of expressed miRNA isoforms directly impacted the activation/deactivation of critical carcinogenesis pathways. Finally, we experimentally validated unique targeting for a shifted and edited miRNA isoform. Our findings outlined once more the importance of going beyond the well-established paradigm of one-mature-miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression.
Publisher: Proceedings of the National Academy of Sciences
Date: 27-12-2010
Abstract: Although expression of non–protein-coding RNA (ncRNA) can be altered in human cancers, their functional relevance is unknown. Ultraconserved regions are noncoding genomic segments that are 100% conserved across humans, mice, and rats. Conservation of gene sequences across species may indicate an essential functional role, and therefore we evaluated the expression of ultraconserved RNAs (ucRNA) in hepatocellular cancer (HCC). The global expression of ucRNAs was analyzed with a custom microarray. Expression was verified in cell lines by real-time PCR or in tissues by in situ hybridization using tissue microarrays. Cellular ucRNA expression was modulated with siRNAs, and the effects on global gene expression and growth of human and murine HCC cells were evaluated. Fifty-six ucRNAs were aberrantly expressed in HepG2 cells compared with nonmalignant hepatocytes. Among these ucRNAs, the greatest change was noted for ultraconserved element 338 (uc.338), which was dramatically increased in human HCC compared with noncancerous adjacent tissues. Although uc.338 is partially located within the poly(rC) binding protein 2 ( PCBP2 ) gene, the transcribed ncRNA encoding uc.338 is expressed independently of PCBP2 and was cloned as a 590-bp RNA gene, termed TUC338. Functional gene annotation analysis indicated predominant effects on genes involved in cell growth. These effects were experimentally demonstrated in both human and murine cells. siRNA to TUC338 decreased both anchorage-dependent and anchorage-independent growth of HCC cells. These studies identify a critical role for TUC338 in regulation of transformed cell growth and of transcribed ultraconserved ncRNA as a unique class of genes involved in the pathobiology of HCC.
Publisher: Impact Journals, LLC
Date: 21-01-2014
Publisher: Elsevier BV
Date: 12-2018
Publisher: Impact Journals, LLC
Date: 31-12-2017
Publisher: Oxford University Press (OUP)
Date: 05-2010
DOI: 10.1093/JNCI/DJQ102
Publisher: American Association for Cancer Research (AACR)
Date: 02-2010
DOI: 10.1158/1078-0432.CCR-09-2123
Abstract: Purpose: Hepatocellular cancer (HCC) is highly resistant to chemotherapy and is associated with poor prognosis. Chronic hepatitis C virus (HCV) infection is a major cause of HCC. However, the effect of viral proteins in mediating chemosensitivity in tumor cells is unknown. We postulated that HCV viral proteins could modulate therapeutic responses by altering host cell microRNA (miRNA) expression. Experimental Design: HepG2 malignant hepatocytes were stably transfected with full-length HCV genome (Hep-394) or an empty vector (Hep-SWX). MiRNA profiling was done by using a custom microarray, and the expression of selected miRNAs was validated by real-time PCR. Protein expression was assessed by Western blotting, whereas caspase activation was assessed by a luminometric assay. Results: The IC50 to sorafenib was lower in Hep-394 compared with Hep-SWX control cells. Alterations in miRNA expression occurred with 10 miRNAs downregulated & -fold and 23 miRNAs upregulated & -fold in Hep-394 cells compared with controls. Of these, miR-193b was overexpressed by 5-fold in Hep-394 cells. miR-193b was predicted to target Mcl-1, an antiapoptotic protein that can modulate the response to sorafenib. The expression of Mcl-1 was decreased, and basal caspase-3/7 activity and poly ADP ribose polymerase cleavage were increased in Hep-394 cells compared with controls. Moreover, transfection with precursors to miR-193b decreased both Mcl-1 expression and the IC50 to sorafenib. Conclusions: Cellular expression of full-length HCV increases sensitivity to sorafenib by the miRNA-dependent modulation of Mcl-1 and apoptosis. Modulation of miRNA responses may be a useful strategy to enhance response to chemotherapy in HCC. Clin Cancer Res 16(3) 957–66
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2015
DOI: 10.1158/0008-5472.CAN-14-2394
Abstract: Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT–MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK–ERK signaling is critical for miR-424–mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT–MET axis. Cancer Res 75(9) 1908–21. ©2015 AACR.
Publisher: Elsevier BV
Date: 02-2019
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2018
DOI: 10.1158/0008-5472.CAN-18-0655
Abstract: The expression of miRNAs in cancer has been widely studied and has allowed the definition of oncomirs and oncosuppressors. We note that it is often underestimated that many mRNAs are expressed, but translationally silent. In spite of this, systematic identification of miRNAs in equilibrium with their target mRNAs on polysomes has not been widely exploited. To identify biologically active oncomirs, we performed a screen for miRNAs acting on the polysomes of malignant mesothelioma (MPM) cells. Only a small percentage of expressed miRNAs physically associated with polysomes. On polysomes, we identified miRNAs already characterized in MPM, as well as novel ones like miR-24-3p, which acted as a promigratory miRNA in all cancer cells tested. miR-24-3p positively regulated Rho-GTP activity, and inhibition of miR-24-3p reduced growth in MPM cells. Analysis of miR-24-3p common targets, in two mesothelioma cell lines, identified a common subset of downregulated genes. These same genes were downregulated during the progression of multiple cancer types. Among the specific targets of miR-24-3p was cingulin, a tight junction protein that inhibits Rho-GTP activity. Overexpression of miR-24-3p only partially abrogated cingulin mRNA, but completely abrogated cingulin protein, confirming its action via translational repression. We suggest that miR-24-3p is an oncomir and speculate that identification of polysome-associated miRNAs efficiently sorts out biologically active miRNAs from inactive ones. Significance: Subcellular localization of miRNAs may predict their role in cancer and identify novel oncogenic miRNAs involved in cancer progression. Graphical Abstract: ontent/canres/78/20/5741/F1.large.jpg. Cancer Res 78(20) 5741–53. ©2018 AACR.
Publisher: American Society of Hematology
Date: 16-06-2022
DOI: 10.1182/BLOODADVANCES.2022007998
Abstract: Chronic lymphocytic leukemia (CLL) is a quiescent B-cell malignancy that depends on transcriptional dysregulation for survival. The histone deacetylases are transcriptional regulators whose role within the regulatory chromatin and consequence on the CLL transcriptome is poorly characterized. Here, we profiled and integrated the genome wide occupancy of HDAC1, BRD4, H3K27Ac and H3K9Ac signals with chromatin accessibility, Pol2 occupancy and target expression signatures in CLL cells. We identified that when HDAC1 was recruited within super-enhancers marked by acetylated H3K27 and BRD4, it functioned as a transcriptional activator that drove the de novo expression of select genes to facilitate survival and progression in CLL. Targeting HDACs reduced BRD4 and Pol2 engagement to downregulate the transcript and proteins levels of specific oncogenic driver genes in CLL such as BLK, a key mediator of the B-cell receptor pathway, core transcription factors such as PAX5 and IKZF3 and the anti-apoptotic gene, BCL2. Concurrently, HDAC1, when recruited in the absence of super-enhancers repressed target gene expression. HDAC inhibition reversed silencing of a defined set of protein coding and noncoding RNA genes. We focused on a specific set of microRNA genes and show that their upregulation was inversely correlated with the expression of CLL specific survival, transcription factor and signaling genes. Our findings identify that the transcriptional activator and repressor functions of HDACs cooperate within the same tumor to establish the transcriptional dependencies essential for survival in CLL.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432112.V1
Abstract: Supplementary Figure from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 30-08-2022
DOI: 10.1158/0008-5472.CAN-22-0240
Abstract: Modified miRNAs may act as cancer biomarkers and function as allies or antagonists of their canonical counterparts in gene regulation, suggesting the concurrent consideration of canonical and modified miRNAs can boost patient stratification.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2021
DOI: 10.1038/S41597-021-00979-8
Abstract: MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at iredibase .
Publisher: American Association for Cancer Research (AACR)
Date: 12-2018
DOI: 10.1158/0008-5472.CAN-17-3878
Abstract: Cancer-associated cachexia is a significant problem for patients with cancer that remain poorly understood, understudied, and inadequately treated these findings report a potential new therapeutic for the treatment of TLR7-mediated cancer cachexia.
Publisher: Proceedings of the National Academy of Sciences
Date: 15-11-2010
Abstract: The overexpression of microRNA-21 (miR-21) is linked to a number of human tumors including colorectal cancer, where it appears to regulate the expression of tumor suppressor genes including p21, phosphatase and tensin homolog, TGFβ receptor II, and B-cell leukemia/lymphoma 2 -associated X protein. Here we demonstrate that miR-21 targets and down-regulates the core mismatch repair (MMR) recognition protein complex, human mutS homolog 2 (hMSH2) and 6 (hMSH6). Colorectal tumors that express a high level of miR-21 display reduced hMSH2 protein expression. Cells that overproduce miR-21 exhibit significantly reduced 5-fluorouracil (5-FU)-induced G2/M damage arrest and apoptosis that is characteristic of defects in the core MMR component. Moreover, xenograft studies demonstrate that miR-21 overexpression dramatically reduces the therapeutic efficacy of 5-FU. These studies suggest that the down-regulation of the MMR mutator gene associated with miR-21 overexpression may be an important clinical indicator of therapeutic efficacy in colorectal cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 03-08-2020
DOI: 10.1101/2020.08.03.232561
Abstract: HDAC1 is a key regulator of gene expression in cancer. We identified a critical role for HDAC1 in establishing the transcriptional dependencies essential for survival in chronic lymphocytic leukemia (CLL) by profiling HDAC1 with BRD4, H3K27Ac superenhancers, H4K9Ac, chromatin accessibility signatures, Pol2 measurements and expression signatures to generate a regulatory chromatin landscape. Superenhancers marked by high levels of acetylation and BRD4 paradoxically also recruited the highest levels of HDAC1. HDAC inhibition poisoned transcription at these loci to selectively disrupt B-cell transcription factors and B-cell receptor signaling. HDAC1 was also recruited genome-wide at promoters without superenhancers to repress expression HDAC inhibition induces these genes which include key microRNA networks that reciprocally downregulate CLL specific survival and driver genes. Our work provides a compelling rationale for profiling HDAC1 across cancers to characterize its role in driving the transcriptional dysregulation that is a hallmark of most cancers and develop epigenetic therapeutic strategies. Our work definitively establishes the composition of the regulatory chromatin that enables HDAC1 to function as an activator and repressor at distinct target genes within the same tumor to drive transcriptional dysregulation and allow the expression of B cell specific signaling and survival networks that are critical for survival.
Publisher: Informa UK Limited
Date: 18-01-2010
DOI: 10.3109/00016480903143978
Abstract: The results reported here provide the first evidence of the production of superoxide, a biologically relevant reactive oxygen species (ROS), in human inner ear perilymph (hIP) in pathological conditions, by the activity of the xanthine dehydrogenase/xanthine oxidase (XA/XO) enzyme system. To investigate the presence of ROS in hIP. Since damage and apoptosis of inner ear hair cells may occur as a result of ROS-mediated injury, we investigated the presence and production of ROS in 105 hIP s les 98 collected from patients affected by profound sensorineural hearing loss, during surgery for cochlear implantation, and 7 controls, collected from patients affected by otosclerosis, in case of spontaneous leakage after stapedotomy. ROS production was investigated by spectrophotometric analysis and polyacrylamide gel electrophoresis (SDS-PAGE). In hIP s les tested by cytochrome c reduction kinetics, the average superoxide production was 27.34 mumoles per mg of total protein, against 0.36 in controls. Some of these hIP s les, analyzed by cytochrome c reduction kinetics in the presence of xanthine, were found to be positive for ROS-producing XA/XO enzyme. These results were supported by SDS-PAGE analysis.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2011
DOI: 10.1200/JCO.2011.29.4_SUPPL.202
Abstract: 202 Background: The role of non-protein coding (nc)RNAs in cancer is unknown but emerging evidence suggests that deregulated expression of ncRNA may contribute to cancer pathogenesis. We sought to examine the role of ultraconserved ncRNA (ucRNA) that are 100% conserved across the human, rat and mouse genomes in hepatocellular cancers (HCC). Methods: Whole genome ucRNA expression profiling was performed using a custom microarray, and verified by real time PCR in cell lines and by in situ hybridization in a tissue microarray comprising of 221 human HCC, 72 non cirrhotic (NC) and 97 cirrhotic (C) liver tissues. ucRNA expression was manipulated with siRNA or plasmid-over-expressing ucRNA, and the effects on anchorage-dependent and independent growth, and cell cycle assessed using cell viability, soft agar assays and flow cytometry. Gene ontology analysis was performed by evaluating uc338-dependent changes on mRNA expression using Affymetrix chips. Results: 56 ucRNAs were aberrantly expressed with 33 increased and 23 decreased in HepG2 cells compared to non-malignant hepatocytes. The greatest change was observed with uc.338 (6.9-fold increase). uc.338 expression was significantly increased in several HCC cell lines. uc.338 expression was detected in 170 cases (77%) of HCC, with 62% of these showing a moderate to strong expression. Compared to non- malignant adjacent tissue, uc.338 expression was increased in 97/156 of HCC. The mean % of cells expressing uc.338 was 4% in NC liver, 15% in C and 24% in HCC. Inhibition of uc.338 reduced anchorage dependent and independent growth, and cell cycle progression in both human and murine malignant hepatocytes. Gene annotation enrichment analysis of mRNAs that were altered by inhibition of uc.338 expression identified the top over-represented GenMAPP pathways as: cell cycle, mRNA processing, RNA transcription, G1 to S cell cycle. Moreover, enforced expression of uc.338 increased cell growth in nonmalignant hepatocytes. Conclusions: These data showing that uc.338 is selectively overexpressed in HCC and promotes cell growth provides new insights into the role of RNA genes in HCC. No significant financial relationships to disclose.
Publisher: Elsevier BV
Date: 04-2014
Publisher: American Society of Hematology
Date: 10-01-2013
DOI: 10.1182/BLOOD-2012-09-457374
Abstract: T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.
Publisher: Impact Journals, LLC
Date: 14-12-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 29-03-2010
Abstract: Inactivation of mismatch repair (MMR) is the cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10–40% of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability [microsatellite instability (MSI)] are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer. Here we show that overexpression of miR-155 significantly down-regulates the core MMR proteins, hMSH2, hMSH6, and hMLH1, inducing a mutator phenotype and MSI. An inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer. Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432106.V1
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432097
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432100.V1
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: Springer Science and Business Media LLC
Date: 13-03-2017
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2019
DOI: 10.1158/1538-7445.SABCS18-P6-05-07
Abstract: BACKGROUND: Elucidating a more universal therapeutic target is key to effectively combat the heterogeneity of breast cancer (BrCa). MicroRNAs (miRs) are small noncoding RNAs that are an abundant class of endogenous regulatory molecules, which act by targeting mRNAs for cleavage and/or translational repression. Continuing studies into BrCa genetics show that the various subtypes of BrCa are also affected by miR activity from the regulation of various cancer-related genes. MiR expression can even influence drug response in multiple cancer types. This prompted our investigation into the nuances of how miRs may influence BrCa behavior and response to treatment with targeted therapies. The Polo-like Kinase 1 (PLK1) enzyme plays an important role in the cell cycle, and is considered to be a proto-oncogene. Inhibiting PLK1 in has shown promise in reducing tumor volume and promoting tumor cell death in various cancers. Understanding how miRs regulate PLK1 in BrCa will improve our understanding of the PLK1 pathway, and whether this miR-directed regulation affects anti-PLK1 therapy. This knowledge could inform future anti-PLK1 BrCa treatment regimens, resulting in better outcomes for patients. METHODS: The effects of an anti-PLK1 drug, NMS-P937, were tested on triple-negative (TN) (MDA-MB-231, BT549) and luminal (ZR-75-1, CAMA-1) BrCa cell lines. From miRNA target prediction sites (TargetScan, MiRTarBase), a panel of miRs predicted to bind to PLK1 was selected and then assessed using dual-reporter luciferase assays. MiR expression was transiently induced in TN and luminal BrCa cell lines, and the effects were verified using western blotting. Apoptosis was assessed by Annexin V staining in BrCa cell lines transiently transfected with the validated miR and treated with different concentration of NMS-P937 for 48 hrs. To validate the contribution of the miR-PLK1 axis for NMS-P937-induced apoptosis, BrCa cells were transfected with PLK1 siRNA, and the Annexin V staining experiment was repeated. RESULTS: From the panel of miRs tested, miR-183-5p was the only one to demonstrate binding to the PLK1 gene. Western blotting showed that PLK1 expression was downregulated when miR-183-5p is overexpressed. Annexin V staining suggests that miR-183-5p induces apoptosis through PLK1 targeting in BrCa cell lines, and this effect seems to lify NMS-P937-induced apoptosis in both cell line subtypes. Apoptotic markers assessed by western blot confirm the over-activation of apoptotic signals by miR-183-5p. Future work will continue to focus on determining the effects of miR-183-5p targeting on pathways downstream of PLK1, and utilizing tumor xenografts to elucidate the effects of miR-183-5p on NMS-P937 response in an in-vivo model. CONCLUSIONS: MiR-183-5p appears to directly target PLK1 and reduce its level of expression. Additionally, miR-183-5p increases the number of apoptotic BrCa cells when used in combination with NMS-P937, and it is the inhibition of PLK1 specifically that contributes to the increase in the apoptosis of BrCa cells treated with NMS-P937. Taken together, our findings identify a new mechanism of PLK1 modulation through miR. Our next steps will focus on studying these modulatory effects in vivo, in an effort to move forward for clinical applications. Citation Format: Zalles N, Gasparini P, Croce CM. The effects of microRNA modulation of polo-like kinase 1 in breast cancer cell lines [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium 2018 Dec 4-8 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2019 (4 Suppl):Abstract nr P6-05-07.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-05-2020
Abstract: The loss of miR-15a/16-1 on chromosome 13q14 and miR-15b/16-2 on chromosome 3q25 is critical for the development of AML in mice. We hypothesized that, at least, a fraction of human AML patients could undergo a comparable mechanism. Here, we evaluated the expression of the two miR-15/16 clusters in 93 MDS patients and 139 AML patients. A significant reduction of miR-15a, miR-15b, and miR-16 expression can predict the progression from MDS to AML transformation. We demonstrated in 40% of AML cell lines analyzed, a combined reduction of miR-15a/-15b expression and an overexpression of their direct/indirect targets. MiR-15/16 cluster expression can be a valuable marker to stratify AML patients for a combined therapy, based on venetoclax and anti-ROR1 antibody.
Publisher: Public Library of Science (PLoS)
Date: 06-02-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 10-03-2014
Abstract: Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability and development of cancer. DNA double-strand breaks are lesions induced by ionizing radiation (IR) and can be efficiently repaired by DNA homologous recombination, a system that requires RAD51 recombinase (RAD51). Here we show that overexpression of miR-155 in human breast cancer cells reduces the levels of RAD51 and affects the cellular response to IR. High miR-155 levels were associated with lower RAD51 expression and with better overall survival of patients in a large series of triple-negative breast cancers. Testing triple-negative breast cancer patients for miR-155 expression may be a useful prognostic tool to identify who will benefit from an IR-based therapeutic approach.
Publisher: Elsevier BV
Date: 03-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432121
Abstract: Supplementary Data from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: No publisher found
Date: 2011
Publisher: Public Library of Science (PLoS)
Date: 05-02-2014
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2011
DOI: 10.1200/JCO.2011.29.4_SUPPL.431
Abstract: 431 Background: MicroRNAs are small non coding RNAs controlling cell homeostasis. Defects in mismatch repair (MMR) genes cause resistance to 5-fluorouracil (5FU). miR-21 is up-regulated in colorectal cancer (CRC) and is associated with poor benefit from adjuvant 5FU. We aimed at studying if miR-21 may induce 5FU resistance by down-regulating MSH2. Methods: Fresh frozen (32) and paraffin-embedded (50) cases of CRC and matched normal tissues were studied for miR-21 expression (Northern Blotting and in situ Hybridization) and MSH2 expression (Western Blotting and Immunohistochemistry). CRC Colo-320DM, SW620 and isogenic Lovo cells with [Lovo(MSH2+)] and without MSH2 [Lovo(MSH2-)] were used. Pre-miR-21 was used for over-expression experiments. Luciferase vectors with MSH2 (Luc-MSH2) and MSH6 (Luc-MSH6) 3'UTRs downstream of the Luciferase gene were used. Cell cycle modifications after 5FU (10uM) were assessed by FACS analysis. Lentiviral vectors encoding for miR-21 or siRNA to MSH2 or empty vectors were used for stable infection. Stable clones were injected in the flank of nude mice. Mice were treated with 5FU i.p. for 2 weeks. Tumor volume was measured once a week and calculated according to the formula Volume=LxW 2 /2. Results: A statistically significant inverse correlation between miR-21 and MSH2 expression was observed by Parson's test in the two CRC cohorts. miR-21 over-expression caused reduction in MSH2 and MSH6 protein expression and in Luciferase activity after transfection with Luc-MSH2 or Luc-MSH6 vectors confirming that miR-21 directly regulates MSH2 and MSH6. miR-21 up-regulation reduced 5FU induced apoptosis and G2/M arrest at the same extent of siRNA to MSH2 in all MMR proficient cells while no significant effect was observed in Lovo(MSH2-). Complementation experiments with plasmid encoding for MSH2 promoted 5FU induced apoptosis that was inhibited by co-transfection with miR-21. Xenograft tumors over-expressing miR-21 or siRNA anti MSH2 achieved the same response to 5FU and both showed to be less responsive to 5FU than controls. Conclusions: miR-21 causes resistance to 5FU in a MSH2 dependent manner and might be a useful marker in predicting therapeutic outcome in CRC patients. No significant financial relationships to disclose.
Publisher: Public Library of Science (PLoS)
Date: 19-03-2013
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2012
DOI: 10.1200/JCO.2012.30.4_SUPPL.457
Abstract: 457 Background: MicroRNAs (miRs) are small non coding RNAs involved in cell homeostasis. miRs are deregulated in colorectal cancer (CRC). Our study aimed at identifying miRs with a driver role in carcinogenesis altered by similar mechanisms in both human and mouse CRC. Goal of the study was to use CRC mouse models for the pre-clinical development of anti-miRs as therapeutic drugs. Methods: Azoximetane (AOM)/Dextran-Sulfate (DSS) treated mice or CDX2-CRE/APC -/- mice were used to study inflammation-associated and sporadic APC-related CRC. Human Inflammatory Bowel Disease associated (n=30), and sporadic (n=90) CRC with their matched normal tissues were collected according to Good Clinical Practice recommendation and subjected to RNA extraction using Trizol. miR and gene expression profiling was assessed by nCounter technology (Nanostring Seattle). Anti-miR-135b and scrambled probes for in vivo studies were synthesized by Girindus. Results: miRs profiling from AOM/DSS and CDX2-CRE/APC -/- CRC. revealed that miR-135b is one of the most up-regulated miRs in both models. In humans miR-135b over-expression was found in both IBD and sporadic CRC and was associated with reduced Progression Free Survival and Overall Survival in CRC patients. Molecular studies in Mouse Embryo Fibroblast and human CRC cell lines highlighted the role of two major pathways in the upstream activation of miR-135b: APC-β-Catenin and SRC-PI3K. MiR-135b up-regulation resulted in reduced apoptosis and increased invasion and metastasis due to the down-regulation of TGFRB2, DAPK1, APC and HIF1AN. Silencing of miR-135b in vivo reduced tumor multiplicity and tumor load in the AOM/DSS CRC model. Mice treated with anti-miR-135b showed well differentiated tumors and microacinar pattern while tumors in the control groups showed low differentiation and adenomatous pattern. Conclusions: Our data suggest that miR-135b is a key molecule whose activation is downstream of oncogenes and oncosuppressor genes frequently altered in CRC. Our study defines specific pathways that converge on the activation of the same microrna. The “in vivo” silencing of miR-135 shows preclinical efficacy with low toxicity and represents the first in vivo study for the use of antimiRs in CRC treatment.
Publisher: Elsevier BV
Date: 02-2013
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432103.V1
Abstract: Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2017
DOI: 10.1158/0008-5472.CAN-16-2984
Abstract: Despite the development of combined modality treatments against liposarcoma in recent years, a significant proportion of patients respond only modestly to such approaches, possibly contributing to local or distant recurrence. Early detection of recurrent or metastatic disease could improve patient prognosis by triggering earlier clinical intervention. However, useful biomarkers for such purposes are lacking. Using both patient plasma s les and cell lines, we demonstrate here that miR-25-3p and miR-92a-3p are secreted by liposarcoma cells through extracellular vesicles and may be useful as potential biomarkers of disease. Both miR-25-3p and miR-92a-3p stimulated secretion of proinflammatory cytokine IL6 from tumor-associated macrophages in a TLR7/8-dependent manner, which in turn promoted liposarcoma cell proliferation, invasion, and metastasis via this interaction with the surrounding microenvironment. Our findings provide novel and previously unreported insight into liposarcoma progression, identifying communication between liposarcoma cells and their microenvironment as a process critically involved in liposarcoma progression. This study establishes the possibility that the pattern of circulating miRNAs may identify recurrence prior to radiological detectability while providing insight into disease outcome and as a possible approach to monitor treatment efficacy. Cancer Res 77(14) 3846–56. ©2017 AACR.
Publisher: Springer Science and Business Media LLC
Date: 24-09-2021
DOI: 10.1038/S41418-021-00864-2
Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that act as endogenous regulatory molecules targeting specific mRNAs for translational repression. Studies of breast cancer genomics indicate that breast cancer subtypes are distinguished and regulated by specific sets of miRNAs which affect activities such as tumor initiation, progression, and even drug response. Polo-like Kinase 1 (PLK1) is widely considered to be a proto-oncogene due to its increased expression in multiple tumor types, as well as its crucial role in regulating mitosis. Pharmacological inhibition of PLK1 can reduce tumor volume and induce tumor cell death in solid and hematologic malignancies. This prompted us to investigate how PLK1 inhibition with the target-specific inhibitor NMS-P937 would impact breast cancer cells, and how miRNAs may influence the overall response of these cells to this inhibition. We found that miR-183-5p targets PLK1 gene, effectively reducing its protein expression. Such miRNA-driven regulation of PLK1 expression sensitizes breast cancer cells to NMS-P937, resulting in synergistically increased apoptosis. We also show that the miRNA-regulated reduction of PLK1 influences the expression of apoptosis-related key proteins and possibly inducing further indirect PLK1 downmodulation through a DNMT1-p53 axis. These results suggest a potential biologically significant link between the expression of miR-183-5p and the efficacy of PLK1-specific inhibitors in breast cancer cells. Our work further elucidates how miR-183-5p regulates PLK1 gene while also enhancing NMS-P937 effect in breast cancer. Future studies assessing the role of miR-183-5p as a novel biomarker for anti-PLK1 chemotherapy agents are warranted.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2021
DOI: 10.1038/S41418-021-00820-0
Abstract: Junctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) ( n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC ( n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432118
Abstract: Supplementary Figure from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432118.V1
Abstract: Supplementary Figure from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: Oxford University Press (OUP)
Date: 07-10-2012
DOI: 10.1093/BIOINFORMATICS/BTS589
Abstract: Motivation: A-to-I RNA editing is an important mechanism that consists of the conversion of specific adenosines into inosines in RNA molecules. Its dysregulation has been associated to several human diseases including cancer. Recent work has demonstrated a role for A-to-I editing in microRNA (miRNA)-mediated gene expression regulation. In fact, edited forms of mature miRNAs can target sets of genes that differ from the targets of their unedited forms. The specific deamination of mRNAs can generate novel binding sites in addition to potentially altering existing ones. Results: This work presents miR-EdiTar, a database of predicted A-to-I edited miRNA binding sites. The database contains predicted miRNA binding sites that could be affected by A-to-I editing and sites that could become miRNA binding sites as a result of A-to-I editing. Availability: miR-EdiTar is freely available online at ireditar. Contact: alessandro.lagana@osumc.edu or carlo.croce@osumc.edu Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Rockefeller University Press
Date: 22-04-2013
DOI: 10.1084/JEM.20120950
Abstract: Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCL-targeting aptamers for the modulation of miRNA expression in the treatment of breast cancer.
Publisher: Proceedings of the National Academy of Sciences
Date: 27-02-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432112
Abstract: Supplementary Figure from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: Proceedings of the National Academy of Sciences
Date: 31-08-2015
Abstract: The role of the microRNA (miR) 15/16 family in oncogenesis and tumor progression has been intensively studied. The miR-15a/16-1 cluster is extensively described in B-cell chronic lymphocytic leukemia, characterized by the deletion of the 13q14 locus. The role of the miR-15b/16-2 cluster on chromosome 3q25 is still far from being elucidated. Because miR-15a is highly similar to miR-15b and miR-16-1 is identical to miR-16-2, we generated miR-15b/16-2 knockout mice to better understand the cluster’s role in vivo. These knockout mice developed B-cell lymphomas by age 15–18 mo, modulating the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. Our results suggest a tumor suppressor role for the miR-15b/16-2 cluster in animal models of B-cell lymphomas.
Publisher: Elsevier BV
Date: 2009
Publisher: Oxford University Press (OUP)
Date: 27-10-2014
DOI: 10.1093/JNCI/DJU373
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432115
Abstract: Supplementary Figure from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Publisher: Proceedings of the National Academy of Sciences
Date: 26-11-2018
Abstract: The loss miR-15a/16-1 cluster at chromosome 13q14 is critical for the development of chronic lymphocytic leukemia (CLL), both in humans and mice. Knockout mice for a homologous locus on chromosome 3, miR-15b/16-2, developed mainly CLL and less frequently diffuse large B cell lymphoma. Here, we studied the biological role of these two different miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout mice. Unexpectedly, the complete deletion of both clusters promoted myeloproliferative disorders in the majority of the mice by the age of 5 months, modulating the expression of Cyclin D1, Cyclin D2, and Bcl-2, well-known targets of these microRNA clusters. Our findings in mouse suggest that a fraction of AML could be caused the by the loss of miR-15/16 clusters.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6514064.V1
Abstract: Abstract Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modification types, including A-to-I miRNA editing and shifted miRNA isoforms, in ,000 adult and pediatric tumor s les across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments data sets. The differences between canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint were investigated. The combination of canonical miRNAs and modified miRNAs boosted the quality of clustering results, outlining unique clinicopathologic features among cohorts. Certain modified miRNAs showed opposite expression from their canonical counterparts in cancer, potentially impacting their targets and function. Finally, a shifted and edited miRNA isoform was experimentally validated to directly bind and suppress a unique target. These findings outline the importance of going beyond the well-established paradigm of one mature miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression. Significance: Modified miRNAs may act as cancer biomarkers and function as allies or antagonists of their canonical counterparts in gene regulation, suggesting the concurrent consideration of canonical and modified miRNAs can boost patient stratification. /
Publisher: Elsevier BV
Date: 02-2013
Publisher: Springer Science and Business Media LLC
Date: 27-06-2011
DOI: 10.1038/ONC.2011.260
Publisher: Proceedings of the National Academy of Sciences
Date: 28-05-2013
Abstract: Toll-like receptor 3 (TLR3) is a key effector of the innate immune system against viruses. Activation of TLR3 exerts an antitumoral effect through a mechanism of action still poorly understood. Here we show that TLR3 activation by polyinosinic:polycytidylic acid induces up-regulation of microRNA-29b, -29c, -148b, and -152 in tumor-derived cell lines and primary tumors. In turn, these microRNAs induce reexpression of epigenetically silenced genes by targeting DNA methyltransferases. In DU145 and TRAMP-C1 prostate and MDA-MB-231 breast cancer cells, we demonstrated that polyinosinic:polycytidylic acid-mediated activation of TLR3 induces microRNAs targeting DNA methyltransferases, leading to demethylation and reexpression of the oncosuppressor retinoic acid receptor beta (RARβ). As a result, cancer cells become sensitive to retinoic acid and undergo apoptosis both in vitro and in vivo. This study provides evidence of an antitumoral mechanism of action upon TLR3 activation and the biological rationale for a combined TLR3 agonist/retinoic acid treatment of prostate and breast cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432121.V1
Abstract: Supplementary Data from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
No related grants have been discovered for Pierluigi Gasparini.