Publications by authors named "Ramona Palombo"

8 Publications

  • Page 1 of 1

Exercise-mediated downregulation of MALAT1 expression and implications in primary and secondary cancer prevention.

Free Radic Biol Med 2020 11 5;160:28-39. Epub 2020 Aug 5.

Unit of Biology and Genetics of Movement, Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis 15, 00135, Rome, Italy. Electronic address:

Long non-coding RNAs (lncRNAs) play critical roles in various biological functions and disease processes including cancer. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was initially identified as a lncRNA with elevated expression in primary human non-small cell lung tumors with high propensity to metastasize, and subsequently shown to be highly expressed in numerous other human cancers including breast, ovarian, prostate, cervical, endometrial, gastric, pancreatic, sarcoma, colorectal, bladder, brain, multiple myeloma, and lymphoma. MALAT1 is deeply involved in several physiological processes, including alternative splicing, epigenetic modification of gene expression, cellular senescence, healthy aging, and redox homeostasis. The aim of this work was to investigate the modulation exerted by a single bout of endurance exercise on the level of MALAT1 expression in peripheral blood mononuclear cells (PBMCs) from healthy male donors displaying different training status and redox homeostasis features. Our findings show that MALAT1 is downregulated after acute endurance exercise in subjects whose fitness level guarantee a high expression of SOD1 and SOD2 antioxidant genes and low levels of endogenous oxidative damage. In vitro protocols in Jurkat lymphoblastoid cells exposed to pro-oxidant environment confirmed the link between MALAT1 expression and antioxidant gene modulation, documenting p53 phosphorylation and its recruitment to MALAT1 promoter. Remarkably, analyses of Microarray-Based Gene Expression Profiling revealed high MALAT1 expression in leukemia patients in comparison to healthy control and a significant negative correlation between MALAT1 and SOD1 expression. Collectively our results highlight the beneficial effect of a physically active lifestyle in counteracting aberrant cancer-related gene expression programs by improving the redox buffering capacity.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.06.037DOI Listing
November 2020

Emerging Contribution of PancRNAs in Cancer.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Laboratory of Cellular and Molecular Neurobiology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.

"Cancer" includes a heterogeneous group of diseases characterized by abnormal growth beyond natural boundaries. Neoplastic transformation of cells is orchestrated by multiple molecular players, including oncogenic transcription factors, epigenetic modifiers, RNA binding proteins, and coding and noncoding transcripts. The use of computational methods for global and quantitative analysis of RNA processing regulation provides new insights into the genomic and epigenomic features of the cancer transcriptome. In particular, noncoding RNAs are emerging as key molecular players in oncogenesis. Among them, the promoter-associated noncoding RNAs (pancRNAs) are noncoding transcripts acting in to regulate their host genes, including tumor suppressors and oncogenes. In this review, we will illustrate the role played by pancRNAs in cancer biology and will discuss the latest findings that connect pancRNAs with cancer risk and progression. The molecular mechanisms involved in the function of pancRNAs may open the path to novel therapeutic opportunities, thus expanding the repertoire of targets to be tested as anticancer agents in the near future.
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http://dx.doi.org/10.3390/cancers12082035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464463PMC
July 2020

Poison-Exon Inclusion in DHX9 Reduces Its Expression and Sensitizes Ewing Sarcoma Cells to Chemotherapeutic Treatment.

Cells 2020 01 31;9(2). Epub 2020 Jan 31.

Laboratory of Cellular and Molecular Neurobiology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.

Alternative splicing is a combinatorial mechanism by which exons are joined to produce multiple mRNA variants, thus expanding the coding potential and plasticity of eukaryotic genomes. Defects in alternative splicing regulation are associated with several human diseases, including cancer. Ewing sarcoma is an aggressive tumor of bone and soft tissue, mainly affecting adolescents and young adults. DHX9 is a key player in Ewing sarcoma malignancy, and its expression correlates with worse prognosis in patients. In this study, by screening a library of siRNAs, we have identified splicing factors that regulate the alternative inclusion of a poison exon in mRNA, leading to its downregulation. In particular, we found that hnRNPM and SRSF3 bind in vivo to this poison exon and suppress its inclusion. Notably, DHX9 expression correlates with that of SRSF3 and hnRNPM in Ewing sarcoma patients. Furthermore, downregulation of SRSF3 or hnRNPM inhibited DHX9 expression and Ewing sarcoma cell proliferation, while sensitizing cells to chemotherapeutic treatment. Hence, our study suggests that inhibition of hnRNPM and SRSF3 expression or activity could be exploited as a therapeutic tool to enhance the efficacy of chemotherapy in Ewing sarcoma.
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http://dx.doi.org/10.3390/cells9020328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072589PMC
January 2020

Small molecule inhibition of Ewing sarcoma cell growth via targeting the long non coding RNA HULC.

Cancer Lett 2020 01 19;469:111-123. Epub 2019 Oct 19.

Laboratory of Molecular and Cellular Neurobiology, IRCCS Santa Lucia Foundation, Rome, 00143, Italy; Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 6, 00135, Rome, Italy. Electronic address:

Ewing sarcomas (ES) are aggressive pediatric cancers of bone and soft tissues characterized by in frame chromosomal translocations giving rise to chimeric transcription factors, such as EWS-FLI1. An emerging strategy to block EWS-FLI1 activity is represented by the small molecule YK-4-279, which binds to EWS-FLI1 and alters its transcriptional activity. The specific effectors of the anti-oncogenic activity of YK-4-279 are still largely unknown. Herein, by performing a high-throughput screening we identify the lncRNA HULC (Highly Upregulated in Liver Cancer) as a prominent target of YK-4-279 activity in ES cells. High levels of HULC correlate with ES aggressiveness, whereas HULC depletion reduces ES cell growth. Mechanistically, we find that HULC promotes the expression of TWIST1 oncogene by sponging miR-186. Downregulation of HULC upon treatment with YK-4-279 reduces the expression of TWIST1 by unleashing miR-186 and favoring its binding to TWIST1 transcripts. Notably, high levels of miR-186 and low levels of TWIST1 correlate with better prognosis in ES patients. Our results disclose a novel oncogenic regulatory circuit mediated by HULC lncRNA that is disrupted by the small molecule YK-4-279, with promising therapeutic implications for ES treatment.
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http://dx.doi.org/10.1016/j.canlet.2019.10.026DOI Listing
January 2020

Luteolin-7--β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes.

Int J Mol Sci 2019 May 31;20(11). Epub 2019 May 31.

Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy.

Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others. Recently, it has been demonstrated that luteolin, in the form of Luteolin-7--β-d-glucoside (LUT-7G) is able to induce the keratinocyte differentiation process in vitro. This flavonoid is able to counteract the proliferative effects of IL-22/IL6 pathway by the inhibition of STAT3 activity also in vivo in a psoriatic mouse model. Observations on energy metabolism changes of differentiating cells led us to perform a complete metabolomics analysis using human primary keratinocytes treated with LUT-7G. Our results show that LUT-7G, is not only able to impair the nuclear translocation of STAT3, but it also blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity. These data confirm that LUT-7G can be proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, but its role as a hexokinase 2 (HEK2) inhibitor opens new perspectives in nutritional science, and especially in cancer therapy, in which the inhibition of the Warburg effect could be relevant.
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http://dx.doi.org/10.3390/ijms20112689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600217PMC
May 2019

The Promoter-Associated Noncoding RNA Assembles a Protein-RNA Complex to Regulate Cyclin D1 Transcription in Ewing Sarcoma.

Cancer Res 2019 07 9;79(14):3570-3582. Epub 2019 May 9.

Laboratory of Cellular and Molecular Neurobiology, Fondazione Santa Lucia, Via del Fosso di Fiorano, Rome, Italy.

Most Ewing sarcomas are characterized by the in-frame chromosomal translocation t(11;22) generating the EWS-FLI1 oncogene. EWS-FLI1 protein interacts with the RNA helicase DHX9 and affects transcription and processing of genes involved in neoplastic transformation, including (the cyclin D1 gene), which contributes to cell-cycle dysregulation in cancer. In this study, we found that expression is significantly higher in patients with Ewing sarcoma compared with other sarcomas and that the RNA, a previously uncharacterized promoter-associated noncoding (pnc) transcript, is expressed in Ewing sarcoma cells. interacted with the RNA-binding protein Sam68 and repressed expression. Notably, knockdown of Sam68 affected subcellular localization and cyclin D1 expression. Pharmacologic impairment of DHX9/EWS-FLI1 interaction promoted RNA-dependent association of Sam68 with DHX9 and recruitment of Sam68 to the promoter, thus repressing it. Conversely, mitogenic stimulation of Ewing sarcoma cells with IGF1 impaired Sam68/DHX9 interaction and positively regulated expression. These studies uncover a fine-tuned modulation of the proto-oncogene in Ewing sarcoma cells via alternative complexes formed by DHX9 with either EWS-FLI1 or -Sam68. SIGNIFICANCE: A pncRNA-based mechanism represses expression of through the formation of a protein-RNA complex and provides new therapeutic opportunities for patients with Ewing sarcoma. http://cancerres.aacrjournals.org/content/canres/79/14/3570/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2403DOI Listing
July 2019

OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development.

Aging (Albany NY) 2015 Nov;7(11):928-36

Biochemistry Laboratory, IDI-IRCCS-FLMM, c/o Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00133 Rome, Italy.

OTX proteins, homologs of the Drosophila orthodenticle (Otd), are important for the morphogenesis of the neuroectoderm, and for the central nervous system formation. OTX1 and OTX2 are important for the cochlea and macula development, indeed when OTX1 is knocked down, these organs undergo developmental failure. Moreover OTX2 transfection revert this effect in OTX1(-/-) mice. The TA isoform of TP63, involved in Notch regulation pathway, has a critical function in the cochlear neuroepithelium differentiation. TAp63 positively regulates Hes5 and Atoh1 transcription. This pathway has been also demonstrated in p63(-/-) mice, and in patients p63 mutated, affected by Ectodermal Dysplasia (ED, OMIM 129810). These patients are affected by mild sensorineural deafness, most likely related to the mutation in p63 gene impairing the Notch pathway. We demonstrated the role of OTX2 on TAp63 regulation necessary for the correct formation of macular neuroepithelium and we confirmed the impairment of vestibular function caused by p63 mutations. Although the abnormalities found in our patient were still at a subclinical extent, aging could exacerbate this impairment and cause a decrease in quality of life.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694063PMC
http://dx.doi.org/10.18632/aging.100839DOI Listing
November 2015