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3. Extracellular Vesicle-Related Non-Coding RNAs in Hepatocellular Carcinoma: An Overview.

Author

Augello, Giuseppa, Cusimano, Alessandra, Cervello, Melchiorre, and Cusimano, Antonella

Subjects
*RNA physiology, *EXTRACELLULAR vesicles, *DRUG resistance in cancer cells, *MICRORNA, *CELL physiology, *TUMOR markers, *METASTASIS, *PATHOLOGIC neovascularization, *HEPATOCELLULAR carcinoma, *DISEASE progression
Abstract

Simple Summary: Hepatocellular carcinoma is a highly malignant tumor with increasing prevalence worldwide. Extracellular vesicles exert their biological functions via the delivery of different biomolecules, including non-coding RNAs. In this review, the diverse roles of the non-coding RNA cargo of hepatocellular carcinoma-derived extracellular vesicles will be discussed. Their function in tumor progression, immune escape, and drug resistance, as well as their potentialvalue as biomarkers of disease, will be summarized. Hepatocellular carcinoma (HCC) is the most common primary liver cancer. It is a major public health problem worldwide, and it is often diagnosed at advanced stages, when no effective treatment options are available. Extracellular vesicles (EVs) are nanosized double-layer lipid vesicles containing various biomolecule cargoes, such as lipids, proteins, and nucleic acids. EVs are released from nearly all types of cells and have been shown to play an important role in cell-to-cell communication. In recent years, many studies have investigated the role of EVs in cancer, including HCC. Emerging studies have shown that EVs play primary roles in the development and progression of cancer, modulating tumor growth and metastasis formation. Moreover, it has been observed that non-coding RNAs (ncRNAs) carried by tumor cell-derived EVs promote tumorigenesis, regulating the tumor microenvironment (TME) and playing critical roles in the progression, angiogenesis, metastasis, immune escape, and drug resistance of HCC. EV-related ncRNAs can provide information regarding disease status, thus encompassing a role as biomarkers. In this review, we discuss the main roles of ncRNAs present in HCC-derived EVs, including micro(mi) RNAs, long non-coding (lnc) RNAs, and circular (circ) RNAs, and their potential clinical value as biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma.

Author

Giannitrapani, Lydia, Di Gaudio, Francesca, Cervello, Melchiorre, Scionti, Francesca, Ciliberto, Domenico, Staropoli, Nicoletta, Agapito, Giuseppe, Cannataro, Mario, Tassone, Pierfrancesco, Tagliaferri, Pierosandro, Seidita, Aurelio, Soresi, Maurizio, Affronti, Marco, Bertino, Gaetano, Russello, Maurizio, Ciriminna, Rosaria, Lino, Claudia, Spinnato, Francesca, Verderame, Francesco, and Augello, Giuseppa

Subjects
GENETIC risk score, HEPATOCELLULAR carcinoma, SORAFENIB, DRUG absorption, BIOMARKERS
Abstract

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Genetic biomarkers of sorafenib response in patients with hepatocellular carcinoma

Author

Augello, Giuseppa, primary, Giannitrapani, Lydia, additional, Gaudio, Francesca Di, additional, Scionti, Francesca, additional, Ciliberto, Domenico, additional, Straropoli, Nicoletta, additional, Agapito, Giuseppe, additional, Cannataro, Mario, additional, Tassone, Pierfrancesco, additional, Tagliaferri, Pierosandro, additional, Seidita, Aurelio, additional, Soresi, Maurizio, additional, Affronti, Marco, additional, Bertino, Gaetano, additional, Russello, Maurizio, additional, Ciriminna, Rosaria, additional, Lino, Claudia, additional, Spinnato, Francesca, additional, Verderame, Francesca, additional, Cervello, Melchiorre, additional, and Arbitrio, Mariamena, additional

Published
2023
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6. Genetic biomarkers for sorafenib response in patients with hepatocellular carcinoma

Author

Augello, Giuseppa, primary, Arbitrio, Mariamena, additional, Giannitrapani, Lydia, additional, Scionti, Francesca, additional, Ciliberto, Domenico, additional, Staropoli, Nicoletta, additional, Agapito, Giuseppe, additional, Tassone, Pierfrancesco, additional, Tagliaferri, Pierosandro, additional, Soresi, Maurizio, additional, Seidita, Aurelio, additional, Affronti, Marco, additional, Bertino, Gaetano, additional, Russello, Maurizio, additional, Di Gaudio, Francesca, additional, Ciriminna, Rosaria, additional, Spinnato, Francesca, additional, Verderame, Francesco, additional, and Cervello, Melchiorre, additional

Published
2023
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9. The clinical impact of an extra virgin olive oil enriched mediterranean diet on metabolic syndrome: Lights and shadows of a nutraceutical approach

Author

Seidita, Aurelio, primary, Soresi, Maurizio, additional, Giannitrapani, Lydia, additional, Di Stefano, Vita, additional, Citarrella, Roberto, additional, Mirarchi, Luigi, additional, Cusimano, Antonella, additional, Augello, Giuseppa, additional, Carroccio, Antonio, additional, Iovanna, Juan Lucio, additional, and Cervello, Melchiorre, additional

Published
2022
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10. Outcome predictors in SARS-CoV-2 disease (COVID-19): The prominent role of IL-6 levels and an IL-6 gene polymorphism in a western Sicilian population

Author

Giannitrapani, Lydia, primary, Augello, Giuseppa, additional, Mirarchi, Luigi, additional, Amodeo, Simona, additional, Veronese, Nicola, additional, Sasso, Bruna Lo, additional, Giglio, Rosaria Vincenza, additional, Licata, Anna, additional, Barbagallo, Mario, additional, Ciaccio, Marcello, additional, Cervello, Melchiorre, additional, and Soresi, Maurizio, additional

Published
2022
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13. miR-126-3p and miR-21-5p as Hallmarks of Bio-Positive Ageing; Correlation Analysis and Machine Learning Prediction in Young to Ultra-Centenarian Sicilian Population

Author

Accardi, Giulia, primary, Bono, Filippa, additional, Cammarata, Giuseppe, additional, Aiello, Anna, additional, Herrero, Maria Trinidad, additional, Alessandro, Riccardo, additional, Augello, Giuseppa, additional, Carru, Ciriaco, additional, Colomba, Paolo, additional, Costa, Maria Assunta, additional, De Vivo, Immaculata, additional, Ligotti, Mattia Emanuela, additional, Lo Curto, Alessia, additional, Passantino, Rosa, additional, Taverna, Simona, additional, Zizzo, Carmela, additional, Duro, Giovanni, additional, Caruso, Calogero, additional, and Candore, Giuseppina, additional

Published
2022
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15. NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response

Author

Teresa Borrello, Maria, primary, Rita Emma, Maria, additional, Listi, Angela, additional, Rubis, Marion, additional, Coslet, Sergiu, additional, Augello, Giuseppa, additional, Cusimano, Antonella, additional, Cabibi, Daniela, additional, Porcasi, Rossana, additional, Giannitrapani, Lydia, additional, Soresi, Maurizio, additional, Pantuso, Gianni, additional, Blyth, Karen, additional, Montalto, Giuseppe, additional, Pin, Christopher, additional, Cervello, Melchiorre, additional, and Iovanna, Juan, additional

Published
2021
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16. Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease

Author

Lo Curto, Alessia, primary, Taverna, Simona, additional, Costa, Maria Assunta, additional, Passantino, Rosa, additional, Augello, Giuseppa, additional, Adamo, Giorgia, additional, Aiello, Anna, additional, Colomba, Paolo, additional, Zizzo, Carmela, additional, Zora, Marco, additional, Accardi, Giulia, additional, Candore, Giuseppina, additional, Francofonte, Daniele, additional, Di Chiara, Tiziana, additional, Alessandro, Riccardo, additional, Caruso, Calogero, additional, Duro, Giovanni, additional, and Cammarata, Giuseppe, additional

Published
2021
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17. SAT-288 - Genetic biomarkers for sorafenib response in patients with hepatocellular carcinoma

Author

Augello, Giuseppa, Arbitrio, Mariamena, Giannitrapani, Lydia, Scionti, Francesca, Ciliberto, Domenico, Staropoli, Nicoletta, Agapito, Giuseppe, Tassone, Pierfrancesco, Tagliaferri, Pierosandro, Soresi, Maurizio, Seidita, Aurelio, Affronti, Marco, Bertino, Gaetano, Russello, Maurizio, Di Gaudio, Francesca, Ciriminna, Rosaria, Spinnato, Francesca, Verderame, Francesco, and Cervello, Melchiorre

Published
2023
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19. Hepatocellular Carcinoma: A Difficult Cancer to Treat

Author

Cusimano, Antonella, primary, Soresi, Maurizio, additional, Montalto, Giuseppe, additional, Augello, Giuseppa, additional, Emma, Maria Rita, additional, Azzolina, Antonina, additional, Cervello, Melchiorre, additional, and Giannitrapani, Lydia, additional

Published
2021
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20. Hepatic and circulating levels of PCSK9 in morbidly obese patients: Relation with severity of liver steatosis

Author

Emma, Maria R., primary, Giannitrapani, Lydia, additional, Cabibi, Daniela, additional, Porcasi, Rossana, additional, Pantuso, Gianni, additional, Augello, Giuseppa, additional, Giglio, Rosaria V., additional, Re, Noemi Lo, additional, Capitano, Adele R., additional, Montalto, Giuseppe, additional, Soresi, Maurizio, additional, and Cervello, Melchiorre, additional

Published
2020
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21. NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response

Author

Borrello, Maria Teresa, primary, Emma, Maria Rita, additional, Listi, Angela, additional, Rubis, Marion, additional, Coslet, Sergiu, additional, Augello, Giuseppa, additional, Cusimano, Antonella, additional, Cabibi, Daniela, additional, Porcasi, Rossana, additional, Giannitrapani, Lydia, additional, Soresi, Maurizio, additional, Pantuso, Gianni, additional, Blyth, Karen, additional, Montalto, Giuseppe, additional, Pin, Christopher, additional, Cervello, Melchiorre, additional, and Iovanna, Juan, additional

Published
2020
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22. GSK-3 in liver diseases: Friend or foe?

Author

Emma, Maria R., primary, Augello, Giuseppa, additional, Cusimano, Antonella, additional, Azzolina, Antonina, additional, Montalto, Giuseppe, additional, McCubrey, James A., additional, and Cervello, Melchiorre, additional

Published
2020
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24. The Prevalence of NAFLD and Fibrosis in Bariatric Surgery Patients and the Reliability of Noninvasive Diagnostic Methods

Author

Soresi, Maurizio, primary, Cabibi, Daniela, additional, Giglio, Rosaria V., additional, Martorana, Stefania, additional, Guercio, Giuseppina, additional, Porcasi, Rossana, additional, Terranova, Antonino, additional, Lazzaro, Luigi A., additional, Emma, Maria R., additional, Augello, Giuseppa, additional, Cervello, Melchiorre, additional, Pantuso, Gianni, additional, Montalto, Giuseppe, additional, and Giannitrapani, Lydia, additional

Published
2020
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26. New landscapes and horizons in hepatocellular carcinoma therapy

Author

Cervello, Melchiorre, primary, Emma, Maria R., additional, Augello, Giuseppa, additional, Cusimano, Antonella, additional, Giannitrapani, Lydia, additional, Soresi, Maurizio, additional, Akula, Shaw M., additional, Abrams, Stephen L., additional, Steelman, Linda S., additional, Gulino, Alessandro, additional, Belmonte, Beatrice, additional, Montalto, Giuseppe, additional, and McCubrey, James A., additional

Published
2020
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28. Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Author

Augello, Giuseppa, primary, Emma, Maria Rita, additional, Cusimano, Antonella, additional, Azzolina, Antonina, additional, Mongiovì, Sarah, additional, Puleio, Roberto, additional, Cassata, Giovanni, additional, Gulino, Alessandro, additional, Belmonte, Beatrice, additional, Gramignoli, Roberto, additional, Strom, Stephen C., additional, McCubrey, James A., additional, Montalto, Giuseppe, additional, and Cervello, Melchiorre, additional

Published
2018
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37. Cationic solid lipid nanoparticles complexed with genetic material for liver tumor treatment

Author

BOTTO, Chiara, BONDI', Maria Luisa, Amore, Erika, EMMA, Maria Rita, AUGELLO, Giuseppa, GIAMMONA, Gaetano, Vincenti, V., Cervello, M., Botto, C., Bondì, M., Amore, E., Vincenti, V., Emma, M., Augello, G., Giammona, G., and Cervello, M.

Subjects
siRNA, DNA plasmid, CATIONIC NANOPARTICLES, cationic nanoparticles, liver, gene delivery, HEPATOCARCINOMA, GENE DELIVERY
Abstract

Concept Gene therapy is a growing field of medicine with great potential for the treatment of several diseases and it is based on the delivery of nucleic acids (DNA, RNA, etc.,) to specific cells. To achieve their therapeutic effects, the nucleic acids need to cross several biological barriers and be protected from the degradation by nucleases, present in biological fluids and intracellular compartments, to successfully gain access to their intracellular targets. To overcome these hurdles, it is necessary to deliver the genetic material with biocompatible carriers able to facilitate its translocation across the cell membranes and protect it from being degraded while circulating in the bloodstream. At this purpose, viral and non-viral vectors have been used. Viral vectors usually have high transfection efficiencies, although there are several concerns about their use in human therapy such as an increased immune response, the possible recombination of oncogenes and the difficulty in scale-up. For these reasons, non-viral vectors have emerged as promising carriers due to their reduced immune response, low toxicity and their safety in comparison to viral vectors. Within this field, the use of solid lipid nanoparticles (SLN), made up of biocompatible and biodegradable lipids, solid at room and body temperatures, is of particular importance [1,2]. Motivations and Objectives In the present study, we aimed to develop cationic solid lipid nanoparticles able to efficiently bind, protect and deliver nucleic acids for the treatment of hepatocellular carcinoma. These nanosystems were designed in order to get features that made them suitable for parenteral administration (size, surface charge and hemocompatibility). We studied their potential as gene delivery systems carrying out biological assays (cytotoxicity, transfection, protection of the genetic material by DNasi degradation) on human hepatocellular carcinoma Hep3B cells. Results and Discussion Two different nanosystems were prepared, characterized in terms of size, polydipersity index and zeta potential, and complexed with siRNA and a DNA plasmid using different weight ratios. The physical binding between SLN and the nucleic acids was confirmed by Dynamic Light Scattering measurements and electrophoretic mobility studies. We also verified the acceptability of prepared formulations for parenteral administration performing hemocompatibility assays on human herytrocytes. Finally, in vitro biological characterization confirmed that these nanosystems are not toxic and able to protect and efficiently transfect genetic material to Hep3B cells.

Published
2015

39. Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma.

Author

Augello, Giuseppa, Emma, Maria Rita, Cusimano, Antonella, Azzolina, Antonina, Mongiovì, Sarah, Puleio, Roberto, Cassata, Giovanni, Gulino, Alessandro, Belmonte, Beatrice, Gramignoli, Roberto, Strom, Stephen C., McCubrey, James A., Montalto, Giuseppe, and Cervello, Melchiorre

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant tumor that responds very poorly to existing therapies, most probably due to its extraordinary inter‐ and intra‐tumor molecular heterogeneity. The modest therapeutic response to molecular targeted agents underlines the need for new therapeutic approaches for HCC. In our study, we took advantage of well‐characterized human HCC cell lines, differing in transcriptomic subtypes, DNA mutation and amplification alterations, reflecting the heterogeneity of primary HCCs, to provide a preclinical evaluation of the specific heat shock protein 90 (HSP90) inhibitor AUY922 (luminespib). Indeed, HSP90 is highly expressed in different tumor types, but its role in hepatocarcinogenesis remains unclear. Here, we analyzed HSP90 expression in primary human HCC tissues and evaluated the antitumor effects of AUY922 in vitro as well as in vivo. HSP90 expression was significantly higher in HCC tissues than in cirrhotic peritumoral liver tissues. AUY922 treatment reduced the cell proliferation and viability of HCC cells in a dose‐dependent manner, but did not do so for normal human primary hepatocytes. AUY922 treatment led to the upregulation of HSP70 and the simultaneous depletion of HSP90 client proteins. In addition, in a cell type‐dependent manner, treatment induced either both caspase‐dependent β‐catenin cleavage and the upregulation of p53, or Mcl‐1 expression, or NUPR1 expression, which contributed to the increased efficacy of, or resistance to, treatment. Finally, in vivo AUY922 inhibited tumor growth in a xenograft model. In conclusion, HSP90 is a promising therapeutic target in HCC, and AUY922 could be a drug candidate for its treatment. What's new? Hepatocellular carcinoma (HCC) exhibits vast molecular heterogeneity, suggesting that therapies aimed against targets that interact with multiple signaling pathways could be key to improving HCC outcome. Here, heat shock protein 90 (HSP90), a modulator of numerous signaling components, was found to be highly expressed in HCC. AUY922, an HSP90 inhibitor, blocked HCC cell growth in vitro and, in HepG2 liver carcinoma cells, induced apoptosis via caspase activation and β‐catenin fragmentation. These effects were not observed in Huh7 or SNU475 HCC cell lines. AUY922 also reduced tumor growth in vivo, marking HSP90 as a promising therapeutic target in HCC. [ABSTRACT FROM AUTHOR]

Published
2019
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41. Association Between <italic>MICA</italic> Gene Variants and the Risk of Hepatitis C Virus-Induced Hepatocellular Cancer in a Sicilian Population Sample.

Author

Augello, Giuseppa, Balasus, Daniele, Fusilli, Caterina, Mazza, Tommaso, Emma, Maria Rita, Giannitrapani, Lydia, Agliastro, Rosalia, Cervello, Melchiorre, and Montalto, Giuseppe

Subjects
*HEPATITIS C virus, *LIVER cancer, *GENOTYPES, *CIRRHOSIS of the liver, *GENETIC polymorphisms
Abstract

There are currently no biomarkers that predict hepatocellular carcinoma (HCC) risk in patients with hepatitis C virus (HCV)-related cirrhosis. We investigated the relationships among major histocompatibility complex (MHC) class I chain-related gene A (MICA) polymorphisms, plasma levels of soluble MICA (sMICA), and HCC risk in patients with HCV-related HCC. One hundred fifty-four HCV-related HCC patients, 93 HCV-related liver cirrhosis (LC) cases, and 244 healthy controls, all sampled from the native Sicilian population, were genotyped using the KASP™ single-nucleotide polymorphism genotyping method. The MICA rs2596542 polymorphism showed that the G/G genotype was significantly more frequent in HCC than control subjects and LC patients (p < 0.005). For MICA rs2596538 polymorphism, the C allele and C/C genotype were significantly more frequent in HCC than in controls and LC cases (p < 0.005), after controlling for potential confounders. These results demonstrate that MICA rs2596542G/G, and particularly the rs2596538C/C polymorphism, are associated with the risk of developing HCV-related HCC in a Sicilian population sample. Importantly, using a machine learning classifier, we found that “age” and either rs2596542 or rs2596538 were important discriminating factors for patients with LC and HCC. Finally, sMICA levels significantly increased during HCV-related liver disease progression, while a significant relationship between both rs2596542 and rs2596538 genotypes and sMICA plasma levels was identified in patients with LC and HCC. In summary, the MICA rs2596538 and rs2596542 variants warrant further research for their clinical validity and utility in relationship to the risk of developing HCV-related HCC in independent populations. [ABSTRACT FROM AUTHOR]

Published
2018
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43. Western Blotting Analysis

Author

ANGILERI, Liliana, AUGELLO, Giuseppa, LAURICELLA, Marianna, Carlisi D, Di Fiore R, Portanova P, Tesoriere G., ANGILERI L, AUGELLO G, and LAURICELLA M

Subjects
Protein Analysis
Published
2008

45. In Human Retinoblastoma Y-79 Cells 3-aminobenzamide induces Differentiation

Author

MANGANO, Valentina, DI LEONARDO, Elvira Rosalia, DE BLASIO, Anna, DRAGO FERRANTE, Rosa, DI FIORE, Riccardo, AUGELLO, Giuseppa, MESSINA, Concetta Maria, SANTULLI, Andrea, VENTO, Renza, Mangano, V, Di Leonardo, E, De Blasio, A, Drago Ferrante, R, Di Fiore, R, Augello, G, Messina, C, Santulli, A, and Vento, R.

Subjects
PARP inhibitor, Retinoblastoma, differentiation
Published
2006

50. Outcome predictors in SARS-CoV-2 disease (COVID-19): The prominent role of IL-6 levels and an IL-6 gene polymorphism in a western Sicilian population

Author

Lydia Giannitrapani, Giuseppa Augello, Luigi Mirarchi, Simona Amodeo, Nicola Veronese, Bruna Lo Sasso, Rosaria Vincenza Giglio, Anna Licata, Mario Barbagallo, Marcello Ciaccio, Melchiorre Cervello, Maurizio Soresi, Giannitrapani, Lydia, Augello, Giuseppa, Mirarchi, Luigi, Amodeo, Simona, Veronese, Nicola, Sasso, Bruna Lo, Giglio, Rosaria Vincenza, Licata, Anna, Barbagallo, Mario, Ciaccio, Marcello, Cervello, Melchiorre, and Soresi, Maurizio

Subjects
Microbiology (medical), Polymorphism, Genetic, Settore MED/09 - Medicina Interna, Infectious Diseases, COVID-19, Interleukin-6, SARS-CoV-2, Human
Published
2022

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