Publications by authors named "Alberto Izzotti"

146 Publications

Prevention of Covid-19 Infection and Related Complications by Ozonized Oils.

J Pers Med 2021 Mar 22;11(3). Epub 2021 Mar 22.

Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.

Background: The COVID-19 pandemic continues to ravage the human population; therefore, multiple prevention and intervention protocols are being rapidly developed. The aim of our study was to develop a new chemo-prophylactic/-therapeutic strategy that effectively prevents COVID-19 and related complications.

Methods: In in vitro studies, COVID-19 infection-sensitive cells were incubated with human oropharyngeal fluids containing high SARS-CoV-2 loads. Levels of infection were determined via intra-cellular virus loads using quantitative PCR (qPCR). Efficacies for infection prevention were determined using several antiviral treatments: lipid-encapsulated ozonized oil (HOO), water-soluble HOO (HOOws), UV, and hydrogen peroxide. In in vivo studies, safety and efficacy of HOO in fighting COVID-19 infection was evaluated in human subjects.

Results: HOO in combination with HOOws was the only treatment able to fully neutralize SARS-CoV-2 as well as its capacity to penetrate and reproduce inside sensitive cells. Accordingly, the feasibility of using HOO/HOOws was tested in vivo. Analysis of expired gas in healthy subjects indicates that HOO administration increases oxygen availability in the lung. For our human studies, HOO/HOOws was administered to 52 cancer patients and 21 healthy subjects at high risk for COVID-19 infection, and all of them showed clinical safety. None of them developed COVID-19 infection, although an incidence of at least 11 cases was expected. Efficacy of HOO/HOOws was tested in four COVID-19 patients obtaining recovery and qPCR negativization in less than 10 days.

Conclusions: Based on our experience, the HOO/HOOws treatment can be administered at standard doses (three pills per day) for chemo-prophylactic purposes to healthy subjects for COVID-19 prevention and at high doses (up to eight pills per day) for therapeutic purposes to infected patients. This combined prevention strategy can provide a novel protocol to fight the COVID-19 pandemic.
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http://dx.doi.org/10.3390/jpm11030226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004285PMC
March 2021

Relationship between the miRNA Profiles and Oncogene Mutations in Non-Smoker Lung Cancer. Relevance for Lung Cancer Personalized Screenings and Treatments.

J Pers Med 2021 Mar 5;11(3). Epub 2021 Mar 5.

Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy.

Oncogene mutations may be drivers of the carcinogenesis process. MicroRNA (miRNA) alterations may be adaptive or pathogenic and can have consequences only when mutation in the controlled oncogenes occurs. The aim of this research was to analyze the interplay between miRNA expression and oncogene mutation. A total of 2549 miRNAs were analyzed in cancer tissue-in surrounding normal lung tissue collected from 64 non-smoking patients and in blood plasma. Mutations in 92 hotspots of 22 oncogenes were tested in the lung cancer tissue. MicroRNA alterations were related to the mutations occurring in cancer patients. Conversely, the frequency of mutation occurrence was variable and spanned from the k-ras and p53 mutation detected in 30% of patients to 20% of patients in which no mutation was detected. The prediction of survival at a 3-year follow up did not occur for mutation analysis but was, conversely, well evident for miRNA analysis highlighting a pattern of miRNA distinguishing between survivors and death in patients 3 years before this clinical onset. A signature of six lung cancer specific miRNAs occurring both in the lungs and blood was identified. The obtained results provide evidence that the analysis of both miRNA and oncogene mutations was more informative than the oncogene mutation analysis currently performed in clinical practice.
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http://dx.doi.org/10.3390/jpm11030182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999775PMC
March 2021

Pro-Environmental Behaviors: Determinants and Obstacles among Italian University Students.

Int J Environ Res Public Health 2021 Mar 23;18(6). Epub 2021 Mar 23.

Department of Medical, Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Catania University, Via Santa Sofia 87, 95123 Catania, Italy.

The awareness of citizens concerning the health risks caused by environmental pollution is growing, but studies on determinants of pro-environmental behaviors have rarely examined health-related aspects. In this study, we investigated these determinants using data from a large survey among Italian university students (15 Universities: 4778 filled questionnaires). Besides the health-related aspects, represented by environmental health risk perception and functional health literacy, we considered social and demographic characteristics (gender, area of residence, sources of information, trust in institutional and non-institutional subjects, and students' capacity of positive actions, indicated as internal locus of control). The attitudes towards pro-environmental behaviors were positive for more than 70% of students and positively related with health risk perception, internal locus of control, and health literacy. The correspondence between the positive attitudes towards pro-environmental behaviors and the real adoption of such behaviors was approximately 20% for most behaviors, except for the separate collection of waste (60%). Such a discrepancy can be attributable to external obstacles (i.e., lack of time, costs, lack of support). The health-related aspects were linked to the pro-environmental attitudes, but to a lesser extent to pro-environmental behaviors, owing to the complexity of their determinants. However, they should be taken in account in planning education interventions.
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http://dx.doi.org/10.3390/ijerph18063306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004768PMC
March 2021

Precision Medicine and Public Health: New Challenges for Effective and Sustainable Health.

J Pers Med 2021 Feb 16;11(2). Epub 2021 Feb 16.

Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.

The development of high-throughput omics technologies represents an unmissable opportunity for evidence-based prevention of adverse effects on human health. However, the applicability and access to multi-omics tests are limited. In Italy, this is due to the rapid increase of knowledge and the high levels of skill and economic investment initially necessary. The fields of human genetics and public health have highlighted the relevance of an implementation strategy at a national level in Italy, including integration in sanitary regulations and governance instruments. In this review, the emerging field of public health genomics is discussed, including the polygenic scores approach, epigenetic modulation, nutrigenomics, and microbiomes implications. Moreover, the Italian state of implementation is presented. The omics sciences have important implications for the prevention of both communicable and noncommunicable diseases, especially because they can be used to assess the health status during the whole course of life. An effective population health gain is possible if omics tools are implemented for each person after a preliminary assessment of effectiveness in the medium to long term.
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http://dx.doi.org/10.3390/jpm11020135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920275PMC
February 2021

Potential Role of miRNAs in the Acquisition of Chemoresistance in Neuroblastoma.

J Pers Med 2021 Feb 7;11(2). Epub 2021 Feb 7.

Department of Experimental Medicine, University of Genova, 16100 Genova, Italy.

Neuroblastoma (NB) accounts for about 8-10% of pediatric cancers, and the main causes of death are the presence of metastases and the acquisition of chemoresistance. Metastatic NB is characterized by amplification that correlates with changes in the expression of miRNAs, which are small non-coding RNA sequences, playing a crucial role in NB development and chemoresistance. In the present study, miRNA expression was analyzed in two human -amplified NB cell lines, one sensitive (HTLA-230) and one resistant to Etoposide (ER-HTLA), by microarray and RT-qPCR techniques. These analyses showed that miRNA-15a, -16-1, -19b, -218, and -338 were down-regulated in ER-HTLA cells. In order to validate the presence of this down-regulation in vivo, the expression of these miRNAs was analyzed in primary tumors, metastases, and bone marrow of therapy responder and non-responder pediatric patients. Principal component analysis data showed that the expression of miRNA-19b, -218, and -338 influenced metastases, and that the expression levels of all miRNAs analyzed were higher in therapy responders in respect to non-responders. Collectively, these findings suggest that these miRNAs might be involved in the regulation of the drug response, and could be employed for therapeutic purposes.
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http://dx.doi.org/10.3390/jpm11020107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916079PMC
February 2021

Common aspects between glaucoma and brain neurodegeneration.

Mutat Res 2020 Oct - Dec;786:108323. Epub 2020 Aug 13.

IRCCS Policlinico San Martino, Genoa, Italy; Department of Experimental Medicine, University of Genoa, Genoa, Italy.

Neurodegeneration can be defined as progressive cell damage to nervous system cells, and more specifically to neurons, which involves morphologic alterations and progressive loss of function until cell death. Glaucoma exhibits many aspects of neurodegenerative disease. This review examines the pathogenesis of glaucoma, comparing it with that of Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting their common features. Indeed, in all three diseases there are not only the same types of pathogenic events, but also similarities of temporal cadences that determine neuronal damage. All three age-related illnesses have oxidative damage and mitochondrial dysfunction as the first pathogenic steps. The consequence of these alterations is the death of visual neurons in glaucoma, cognitive neurons in AD and regulatory motor neurons (substantia nigra) in PD. The study of these common pathogenic events (oxidative stress, mitochondrial dysfunction, protein degradation, apoptosis and autophagy) leads us to consider common therapeutic strategies for the treatment and prevention of these diseases. Also, examination of the genetic aspects of the pathways involved in neurodegenerative processes plays a key role in shedding light on the details of pathogenesis and can suggest new treatments. This review discusses the common molecular aspects involved in these three oxidative-stress and age-related diseases.
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http://dx.doi.org/10.1016/j.mrrev.2020.108323DOI Listing
February 2021

A 3D Model of Human Trabecular Meshwork for the Research Study of Glaucoma.

Front Neurol 2020 1;11:591776. Epub 2020 Dec 1.

Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.

Glaucoma is a multifactorial syndrome in which the development of pro-apoptotic signals are the causes for retinal ganglion cell (RGC) loss. Most of the research progress in the glaucoma field have been based on experimentally inducible glaucoma animal models, which provided results about RGC loss after either the crash of the optic nerve or IOP elevation. In addition, there are genetically modified mouse models (DBA/2J), which make the study of hereditary forms of glaucoma possible. However, these approaches have not been able to identify all the molecular mechanisms characterizing glaucoma, possibly due to the disadvantages and limits related to the use of animals. In fact, the results obtained with small animals (i.e., rodents), which are the most commonly used, are often not aligned with human conditions due to their low degree of similarity with the human eye anatomy. Although the results obtained from non-human primates are in line with human conditions, they are little used for the study of glaucoma and its outcomes at cellular level due to their costs and their poor ease of handling. In this regard, according to at least two of the 3Rs principles, there is a need for reliable human-based models to better clarify the mechanisms involved in disease progression, and possibly to broaden the scope of the results so far obtained with animal models. The proper selection of an model with a "closer to " microenvironment and structure, for instance, allows for the identification of the biomarkers involved in the early stages of glaucoma and contributes to the development of new therapeutic approaches. This review summarizes the most recent findings in the glaucoma field through the use of human two- and three-dimensional cultures. In particular, it focuses on the role of the scaffold and the use of bioreactors in preserving the physiological relevance of conditions of the human trabecular meshwork cells in three-dimensional cultures. Moreover, data from these studies also highlight the pivotal role of oxidative stress in promoting the production of trabecular meshwork-derived pro-apoptotic signals, which are one of the first marks of trabecular meshwork damage. The resulting loss of barrier function, increase of intraocular pressure, as well the promotion of neuroinflammation and neurodegeneration are listed as the main features of glaucoma. Therefore, a better understanding of the first molecular events, which trigger the glaucoma cascade, allows the identification of new targets for an early neuroprotective therapeutic approach.
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http://dx.doi.org/10.3389/fneur.2020.591776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736413PMC
December 2020

MicroRNA-Mutant P53 Crosstalk in Chemoresistance: A Hint to Monitor Therapy Outcome.

Microrna 2020 ;9(5):322-335

Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, Genoa, Italy.

The chemoresistance of cancer cells is a multifactorial mechanism in which de-regulated apoptotic pathways, the oxidative response and cancer cell migration play a crucial role. A key player in the control of such pathways is the tumor suppressor gene TP53, also defined as the "guardian of the genome", encoding the P53 tetrameric transcription factor. P53, following cell injuries, can activate the transcription of several target genes crucial for the induction of apoptosis, cell cycle arrest, modulation of senescence, DNA repair, autophagy and metabolism. Importantly, TP53 gene is mutated in nearly 50% of human cancers, implying an altered expression of target genes in cancer cells. The presence of TP53 mutations can also affect the expression of several small noncoding RNAs (microRNAs or miRNAs) involved in the same regulation of the apoptotic signaling, cell cycle regulation and cell migration. In mutant P53 expressing tumors, some miRNAs resulted in being down-regulated, while others appeared to be up-regulated as demonstrated by in vitro and in vivo studies. Thus, the expression level of specific P53 responsive miRNAs could be used as a marker of cancer progression and therapy performance. In the present review, we will summarize the role of P53-related miRNAs and their clinical relevance in monitoring therapy outcome and progression of cancers with mutant P53.
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http://dx.doi.org/10.2174/2211536609666201209151659DOI Listing
January 2020

Can Polyphenols in Eye Drops Be Useful for Trabecular Protection from Oxidative Damage?

J Clin Med 2020 Nov 6;9(11). Epub 2020 Nov 6.

Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy.

Polyphenols, with anti-oxidant properties, counteract oxidative stress effects. Increasing evidence has found oxidative stressto be the main risk factor for trabecular meshwork (TM) damage, leading to high-tension glaucoma. Topical anti-oxidants could represent a new target for glaucoma treatment. Our aim is to investigate the protective mechanisms on a human TM culture of a patented polyphenol and fatty acid (iTRAB)formulation in response to oxidative stress using an advanced invitromodel consisting of 3D-human TM cells, embedded in a natural hydrogel, and a milli-scaled multi-organ device model for constantdynamic conditions. The 3D-human TM cells(3D-HTMCs) were treated daily with 500 µM HOor 500 µM HOand 0.15% iTRAB(m/v) for 72 h, and molecular differences in the intracellular reactive oxygen species (iROS), state of the cells, activation of the apoptosis pathway and NF-kB and the expression ofinflammatory and fibrotic markers wereanalyzed at different time-points.Concomitant exposure significantly reduced iROS and restored TM viability, iTRAB having a significant inhibitory effect on the apoptotic pathway, activation of NF-κB, induction of pro-inflammatory (IL-1α, IL-1ß and TNFα) and pro-fibrotic (TGFβ) cytokines and the matrix metalloproteinase expressions. It is clear that this specific anti-oxidant provides a valid TM protection, suggesting iTRAB could be an adjuvant therapy in primary open-angle glaucoma (POAG).
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http://dx.doi.org/10.3390/jcm9113584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694784PMC
November 2020

The Molecular Mechanisms of Adaptive Response Related to Environmental Stress.

Int J Mol Sci 2020 Sep 25;21(19). Epub 2020 Sep 25.

Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine, 14220 Prague, Czech Republic.

The exposure of living organisms to environmental stress triggers defensive responses resulting in the activation of protective processes. Whenever the exposure occurs at low doses, defensive effects overwhelm the adverse effects of the exposure; this adaptive situation is referred to as "hormesis". Environmental, physical, and nutritional hormetins lead to the stimulation and strengthening of the maintenance and repair systems in cells and tissues. Exercise, heat, and irradiation are examples of physical hormetins, which activate heat shock-, DNA repair-, and anti-oxidative-stress responses. The health promoting effect of many bio-actives in fruits and vegetables can be seen as the effect of mildly toxic compounds triggering this adaptive stimulus. Numerous studies indicate that living organisms possess the ability to adapt to adverse environmental conditions, as exemplified by the fact that DNA damage and gene expression profiling in populations living in the environment with high levels of air pollution do not correspond to the concentrations of pollutants. The molecular mechanisms of the hormetic response include modulation of (a) transcription factor Nrf2 activating the synthesis of glutathione and the subsequent protection of the cell; (b) DNA methylation; and (c) microRNA. These findings provide evidence that hormesis is a toxicological event, occurring at low exposure doses to environmental stressors, having the benefit for the maintenance of a healthy status.
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http://dx.doi.org/10.3390/ijms21197053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582272PMC
September 2020

Molecular changes in glaucomatous trabecular meshwork. Correlations with retinal ganglion cell death and novel strategies for neuroprotection.

Prog Brain Res 2020 1;256(1):151-188. Epub 2020 Jul 1.

Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy; Mutagenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Glaucoma is a chronic neurodegenerative disease characterized by retinal ganglion cell loss. Although significant advances in ophthalmologic knowledge and practice have been made, some glaucoma mechanisms are not yet understood, therefore, up to now there is no effective treatment able to ensure healing. Indeed, either pharmacological or surgical approaches to this disease aim in lowering intraocular pressure, which is considered the only modifiable risk factor. However, it is well known that several factors and metabolites are equally (if not more) involved in glaucoma. Oxidative stress, for instance, plays a pivotal role in both glaucoma onset and progression because it is responsible for the trabecular meshwork cell damage and, consequently, for intraocular pressure increase as well as for glaucomatous damage cascade. This review at first shows accurately the molecular-derived dysfunctions in antioxidant system and in mitochondria homeostasis which due to both oxidative stress and aging, lead to a chronic inflammation state, the trabecular meshwork damage as well as the glaucoma neurodegeneration. Therefore, the main molecular events triggered by oxidative stress up to the proapoptotic signals that promote the ganglion cell death have been highlighted. The second part of this review, instead, describes some of neuroprotective agents such as polyphenols or polyunsaturated fatty acids as possible therapeutic source against the propagation of glaucomatous damage.
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http://dx.doi.org/10.1016/bs.pbr.2020.06.003DOI Listing
July 2020

Predicting Response to Neoadjuvant Therapy in Colorectal Cancer Patients the Role of Messenger-and Micro-RNA Profiling.

Cancers (Basel) 2020 Jun 22;12(6). Epub 2020 Jun 22.

Department of Health Sciences, University of Genova, 16132 Genova, Italy.

Colorectal cancer patients' responses to neoadjuvant therapy undergo broad inter-individual variations. The aim of this systematic review is to identify a molecular signature that is predictive of colon cancer downstaging and/or downgrading after neoadjuvant therapy. Among the hundreds analysed in the available studies, only 19 messenger-RNAs (mRNAs) and six micro-RNAs (miRNAs) were differentially expressed in responders versus non-responders in two or more independent studies. Therefore, a mRNA/miRNA signature can be designed accordingly, with limitations caused by the retrospective nature of these studies, the heterogeneity in study designs and the downgrading/downstaging assessment criteria. This signature can be proposed to tailor neoadjuvant therapy regimens on an individual basis.
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http://dx.doi.org/10.3390/cancers12061652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352797PMC
June 2020

Anticancer effect of physical activity is mediated by modulation of extracellular microRNA in blood.

Oncotarget 2020 Jun 2;11(22):2106-2119. Epub 2020 Jun 2.

Department of Experimental Medicine, University of Genoa, Genoa, Italy.

Epidemiological studies provide evidence that physical activity reduces the risk of cancer, particularly of breast cancer. However, little is known about the underlying molecular mechanisms as related to microRNAs. The goal of the herein presented study is to explore the involvement of miRNAs in beneficial effects exerted by physical activity in breast cancer prevention. Thirty subjects (mean age: 57.1 ± 14.7 years) underwent 45 minutes of treadmill walking under standardized conditions. The levels of extracellular miRNAs were evaluated in blood plasma before and after structured exercise by means of microarray analysis of 1,900 miRNAs identifying mostly modulated miRNAs. Structured exercise has been found to modulate the expression of 14 miRNAs involved in pathways relevant to cancer. The different expression of two miRNAs involved in breast cancer progression, i. e. up-regulation of miR-206 and down-regulation of anti-miR-30c, were the most striking effects induced by exercise. The biological effects of these miRNAs were investigated in MCF-7 human breast cancer cells. miR-206 transfection and anti-miR-30c silencing, inhibited cell growth and increased apoptosis of MCF-7 cells. Moreover, the combined use of the two miRNAs further enhanced apoptosis and induced growth arrest in the G1/S phase of cell cycle. Our results support that physical activity effectively change the expression of extracellular miRNAs. Specifically, miR-206 up-regulation and anti-miR-30c down-regulation act as suppressors in breast cancer cells. The evaluation of these miRNAs in blood can be used as non-invasive biomarkers for breast cancer prevention.
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http://dx.doi.org/10.18632/oncotarget.27609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275780PMC
June 2020

Attenuation of oxidative stress and chromosomal aberrations in cultured macrophages and pulmonary cells following self-sustained high temperature synthesis of asbestos.

Sci Rep 2020 05 22;10(1):8581. Epub 2020 May 22.

Department of Earth, Environment and Life Sciences, University of Genoa, Corso Europa 26, 16132, Genoa, Italy.

Inhalation of asbestos fibres can cause lung and pleural diseases in humans and constitutes a severe public health threat worldwide. The aim of the present study was to assess the biological effects induced in both pulmonary cells (A549) and monocyte/macrophage (RAW 264.7) cell lines by combustion slags obtained from asbestos through a self-sustained high-temperature synthesis (SHS) reaction. The SHS reaction involves rapid thermal treatment and displays great ability to neutralise asbestos. Cytotoxicity, redox status imbalance, lipid peroxide production, DNA strand breaks (comet assay) and chromosomal aberrations (cytokinesis block micronucleus test) were evaluated in cells exposed either to untreated asbestos fibres or to grinded SHS-generated slags of different granulometry, tested in cultured cells at varying doses and for varying exposure times. Our results show that asbestos fibres cause redox status imbalance, especially in monocyte/macrophage cell lines. Moreover, they promote lipid peroxidation and trigger genomic alterations. When the cells were exposed to slag powders, which are the products of SHS asbestos treatment, generation of lipid peroxides and induction of DNA strand breaks still persisted, due to the high content in iron and other metals detected in these samples. However, there was an attenuation of redox status imbalance and an absence of chromosomal aberrations, which probably reflects the loss of the asbestos fibrous structure following SHS reaction, as demonstrated by electron microscopy analyses. In conclusions, SHS-treated asbestos wastes can potentially have deleterious health effects due to the oxidative stress induced by inhaled powders but they loose the asbestos ability to induce chromosomal alterations.
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http://dx.doi.org/10.1038/s41598-020-65620-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244567PMC
May 2020

Radon Biomonitoring and microRNA in Lung Cancer.

Int J Mol Sci 2020 Mar 20;21(6). Epub 2020 Mar 20.

Department of Experimental Medicine, University of Genoa, I-16132 Genoa, Italy.

Radon is the number one cause of lung cancer in non-smokers. microRNA expression in human bronchial epithelium cells is altered by radon, with particular reference to upregulation of miR-16, miR-15, miR-23, miR-19, miR-125, and downregulation of let-7, miR-194, miR-373, miR-124, miR-146, miR-369, and miR-652. These alterations alter cell cycle, oxidative stress, inflammation, oncogene suppression, and malignant transformation. Also DNA methylation is altered as a consequence of miR-29 modification induced by radon. Indeed miR-29 targets DNA methyltransferases causing inhibition of CpG sites methylation. Massive microRNA dysregulation occurs in the lung due to radon expose and is functionally related with the resulting lung damage. However, in humans this massive lung microRNA alterations only barely reflect onto blood microRNAs. Indeed, blood miR-19 was not found altered in radon-exposed subjects. Thus, microRNAs are massively dysregulated in experimental models of radon lung carcinogenesis. In humans these events are initially adaptive being aimed at inhibiting neoplastic transformation. Only in case of long-term exposure to radon, microRNA alterations lead towards cancer development. Accordingly, it is difficult in human to establish a microRNA signature reflecting radon exposure. Additional studies are required to understand the role of microRNAs in pathogenesis of radon-induced lung cancer.
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http://dx.doi.org/10.3390/ijms21062154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139524PMC
March 2020

MicroRNAs as Mediators between Genotype and Phenotype from Basic Science to On-Field Applications.

Authors:
Alberto Izzotti

Microrna 2020 ;9(1):2-7

Department of Experimental Medicine University of Genoa Genoa, Italy.

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http://dx.doi.org/10.2174/221153660901191202101357DOI Listing
January 2020

Small RNAs in eucaryotes: new clues for amplifying microRNA benefits.

Cell Biosci 2020 3;10. Epub 2020 Jan 3.

Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, L.Go R. Benzi, 10, Genoa, Italy.

miRNAs, the smallest nucleotide molecules able to regulate gene expression at post transcriptional level, are found in both animals and plants being involved in fundamental processes for growth and development of living organisms. The number of miRNAs has been hypothesized to increase when some organisms specialized the process of mastication and grinding of food. Further to the vertical transmission, miRNAs can undergo horizontal transmission among different species, in particular between plants and animals. In the last years, an increasing number of studies reported that miRNA passage occurs through feeding, and that in animals, plant miRNAs can survive the gastro intestinal digestion and transferred by blood into host cells, where they can exert their functions modulating gene expression. The present review reports studies on miRNAs during evolution, with particular focus on biogenesis and mechanisms regulating their stability in plants and animals. The different biogenesis and post biogenesis modifications allow to discriminate miRNAs of plant origin from those of animal origin, and make it possible to better clarify the controversial question on whether a possible cross-kingdom miRNA transfer through food does exist. The majority of human medicines and supplements derive from plants and a regular consumption of plant food is suggested for their beneficial effects in the prevention of metabolic diseases, cancers, and dietary related disorders. So far, these beneficial effects have been generally attributed to the content of secondary metabolites, whereas mechanisms regarding other components remain unclear. Therefore, in light of the above reported studies miRNAs could result another component for the medical properties of plants. miRNAs have been mainly studied in mammals characterizing their sequences and molecular targets as available in public databases. The herein presented studies provide evidences that miRNA situation is much more complex than the static situation reported in databases. Indeed, miRNAs may have redundant activities, variable sequences, different methods of biogenesis, and may be differently influenced by external and environmental factors. In-depth knowledge of mechanisms of synthesis, regulation and transfer of plant miRNAs to other species can open new frontiers in the therapy of many human diseases, including cancer.
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http://dx.doi.org/10.1186/s13578-019-0370-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942390PMC
January 2020

miRNA Regulation of Glutathione Homeostasis in Cancer Initiation, Progression and Therapy Resistance.

Microrna 2020 ;9(3):187-197

Department of Experimental Medicine, University of Genoa, Genoa, Italy.

Glutathione (GSH) is the most abundant antioxidant that contributes to regulating the cellular production of Reactive Oxygen Species (ROS) which, maintained at physiological levels, can exert a function of second messengers in living organisms. In fact, it has been demonstrated that moderate amounts of ROS can activate the signaling pathways involved in cell growth and proliferation, while high levels of ROS induce DNA damage leading to cancer development. Therefore, GSH is a crucial player in the maintenance of redox homeostasis and its metabolism has a role in tumor initiation, progression, and therapy resistance. Our recent studies demonstrated that neuroblastoma cells resistant to etoposide, a common chemotherapeutic drug, show a partial monoallelic deletion of the locus coding for miRNA 15a and 16-1 leading to a loss of these miRNAs and the activation of GSH-dependent responses. Therefore, the aim of this review is to highlight the role of specific miRNAs in the modulation of intracellular GSH levels in order to take into consideration the use of modulators of miRNA expression as a useful strategy to better sensitize tumors to current therapies.
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http://dx.doi.org/10.2174/2211536609666191218103220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366003PMC
January 2020

Public health issues from crude-oil production in the Ecuadorian Amazon territories.

Sci Total Environ 2020 Jun 22;719:134647. Epub 2019 Nov 22.

Department of Experimental Medicine, University of Genova, Via L.B. Albertis 2, Genoa, Italy; Policlinic Hospital San Martino, Genoa, Italy. Electronic address:

Crude oil production (COP) is a high-pollution industry but the vast Amazon rainforest has been an active COP zone for South America. Although COP has been associated with a variety of health effects among workers around the world, such effects have not been adequately investigated in the Amazon region, especially at the community level. Therefore, this review was conducted to provide a report about COP in the Amazon of Ecuador and about its association with health status of indigenous human populations. Some epidemiological surveys in the Amazonian Territories indicate that COP has been associated with health problems in the surrounding populations, e.g. cancers in the stomach, rectum, skin, soft tissue, kidney and cervix in adults, and leukemia in children. In addition, some biomarkers and mechanistic studies show exposure effects. However, due to limitations from these studies, contradictory associations have been reported. Our review indicates that COP in the Amazonian territories of northern Ecuador was characterised by contamination which could have affected the indigenous and non-indigenous populations. However, there have not been dedicated investigations to provide relationships between the contamination and the subsequent exposure-health effects. Since indigenous populations have different lifestyle and cultures from regular city dwellers, systematic studies on their potential health hazards need to be conducted. Due to the remote locations and sparse populations, these new studies may involve the use of novel and genomic-based biomarkers as well as using high technology in the remote regions.
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http://dx.doi.org/10.1016/j.scitotenv.2019.134647DOI Listing
June 2020

Human Papillomavirus Infections, Cervical Cancer and MicroRNAs: An Overview and Implications for Public Health.

Microrna 2020 ;9(3):174-186

Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy.

Human Papillomavirus (HPV) is among the most common sexually transmitted infections in both females and males across the world that generally do not cause symptoms and are characterized by high rates of clearance. Persistent infections due at least to twelve well-recognized High-Risk (HR) or oncogenic genotypes, although less frequent, can occur, leading to diseases and malignancies, principally cervical cancer. Three vaccination strategies are currently available for preventing certain HR HPVs-associated diseases, infections due to HPV6 and HPV11 low-risk types, as well as for providing cross-protection against non-vaccine genotypes. Nevertheless, the limited vaccine coverage hampers reducing the burden of HPV-related diseases globally. For HR HPV types, especially HPV16 and HPV18, the E6 and E7 oncoproteins are needed for cancer development. As for other tumors, even in cervical cancer, non-coding microRNAs (miRNAs) are involved in posttranscriptional regulation, resulting in aberrant expression profiles. In this study, we provide a summary of the epidemiological background for HPV occurrence and available immunization programs. In addition, we present an overview of the most relevant evidence of miRNAs deregulation in cervical cancer, underlining that targeting these biomolecules could lead to wide translational perspectives, allowing better diagnosis, prognosis and therapeutics, and with valuable applications in the field of prevention. The literature on this topic is rapidly growing, but advanced investigations are required to achieve more consistent findings on the up-regulated and down-regulated miRNAs in cervical carcinogenesis. Because the expression of miRNAs is heterogeneously reported, it may be valuable to assess factors and risks related to individual susceptibility.
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http://dx.doi.org/10.2174/2211536608666191026115045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366004PMC
January 2020

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor.

Carcinogenesis 2020 03;41(1):91-99

Department of Health Sciences, University of Genoa, Genoa, Italy.

Chronic inflammation plays a crucial role in the carcinogenesis process and, in particular, in smoking-related carcinogenesis. Therefore, anti-inflammatory agents provide an interesting perspective in the prevention of smoking-associated cancers. Among nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone is a triple inhibitor of both cyclooxygenases (COX-1 and COX-2) and of 5-lipooxygenase (5-LOX) that has shown some encouraging results in cancer prevention models. We previously showed that the dietary administration of licofelone, starting after weanling, to Swiss H mice exposed for 4 months to mainstream cigarette smoke since birth attenuated preneoplastic lesions of inflammatory nature in both lung and urinary tract, and had some effects on the yield of lung tumors at 7.5 months of age. The present study aimed at evaluating the early modulation by licofelone of pulmonary DNA and RNA alterations either in smoke-free or smoke-exposed H mice after 10 weeks of exposure. Licofelone protected the mice from the smoke-induced loss of body weight and significantly attenuated smoke-induced nucleotide alterations by decreasing the levels of bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine in mouse lung. Moreover, the drug counteracted dysregulation by smoke of several pulmonary microRNAs involved in stress response, inflammation, apoptosis, and oncogene suppression. However, even in smoke-free mice administration of the drug had significant effects on a broad panel of microRNAs and, as assessed in a subset of mice used in a parallel cancer chemoprevention study, licofelone even enhanced the smoke-induced systemic genotoxic damage after 4 months of exposure. Therefore, caution should be paid when administering licofelone to smokers for long periods.
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http://dx.doi.org/10.1093/carcin/bgz158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456342PMC
March 2020

Human primary endothelial cells are impaired in nucleotide excision repair and sensitive to benzo[a]pyrene compared with smooth muscle cells and pericytes.

Sci Rep 2019 09 24;9(1):13800. Epub 2019 Sep 24.

Institute of Toxicology, University Medical Center, Mainz, 55131, Germany.

The endothelium represents the inner cell layer of blood vessels and is supported by smooth muscle cells and pericytes, which form the vessel structure. The endothelium is involved in the pathogenesis of many diseases, including the development of atherosclerosis. Due to direct blood contact, the blood vessel endothelium is inevitably exposed to genotoxic substances that are systemically taken up by the body, including benzo[a]pyrene, which is a major genotoxic component in cigarette smoke and a common environmental mutagen and human carcinogen. Here, we evaluated the impact of benzo[a]pyrene diol epoxide (BPDE), which is the reactive metabolite of benzo[a]pyrene, on the three innermost vessel cell types. Primary human endothelial cells (HUVEC), primary human smooth muscle cells (HUASMC) and primary human pericytes (HPC) were treated with BPDE, and analyses of cytotoxicity, cellular senescence and genotoxic effects were then performed. The results showed that HUVEC were more sensitive to the cytotoxic activity of BPDE than HUASMC and HPC. We further show that HUVEC display a detraction in the repair of BPDE-induced adducts, as determined through the comet assay and the quantification of BPDE adducts in post-labelling experiments. A screening for DNA repair factors revealed that the nucleotide excision repair (NER) proteins ERCC1, XPF and ligase I were expressed at lower levels in HUVEC compared with HUASMC and HPC, which corresponds with the impaired NER-mediated removal of BPDE adducts from DNA. Taken together, the data revealed that HUVEC exhibit an unexpected DNA repair-impaired phenotype, which has implications on the response of the endothelium to genotoxicants that induce bulky DNA lesions, including the development of vascular diseases resulting from smoking and environmental pollution.
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http://dx.doi.org/10.1038/s41598-019-49953-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760230PMC
September 2019

Characterization of C2C12 cells in simulated microgravity: Possible use for myoblast regeneration.

J Cell Physiol 2020 04 24;235(4):3508-3518. Epub 2019 Sep 24.

Mutagenesis and Preventive Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Muscle loss is a major problem for many in lifetime. Muscle and bone degeneration has also been observed in individuals exposed to microgravity and in unloading conditions. C2C12 myoblst cells are able to form myotubes, and myofibers and these cells have been employed for muscle regeneration purposes and in myogenic regeneration and transplantation studies. We exposed C2C12 cells in an random position machine to simulate microgravity and study the energy and the biochemical challenges associated with this treatment. Simulated microgravity exposed C2C12 cells maintain positive proliferation indices and delay the differentiation process for several days. On the other hand this treatment significantly alters many of the biochemical and the metabolic characteristics of the cell cultures including calcium homeostasis. Recent data have shown that these perturbations are due to the inhibition of the ryanodine receptors on the membranes of intracellular calcium stores. We were able to reverse this perturbations treating cells with thapsigargin which prevents the segregation of intracellular calcium ions in the mitochondria and in the sarco/endoplasmic reticula. Calcium homeostasis appear a key target of microgravity exposure. In conclusion, in this study we reported some of the effects induced by the exposure of C2C12 cell cultures to simulated microgravity. The promising information obtained is of fundamental importance in the hope to employ this protocol in the field of regenerative medicine.
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http://dx.doi.org/10.1002/jcp.29239DOI Listing
April 2020

Environment and health: Risk perception and its determinants among Italian university students.

Sci Total Environ 2019 Nov 16;691:1162-1172. Epub 2019 Jul 16.

Department of Medical, Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Catania University, Catania, Italy.

Among the determinants of environmental health risk perception, health literacy and social media messages have been generally neglected. This study details the environmental health risk perception and its determinants in Italian university students, including a measure of functional health literacy and an analysis of newspapers and social media. A cross sectional survey was carried out among students from 15 Italian universities and different disciplines (grouped into Scientific-Health and Humanistic-Legal-Social sectors) using a self-administered anonymous questionnaire, divided into six sections: socio-demographic characteristics, information on health and environment, environmental health risk perception, trust, attitudes and behaviors and functional health literacy. Local newspapers and tweets in the same areas and period were analyzed in relation to quantity and topics. The study population included 4778 students (65.1% female) aged 21 ± 4.3 years, and functional health literacy was low (below the cutoff value) for 44.4% of students. A new outcome of the survey is that the detected association between high functional health literacy a higher global health risk perception and trust in institutions both as sources of information and as actors for protection against environmental risks. The internet and social networks were the most frequently consulted sources of information (77.7%), which was predictive of a higher risk perception. The possible relation between environmental health risk perception and tweet communication was highlighted by a comparison between the risk perception in the city with the highest number of tweets (Modena) and another one similar for socio-demographic characteristics (Pisa). In conclusion, the results of our study may be of help to strengthen information and education programs: functional health literacy should be taken into account in school programs, to produce a basic knowledge for a better understanding of health and environment. Moreover, mass and social media should be included in planning communication intervention and in verifying their results.
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http://dx.doi.org/10.1016/j.scitotenv.2019.07.201DOI Listing
November 2019

Prediction of Titanium Implant Success by Analysis of microRNA Expression in Peri-Implant Tissue. A 5-Year Follow-Up Study.

J Clin Med 2019 Jun 21;8(6). Epub 2019 Jun 21.

Department of Health Sciences, University of Genoa, 16126 Genoa, Italy.

The aim of the present study is to evaluate the expression of microRNA (miRNA) in peri-implant soft tissue and to correlate epigenetic information with the clinical outcomes of the implants up to the five-year follow-up. Seven patients have been rehabilitated with fixed screw-retained bridges each supported by implants. Peri-implant bone resorption and soft tissue health parameters have been recorded over time with a five-year follow-up. Mini-invasive samples of soft peri-implant tissue have been taken three months after implant insertion. miRNA have been extracted from cells of the soft tissue samples to evaluate gene-expression at the implant sites by microarray analysis. The epigenomic data obtained by microarray technology has been statistically analyzed by dedicated software and compared with measured clinical parameters. Specific miRNA expression profiles predictive of specific clinical outcomes were found. In particular, some specific miRNA signatures appeared to be "protective" from bone resorption despite the presence of plaque accumulation. miRNA may be predictors of dental implant clinical outcomes and may be used as biomarkers for diagnostic and prognostic purposes in the field of implant dentistry.
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http://dx.doi.org/10.3390/jcm8060888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617176PMC
June 2019

MicroRNA from Small Oligunucletoides to Giant Players of Biological Processes and Diseases.

Authors:
Alberto Izzotti

Microrna 2019 ;8(1):2-3

Department of Health Sciences University of Genoa Genoa, Italy.

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http://dx.doi.org/10.2174/221153660801181024142302DOI Listing
January 2019

Gene expression and genotoxicity in Manila clam (Ruditapes philippinarum) modulated by sediment contamination and lagoon dynamics in the Po river delta.

Mar Environ Res 2018 Nov 21;142:257-274. Epub 2018 Oct 21.

CNR- National Research Council of Italy, IRSA - Water Research Institute, Via del Mulino 19, 20861, Brugherio, MB, Italy. Electronic address:

The lagoons of the Po River delta are potentially exposed to complex mixtures of contaminants, nevertheless, there is a substantial lack of information about the biological effects of these contaminants in the Po delta lagoons. These environments are highly dynamic and the interactions between chemical and environmental stressors could prevent the proper identification of biological effects and their causes. In this study, we aimed to disentangle such interactions focusing on Manila clams, previously exposed to six lagoons of the Po delta, adopting three complementary tools: a) the detailed description via modelling techniques of lagoon dynamics for salinity and water temperature; b) the response sensitivity of a number of target genes (ahr, cyp4, ρ-gst, σ-gst, hsp22, hsp70, hsp90, ikb, dbh, ach, cat, Mn-sod, Cu/Zn-sod, cyp-a, flp, grx, TrxP) investigated in clam digestive glands by Real Time PCR; and c) the relevance of DNA adducts determined in clams as markers of exposure to genotoxic chemicals. The lagoons showed specific dynamics, and two of them (Marinetta and Canarin) could induce osmotic stress. A group of genes (ahr, cyp4, Mn-sod, σ-gst, hsp-22, cyp-a, TrxP) seemed to be associated with overall lagoon characteristics as may be described by salinity and its variations. Lagoon modelling and a second group of genes (hsp70, hsp90, cat, ikb, ach, grx, Cu/Zn-sod) also suggested that moderate increases of river discharge may imply worse exposure conditions. Oxidative stress seemed to be associated with such events but it was slightly evident also under normal exposure conditions. DNA adduct formation was mainly associated with overwhelmed antioxidant defences (e.g. low Cu/Zn-sod) or seemingly with their lack of response in due time. In Po delta lagoons, Manila clam can be affected by chemical and environmental factors which can contribute to induce oxidative stress, DNA adduct formation and, ultimately, to affect clam condition and health.
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http://dx.doi.org/10.1016/j.marenvres.2018.10.010DOI Listing
November 2018

A Global MicroRNA Profile in Fanconi Anemia: A Pilot Study.

Metab Syndr Relat Disord 2019 02 30;17(1):53-59. Epub 2018 Oct 30.

1 Mutagenesis and Preventive Oncology, Ospedale Policlinico San Martino, Genova, Italy.

Purpose: Fanconi anemia (FA) is a complex tumor-prone disease defined by an entangled genotype and phenotype. Despite enormous efforts in the last 20 years, a comprehensive and integrated view of the disease is still missing. The aim of this pilot study was to establish whether a global microRNA (miRNA) analysis approach could be helpful in defining aspects in FA phenotype, which might deserve future attention with the perspective to develop miRNA-based therapies.

Methods: miRNA array were employed to characterize the global miRNA (miRNoma) profile of FA RNA samples with respect to normal samples.

Results: We report and compare miRNA profile from two FA established cell lines and three FA patients. This analysis reveals that 36 and 64 miRNAs, respectively, are found differentially expressed (>2-fold variation and P < 0.05) in the samples from FA cell lines and FA patients. Overlap of these data results in 24 miRNAs as shared in the two sample populations. Available bioinformatics methods were used to predict target genes for the differentially expressed miRNAs and to perform pathway enrichment analysis.

Conclusions: Seven pathway results associated with the FA phenotype. It is interesting to note that some of these pathways were previously unrelated to FA phenotype. It might be important to focus on these pathways not previously emerged as dysfunctional in FA to better define the pathophysiological context of this disease. This is the first report of a global miRNA analysis in FA.
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http://dx.doi.org/10.1089/met.2018.0085DOI Listing
February 2019

Modulation of genomic and epigenetic end-points by celecoxib.

Oncotarget 2018 Sep 14;9(72):33656-33681. Epub 2018 Sep 14.

Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.

Celecoxib, a nonsteroidal anti-inflammatory drug that selectively targets cyclooxygenase-2, is a promising cancer chemopreventive agent. However, safety concerns have been raised in clinical trials evaluating its ability to prevent colorectal adenomas. The rationale for the herein reported studies was to analyze genomic and epigenetic end-points aimed at investigating both the chemopreventive properties of celecoxib towards cigarette smoke-associated molecular alterations and its possible adverse effects. We carried out three consecutive studies in mice treated with either smoke and/or celecoxib. investigated early DNA alterations (DNA adducts, oxidative DNA damage, and systemic genotoxic damage) and epigenetic alterations (expression of 1,135 microRNAs) in lung and blood of Swiss H mice; evaluated the formation of DNA adducts in lung, liver, and heart; and evaluated the expression of microRNAs in 10 organs and 3 body fluids of ICR (CD-1) mice. Surprisingly, the oral administration of celecoxib to smoke-free mice resulted in the formation of DNA adducts in both lung and heart and in dysregulation of microRNAs in mouse organs and body fluids. On the other hand, celecoxib attenuated smoke-related DNA damage and dysregulation of microRNA expression. In conclusion, celecoxib showed pleiotropic properties and multiple mechanisms by counteracting the molecular damage produced by smoke in a variety of organs and body fluids. However, administration of celecoxib to non-smoking mice resulted in evident molecular alterations, also including DNA and RNA alterations in the heart, which may bear relevance in the pathogenesis of the cardiovascular adverse effects of this drug.
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http://dx.doi.org/10.18632/oncotarget.26062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154745PMC
September 2018

Etoposide-resistance in a neuroblastoma model cell line is associated with 13q14.3 mono-allelic deletion and miRNA-15a/16-1 down-regulation.

Sci Rep 2018 09 13;8(1):13762. Epub 2018 Sep 13.

Department of Experimental Medicine, General Pathology Section, University of Genova, Genova, Italy.

Drug resistance is the major obstacle in successfully treating high-risk neuroblastoma. The aim of this study was to investigate the basis of etoposide-resistance in neuroblastoma. To this end, a MYCN-amplified neuroblastoma cell line (HTLA-230) was treated with increasing etoposide concentrations and an etoposide-resistant cell line (HTLA-ER) was obtained. HTLA-ER cells, following etoposide exposure, evaded apoptosis by altering Bax/Bcl2 ratio. While both cell populations shared a homozygous TP53 mutation encoding a partially-functioning protein, a mono-allelic deletion of 13q14.3 locus, where the P53 inducible miRNAs 15a/16-1 are located, and the consequent miRNA down-regulation were detected only in HTLA-ER cells. This event correlated with BMI-1 oncoprotein up-regulation which caused a decrease in p16 tumor suppressor content and a metabolic adaptation of HTLA-ER cells. These results, taken collectively, highlight the role of miRNAs 15a/16-1 as markers of chemoresistance.
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http://dx.doi.org/10.1038/s41598-018-32195-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137223PMC
September 2018