Gabriella Esposito

Ceinge Biotecnologie Avanzate (Italy)

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Francesco Salvatore

University of Naples Federico II

Tiziana Fioretti

Ceinge Biotecnologie Avanzate (Italy)

Fabio Cattaneo

University of Naples Federico II

Rosario Ammendola

University of Naples Federico II

Francesco Testa

University of Campania "Luigi Vanvitelli"

Francesca Simonelli

University of Campania "Luigi Vanvitelli"

Armando Cevenini

University of Naples Federico II

Adriana Zagari

Ceinge Biotecnologie Avanzate (Italy)

Luigi Vitagliano

Institute of Biostructure and Bioimaging

Carmelo Piscopo

Ospedale Antonio Cardarelli

Cooperative Institutions

University of Naples Federico II

201

Federico II University Hospital

102

Ceinge Biotecnologie Avanzate (Italy)

Istituti di Ricovero e Cura a Carattere Scientifico

University of Campania "Luigi Vanvitelli"

Ospedale Antonio Cardarelli

University of Salerno

Sapienza University of Rome

Regione Campania

Fatebenefratelli Hospital

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MALAT1-dependent hsa_circ_0076611 regulates translation rate in triple-negative breast cancer

Communications Biology (2022)

Chiara Turco Gabriella Esposito Alessia Iaiza Frauke Goeman Anna Benedetti

Abstract Vascular Endothelial Growth Factor A (VEGFA) is the most commonly expressed angiogenic growth factor in solid tumors and is generated as multiple isoforms through alternative mRNA splicing. Here, we show that lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and ID4 (inhibitor of DNA-binding 4) protein, previously referred to as regulators of linear isoforms of VEGFA , induce back-splicing of VEGFA exon 7, producing circular RNA circ_0076611. Circ_0076611 is detectable in triple-negative breast cancer (TNBC) cells and tissues, in exosomes released from TNBC cells and in the serum of breast cancer patients. Circ_0076611 interacts with a variety of proliferation-related transcripts, included MYC and VEGFA mRNAs, and increases cell proliferation and migration of TNBC cells. Mechanistically, circ_0076611 favors the expression of its target mRNAs by facilitating their interaction with components of the translation initiation machinery. These results add further complexity to the multiple VEGFA isoforms expressed in cancer cells and highlight the relevance of post-transcriptional regulation of VEGFA expression in TNBC cells.

Triple-negative breast cancer

MALAT1

10.1038/s42003-022-03539-x

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Citations (17)

Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase

Antioxidants (2024)

Tiziana Pecchillo Cimmino Iolanda Panico Simona Scarano Mariano Stornaiuolo Gabriella Esposito

Phospholipases (PL) A2 catalyzes the hydrolysis of membrane phospholipids and mostly generates arachidonic acid (AA). The enzyme 5-lipoxygenase (5-LOX) can metabolize AA to obtain inflammatory leukotrienes, whose biosynthesis highly depends on cPLA2 and 5-LOX activities. Formyl Peptide Receptor 2 (FPR2) belongs to a subfamily of class A GPCRs and is considered the most versatile FPRs isoform. Signaling triggered by FPR2 includes the activation of several downstream kinases and NADPH oxidase (NOX)-dependent ROS generation. In a metabolomic analysis we observed a significant increase in AA concentration in FPR2-stimulated lung cancer cell line CaLu-6. We analyzed cPLA2 phosphorylation and observed a time-dependent increase in cPLA2 Ser505 phosphorylation in FPR2-stimulated cells, which was prevented by the MEK inhibitor (PD098059) and the p38MAPK inhibitor (SB203580) and by blocking NOX function. Similarly, we demonstrated that phosphorylation of 5-LOX at Ser271 and Ser663 residues requires FPR2-dependent p38MAPK and ERKs activation. Moreover, we showed that 5-LOX Ser271 phosphorylation depends on a functional NOX expression. Our overall data demonstrate for the first time that FPR2-induced ERK- and p38MAPK-dependent phosphorylation/activation of cPLA2 and 5-LOX requires a functional NADPH oxidase. These findings represent an important step towards future novel therapeutic possibilities aimed at resolving the inflammatory processes underlying many human diseases.

10.3390/antiox13020220

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Citations (2)

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML.

Research Square (Research Square) (2023)

Antonella Di Mambro Yoana Arroyo Tiziana Fioretti Michael J. Randles Luca Cozzuto

Abstract Background KMT2A -rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A -R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. We explored the role of SET, the endogenous inhibitor of SER/THR phosphatase PP2A in KMT2A -R leukemia. Material and Methods The expression of SET was analysed in a large acute myeloid leukemia (AML)- RNA-seq dataset and in primary KMT2A -R samples and aged matched-controls. Stable SET knockdown (KD) was established by RNA interference in three KMT2A wild-type (wt) and four KMT2A -R leukemic cell lines. Gene and protein expression were analysed by RT-qPCR, ChiP, IP and western blot. RNA-seq and phospho-proteomics were employed to evaluate the effect of the SET-PP2A inhibitor FTY720 on global protein phosphorylation and gene expression. The cellular impact of FTY720 was evaluated by analysing proliferation, cell cycle and apoptosis in leukemic cell lines and by colony formation assay in two patient-derived xenograft (PDX). Results SET mRNA was found expressed in blasts from KMT2A -R-patients and in leukemic stem cells. SET protein interacted with both KMT2A wt and fusion proteins. Knockdown of SET inhibited the transcription of KMT2A target genes HOXA9 and HOXA10 and abolished the self-renewal of KMT2A -R leukemic cells. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest, apoptosis and increased sensitivity to chemotherapy in KMT2A -R-leukemic models. Phospho-proteomic and western blot analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3b, ARKB, and led to degradation of MYC, supporting the hypothesis of a feedback loop among SET, PP2A and MYC. The RNA-seq indicated that FTY720 reduced the activity of signalling pathways implicated in gene transcription and it compromised the expression of several genes belonging to the KMT2A -R leukemia signature. Conclusions Taken together our results identify SET as a novel player in KMT2A -R leukemia and provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

10.21203/rs.3.rs-2583091/v1

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Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance

The Italian Journal of Pediatrics/Italian journal of pediatrics (2012)

Giulia Paolella Pasquale Pisano Raffaele Albano Lucio Cannaviello Carolina Saori Ishii Mauro

Abstract We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with “cryptogenic” hypertransaminasemia.

10.1186/1824-7288-38-64

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Citations (14)

New Molecular Mechanisms and Clinical Impact of circRNAs in Human Cancer

Cancers (2021)

Giulia Fontemaggi Chiara Turco Gabriella Esposito Silvia Di Agostino

Next generation RNA sequencing techniques, implemented in the recent years, have allowed us to identify circular RNAs (circRNAs), covalently closed loop structures resulting in RNA molecules that are more stable than linear RNAs. This class of non-coding RNA is emerging to be involved in a variety of cell functions during development, differentiation, and in many diseases, including cancer. Among the described biological activities, circRNAs have been implicated in microRNA (miRNA) sequestration, modulation of protein-protein interactions and regulation of mRNA transcription. In human cancer, circRNAs were implicated in the control of oncogenic activities such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. The most widely described mechanism of action of circRNAs is their ability to act as competing endogenous RNAs (ceRNAs) for miRNAs, lncRNAs and mRNAs, thus impacting along their axis, despite the fact that a variety of additional mechanisms of action are emerging, representing an open and expanding field of study. Furthermore, research is currently focusing on understanding the possible implications of circRNAs in diagnostics, prognosis prediction, effectiveness of therapies and, eventually, therapeutic intervention in human cancer. The purpose of this review is to discuss new knowledge on the mechanisms of circRNA action, beyond ceRNA, their impact on human cancer and to dissect their potential value as biomarkers and therapeutic targets.

10.3390/cancers13133154

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Citations (65)

Recent advances in diagnostic techniques in Caroli's disease.

PubMed (1982)

Galloro O. Cuomo Gabriella Esposito Generoso Uomo Mario Visconti

Preoperative diagnosis of congenital dilatation of the intrahepatic bile ducts (Caroli's disease) is difficult. The best techniques for this diagnosis are endoscopic retrograde cholangiopancreatography, abdominal ultrasonography and computerized tomography. The authors present a case of Caroli's disease diagnosed using ultrasonography and computerized tomography. They discuss the usefulness and the real possibilities of existing techniques in the diagnosis of intra- and extrahepatic bile duct disease.

Bile Duct Diseases

Intrahepatic bile ducts

Abdominal ultrasonography

Abdominal computed tomography

Endoscopic ultrasonography

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Citations (1)

Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression

Life (2021)

Valentina Maria Caso Valentina Manzo Tiziana Pecchillo Cimmino Valeria Conti Pio Caso

G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases.

Proinflammatory cytokine

Formyl peptide receptor

10.3390/life11030243

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Citations (33)

[Non-alcoholic hepatic steatosis: the role of policosanols in associated hyperlipidemia].

Minerva Gastroenterologica e Dietologica (2010)

Dario Musto L. Martorelli Maria Francesca Russo Gabriella Esposito M R Amato

The purpose of this study was to evaluate the efficacy of policosanols in the treatment of associated hyperlipidemia in patients with non-alcoholic fatty liver disease (NAFLD).We conducted a retrospective study on 52 patients with NAFLD. Pretreatment patients' data (total cholesterol, LDL cholesterol, triglycerides, ALT, and AST) were collected and analyzed. Furthermore, based on weight and height, we calculated the Body Mass Index (BMI) and, based on blood glucose and insulin levels, we estimated the Human Omeostatic Assesment Index (HOMA). After that, all patients were treated with a policosanols' supplement (Frilipid®) and a hypocaloric balanced diet, and then followed over time with quarterly inspections. We collected and analyzed data on three subsequent quarterly monitoring during treatment.The collected and analyzed data showed a significant reduction in total cholesterol, LDL cholesterol and HOMA index (P<0.002). It was also found a trend not statistically significant for a marked reduction in ALT, AST, triglycerides, and BMI.The use of policosanols is shown effective in the treatment of associated hyperlipidemia and insulin resistance in patients with fatty liver disease.

Hyperlipidemia

Steatosis

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Citations (4)

Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy

Scientific Reports (2022)

Marianthi Karali Francesco Testa Valentina Di Iorio Annalaura Torella Roberta Zeuli

Inherited retinal diseases (IRDs) are the leading cause of vision loss in the working-age population. We performed a retrospective epidemiological study to determine the genetic basis of IRDs in a large Italian cohort (n = 2790) followed at a single referral center. We provided, mainly by next generation sequencing, potentially conclusive molecular diagnosis for 2036 patients (from 1683 unrelated families). We identified a total of 1319 causative sequence variations in 132 genes, including 353 novel variants, and 866 possibly actionable genotypes for therapeutic approaches. ABCA4 was the most frequently mutated gene (n = 535; 26.3% of solved cases), followed by USH2A (n = 228; 11.2%) and RPGR (n = 102; 5.01%). The other 129 genes had a lower contribution to IRD pathogenesis (e.g. CHM 3.5%, RHO 3.5%; MYO7A 3.4%; CRB1 2.7%; RPE65 2%, RP1 1.8%; GUCY2D 1.7%). Seventy-eight genes were mutated in five patients or less. Mitochondrial DNA variants were responsible for 2.1% of cases. Our analysis confirms the complex genetic etiology of IRDs and reveals the high prevalence of ABCA4 and USH2A mutations. This study also uncovers genetic associations with a spectrum of clinical subgroups and highlights a valuable number of cases potentially eligible for clinical trials and, ultimately, for molecular therapies.

ABCA4

GUCY2D

Proband

Etiology

10.1038/s41598-022-24636-1

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Citations (37)

Transglutaminase 1 deficiency and corneocyte collapse: an indication for targeted molecular screening in autosomal recessive congenital ichthyosis

British Journal of Dermatology (2007)

Gabriella Esposito Gianluca Tadini Francesco Paparo Antonietta Viola Luigi Ieno

Conflicts of interest: none declared. Sir, Autosomal recessive congenital ichthyosis (ARCI) is a rare clinically and genetically heterogeneous skin disease.1 In childhood, ARCI phenotypes range from severe nonerythrodermic lamellar ichthyosis (NELI) to mild congenital ichthyosiform erythroderma (CIE).1 ARCI‐related genes are TGM1 on 14q11.2,2,ABCA12 on 2q33–35,3,FLJ39501 on 19p12–q12,4,ALOXE3/ALOX12B on 17p13,3 and ichthyn on 5q33.3 This genetic heterogeneity makes genetic counselling and prenatal diagnosis of ARCI difficult. However, about 35–40% of patients with ARCI have complete or partial transglutaminase 1 (TGase1) deficiency.5 Because clinical manifestations may differ among TGase1‐deficient patients,5 it is difficult to identify candidates for TGM1 mutation screening. At present, TGase1 deficiency is detected by electron microscopy and/or TGase1 assay of a skin punch biopsy, which is an invasive procedure.6 However, although the epidermis of patients with NELI or CEI and TGase1 deficiency is usually characterized by a specific ultrastructure, patients with the same TGM1 genotype may have different ultrastructures and/or phenotypes.5, 6 Therefore, ultrastructure alone does not invariably discriminate TGase1‐deficient patients.

Lamellar ichthyosis

Congenital ichthyosis

10.1111/j.1365-2133.2007.08070.x

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Citations (16)