TROP-2 Is Not a Therapeutic Target in Melanoma: a Morphological Study Sonia Fantone, Daniela Marzioni, Elisa Molinelli, Alessandra Filosa, Gaia Goteri, Anna Campanati, Roberto Campagna, Giovanni Tossetta Dermatology and Therapy, 2026 INTRODUCTION: Cutaneous malignant melanoma represents only 1% of all skin cancers, but it has become a leading cause of cancer death, especially in young adults, owing to the high number of patients with disease progression and recurrence. In fact, disease progression and recurrence is still an important issue in treatment of this disease. Trophoblast surface antigen-2 (TROP-2) is a type I transmembrane glycoprotein belonging to the epithelial cell adhesion molecule (EpCAM) family, a group of proteins involved in cell adhesion and anti-TROP-2 antibody-drug conjugate, and showed important beneficial effects in cancers. We hypothesized that if TROP-2 was expressed in melanomas, it could represent a therapeutic target. METHODS: In total, 50 primary melanomas at different stages and ten melanocytic nevi (used as control group) were analyzed for TROP-2 protein expression by immunohistochemistry and confocal microscopy. RESULTS: TROP-2 was expressed on the cell membranes of epidermal melanocytes and keratinocytes, while melanocytic nevi and melanoma tissues (at any stage) did not show TROP-2 expression. CONCLUSIONS: Our findings suggest that TROP-2 could not be considered a therapeutic target for melanoma treatment because of the absence of detectable expression in the analyzed cohort.
Novel Ti6Al4V Surface Treatment for Subperiosteal Dental Implants (Part II): Matrix Deposition and Osteogenic Markers Valentina Schiavoni, Lucia Memé, Giovanni Tossetta, Daniela Marzioni, Fabrizio Bambini, Andrea Frontini, Chiara Santoni, Paolo Moretti, Arianna Vignini, Roberto Campagna, Eleonora Salvolini Materials, 2026 In a previous study, we demonstrated that a novel surface treatment applied to laser-melted Ti6Al4V substrates supports osteoblast-like cell adhesion, proliferation, and the activation of early osteogenic pathways. Building on these preliminary findings, the present work aimed to further investigate the ability of the same surface to promote extracellular matrix (ECM) deposition, organization, and osteogenic maturation, which are critical events for the establishment of a stable bone–implant interface in subperiosteal dental implants. Human osteoblast-like MG-63 cells were cultured on Ti6Al4V discs subjected to different surface treatments, including a proprietary surface modification (ATcs) specifically designed for subperiosteal applications. ECM formation and maturation were evaluated through scanning electron microscopy coupled with energy-dispersive spectroscopy, immunofluorescence, and semiquantitative analyses of osteogenic markers type I collagen (COL1A1), secreted protein acidic and rich in cysteine (SPARC), and dentin matrix protein 1 (DMP1) through Western blotting. The results showed that, while all tested surfaces supported cell adhesion, the ATcs surface promoted a distinct osteogenic profile characterized by enhanced DMP1 expression, organized collagen deposition, and the formation of calcium–phosphate–rich mineralized structures. Compared to surfaces that primarily stimulated cell proliferation or early matrix production, ATcs appeared to favour progression toward late-stage osteogenic maturation and matrix mineralization. Taken together, these findings extend our previous observations and indicate that this novel surface treatment not only supports osteoblast viability and early differentiation but also promotes extracellular matrix maturation, a key prerequisite for effective osseointegration. Although further in vivo studies are required, the present data provide additional biological rationale for the use of ATcs-treated Ti6Al4V surfaces in next-generation custom-made subperiosteal implant designs.
Short and Long Non-Coding RNAs in Renal Cell Carcinoma Monia Cecati, Valentina Pozzi, Valentina Schiavoni, Giuseppina Barrasso, Veronica Pompei, Daniela Marzioni, Nicoletta Bonci, Stefania Fumarola, Andrea Ballini, Davide Sartini, Roberto Campagna Non Coding RNA, 2026 Renal cell carcinoma (RCC) represents the most frequent kidney malignancy and remains a major clinical challenge due to its often silent onset, high metastatic potential, and limited responsiveness to conventional chemotherapy. Increasing evidence indicates that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are key regulators of RCC tumorigenesis, progression, and therapy resistance. Rather than providing a purely descriptive overview, this review focuses on emerging mechanistic paradigms through which ncRNAs actively shape tumor behavior and therapeutic response in RCC. This review summarizes current knowledge on the biological and clinical relevance of ncRNAs in RCC, highlighting their dual roles as oncogenic drivers or tumor suppressors through the modulation of pathways involved in proliferation, apoptosis, angiogenesis, invasion, immune evasion, metabolic reprogramming, and ferroptosis. Particular emphasis is placed on mechanistically defined ncRNA regulatory axes controlling ferroptosis, autophagy, metabolic reprogramming, and immune escape, as well as on ncRNA-mediated intercellular communication via extracellular vesicles, which promotes the dissemination of resistance to targeted therapies. The review also addresses ncRNA-based diagnostic and prognostic applications, including miRNA signatures capable of discriminating RCC subtypes and circulating ncRNAs as minimally invasive biomarkers. Moreover, the manuscript discusses ncRNA-mediated mechanisms of resistance to targeted therapies such as sunitinib, sorafenib, and axitinib, emphasizing regulatory networks involving miRNA targets, lncRNA–miRNA sponging, RNA-binding proteins, extracellular vesicle transfer, and epigenetic modulation. Emerging therapeutic opportunities are also addressed, including strategies aimed at inhibiting oncogenic ncRNAs or restoring tumor-suppressive ncRNAs to enhance drug sensitivity and improve patient stratification.
Dose-dependent effects of curcumin on 22Rv1 prostate cancer cell line Giovanni Tossetta, Sonia Fantone, Elena Marinelli Busilacchi, Daniela Marzioni, Roberta Mazzucchelli Molecular Biology Reports, 2025 Background Prostate cancer (PCa) is the second most frequent cancer type in the male population over 66 years. Curcumin is a polyphenolic natural compound extract from the rhizomes of Curcuma longa Linn (Zingiberaceae family) which showed important anticancer effects by inhibiting cell proliferation and inducing apoptosis in several cancer types. Recently, some studies reported that oral curcumin lowered PSA levels, but it did not modify the clinical outcomes in patients with prostate cancer who received intermittent androgen deprivation (IAD). Other studies reported that high concentrations of curcumin were toxic for patients. Methods and results In this study we showed that low doses of curcumin can induce senescence-like effects in 22Rv1 cell line while higher concentrations have cytotoxic effects. Five,15 and 30 µM curcumin blocked cell cycle in G2/M phase but only 15 and 30 µM curcumin induced cell death. In addition, an increased expression of p21, a known senescence marker, was detected in 22Rv1 cells treated with curcumin in every experimental condition. However, the expression of p16, another known senescence marker, increased only to 30 µM curcumin. Conclusion In the context of personalized approach in PCa care, we suggest that the appropriate concentration of curcumin used in combination with radiotherapy or with androgen deprivation therapy (ADT) could be taken into consideration.
Effect of natural compounds on NRF2/KEAP1 signaling in periodontitis: a potential use to prevent age-related disorders Giovanni Tossetta, Sonia Fantone, Fabiola Olivieri, Roberta Mazzucchelli, Lucrezia Togni, Andrea Santarelli, Daniela Marzioni, Maria Rita Rippo Molecular Biology Reports, 2025 40% of the population over 60 years of age is affected by periodontitis which is characterized by chronic inflammation, periodontal damage and alveolar bone resorption. The nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2)/ Kelch-like ECH-Associated Protein 1 (KEAP1) (NRF2/KEAP1) signaling pathway plays a key role in periodontitis modulating redox balance and periodontium inflammation. However, NRF2 expression decreases in gingival tissues of severe periodontitis patients while Reactive Oxygen Species (ROS) levels are increased during periodontitis. ROS and lipopolysaccharide (LPS) produced by gram-negative bacteria favor the production of inflammatory cytokines, then causing periodontal inflammation and favoring alveolar bone loss (due to excessive osteoclast formation and activation). Periodontitis has also been associated to the development of age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases since the increased cytokines levels and the bacteria themselves present in the periodontium can easily reach the brain due to their anatomical proximity. Thus, periodontitis could be considered a risk factor for the development of Alzheimer’s and Parkinson’s diseases. In this review we explored the role of NRF2/KEAP1 signaling activation in in vitro and in vivo models of periodontitis to suggest potential treatments of periodontitis and avoid/delay the development of age-related neurodegenerative diseases.
NNMT expression in preeclampsia: Analyses on placental tissues and cell lines Giovanni Tossetta, Roberto Campagna, Sonia Fantone, Nicoletta Di Simone, Veronica Pompei, Stefano Raffaele Giannubilo, Andrea Ciavattini, Davide Sartini, Monica Emanuelli, Daniela Marzioni Placenta, 2025 OBJECTIVE: Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension and proteinuria during pregnancy. Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyzes the N-methylation of nicotinamide (NAM) to form 1-methylnicotinamide (MNA) and S-adenosyl-L-homocysteine (SAH). The aim of this study was to investigate NNMT expression in normal and PE placentas, and evaluate whether hypoxia, oxidative stress and inflammation could modulate NNMT expression. MATERIALS AND METHODS: ) and inflammatory (by TNF-α) conditions. RESULTS: NNMT was expressed in cytotrophoblast and syncytiotrophoblast of first, third and PE placentas. Endothelial vessels were positive for NNMT expression in first and third trimester but mainly negative in PE placentas. NNMT expression did not change from first to third trimester but significantly decreased in PE placentas compared to control placentas. NNMT was expressed in the cytoplasm of both HTR-8/SVneo and BeWo cell lines, and its expression was not altered by syncytialization. Hypoxia decreased NNMT expression in BeWo but not HTR-8/SVneo cells while oxidative stress did not alter NNMT expression in both cell lines. TNF-α treatment significantly decreased NNMT expression in both cell lines. CONCLUSIONS: Low NNMT expression found in PE placentas may represent a response to the hypoxia and inflammation featuring this disorder. Therefore, the enzyme could contribute to the normal human placental development, by defending trophoblast cells form PE-induced damages.
γ-H2AX: A useful tool to detect DNA damage in sudden cardiac death heart tissues, an experimental study Giovanni Tossetta, Sonia Fantone, Paolo Compagnucci, Daniela Marzioni, Eva Montanari, Margherita Neri, Francesco Paolo Busardò, Angelo Montana Tissue and Cell, 2025 Sudden cardiac death (SCD) is defined as death due to cardiovascular or unidentifiable causes that occurs within an hour of the onset of symptoms. Several lines of evidence suggest that oxidative stress, which is due to an increased production/accumulation of reactive oxygen species (ROS) in cells, may be associated with SCD. ROS can induce DNA damage leading to DNA double-strand break (DSB) that, if not repaired, can lead to cell death. In presence of a DNA DSB, H2AX (a histone H2A variant) is phosphorylated to form γ-H2AX, which binds the DNA DSBs and recruits DNA repair proteins. If DNA damage is excessive and cannot be repaired, cells undergo apoptosis. In the present study, we sought to evaluate the myocardial immunohistochemical expression of γ-H2AX in samples from patients suffering SCD as well as from healthy controls, in order to assess its potential role as a SCD biomarker.
Importance of STAT3 signaling in preeclampsia (Review) Daniela Marzioni, Federica Piani, Nicoletta Di Simone, Stefano Giannubilo, Andrea Ciavattini, Giovanni Tossetta International Journal of Molecular Medicine, 2025 Placentation is a key process that is tightly regulated that ensures the normal placenta and fetal development. Preeclampsia (PE) is a hypertensive pregnancy-associated disorder characterized by increased oxidative stress and inflammation. STAT3 signaling plays a key role in modulating important processes such as cell proliferation, differentiation, invasion and apoptosis. The present review aimed to analyse the role of STAT3 signaling in PE pregnancies, discuss the main natural and synthetic compounds involved in modulation of this signaling both in vivo and in vitro and summarize the main cellular modulators of this signaling to identify possible therapeutic targets and treatments to improve the outcome of PE pregnancies.
Effects of mineral fibres in an in vitro placental syncytiotrophoblast model Giovanni Tossetta, Sonia Fantone, Antonio Domenico Procopio, Armanda Pugnaloni, Alessandro Francesco Gualtieri, Daniela Marzioni Current Research in Toxicology, 2025 • UICC, VM and ERI did not alter BeWo cells syncytialization. • These fibres have a cytotoxic effect in BeWo cells. • UICC, VM and ERI fibres altered cell cycle, damage and repair mechanisms in BeWo cells. • Only UICC fibre significantly increased apoptosis in BeWo cells. It is known that mineral fibres can be found in placental tissues, but their effect is not known on these tissues. BeWo in vitro model of syncytiotrophoblast, the outer layer of maternal-foetal barrier, is necessary to understand if mineral fibres can alter placental cell turnover and consequently to influence the outcome of pregnancy. We performed in vitro experiments using chrysotile UICC (UICC), chrysotile Valmalenco (VM) and erionite (ERI) to investigate the potential cytotoxic effects of these mineral fibres on BeWo cells. We demonstrated that all fibres are toxic while only UICC fibres caused a DNA damage that the cells were not able to repair through RAD51 activity. In addition, we demonstrated that DNA replication is not altered while cyclin D1 showed a significant decrease in VM and UICC suggesting that the cell cycle is altered in G1 phase. Moreover, UICC increased active form of caspase 3 demonstrating that apoptosis can be induced in BeWo cells. We suggest that although morphological changes are not visible in BeWo cells treated with these mineral fibres, DNA damage can lead to altered placenta physiology that can be seen late when the damage at the foetal tissues has already occurred.
First Trimester Placental Biomarkers for Pregnancy Outcomes Martina Cristodoro, Martina Messa, Giovanni Tossetta, Daniela Marzioni, Marinella Dell’Avanzo, Annalisa Inversetti, Nicoletta Di Simone International Journal of Molecular Sciences, 2024
Role of SLC7A11/xCT in Ovarian Cancer Sonia Fantone, Federica Piani, Fabiola Olivieri, Maria Rita Rippo, Angelo Sirico, Nicoletta Di Simone, Daniela Marzioni, Giovanni Tossetta International Journal of Molecular Sciences, 2024
The Role of NQO1 in Ovarian Cancer Giovanni Tossetta, Sonia Fantone, Gaia Goteri, Stefano Raffaele Giannubilo, Andrea Ciavattini, Daniela Marzioni International Journal of Molecular Sciences, 2023
Pre-eclampsia predictive ability of maternal miR-125b: a clinical and experimental study Caterina Licini, Chiara Avellini, Elena Picchiassi, Emanuela Mensà, Sonia Fantone, Deborah Ramini, Chiara Tersigni, Giovanni Tossetta, Clara Castellucci, Federica Tarquini, Giuliana Coata, Irene Giardina, Andrea Ciavattini, Giovanni Scambia, Gian Carlo Di Renzo, Nicoletta Di Simone, Rosaria Gesuita, Stefano R. Giannubilo, Fabiola Olivieri, Daniela Marzioni Translational Research, 2021
Ciliary neurotrophic factor (CNTF) and its receptor (CNTFRα) signal through MAPK/ERK pathway in human prostate tissues: A morphological and biomolecular study European Journal of Histochemistry, 2020
The trophoblast cell surface antigen 2 and miR-125b axis in urothelial bladder cancer Chiara Avellini, Caterina Licini, Raffaella Lazzarini, Rosaria Gesuita, Emanuela Guerra, Giovanni Tossetta, Clara Castellucci, Stefano Raffaele Giannubilo, Antonio Procopio, Saverio Alberti, Roberta Mazzucchelli, Fabiola Olivieri, Daniela Marzioni Oncotarget, 2017
Low HtrA1 expression in patients with long-standing ulcerative colitis and colorectal cancer Emma Altobelli, Giovanni Latella, Manrico Morroni, Caterina Licini, Giovanni Tossetta, Roberta Mazzucchelli, Valerio F. Profeta, Gino Coletti, Pietro Leocata, Mario Castellucci, Mario Guerrieri, Reimondo Petrocelli, Berardo De Berardis, Marina De Padova, Gabriella Di Leonardo, Antonella Paladini, Filippo Mignosi, Gina Quaglione, Roberto Fagnano, Daniela Marzioni Oncology Reports, 2017
The novel role of HtrA1 in gingivitis, chronic and aggressive periodontitis Teresa Lorenzi, Elena Annabel Niţulescu, Antonio Zizzi, Maria Lorenzi, Francesca Paolinelli, Simone Domenico Aspriello, Monica Baniţă, Ştefania Crăiţoiu, Gaia Goteri, Giorgio Barbatelli, Tommaso Lombardi, Roberto Di Felice, Daniela Marzioni, Corrado Rubini, Mario Castellucci Plos One, 2014
TGF beta family members function in uterine healthy and fibrotic smooth muscle cells Italian Journal of Anatomy and Embryology, 2013
HtrA1 in human urothelial bladder cancer: A secreted protein and a potential novel biomarker Teresa Lorenzi, Maria Lorenzi, Emma Altobelli, Daniela Marzioni, Emanuela Mensà, Alexia Quaranta, Francesca Paolinelli, Manrico Morroni, Roberta Mazzucchelli, Antonio De Luca, Antonio Domenico Procopio, Alfonso Baldi, Giovanni Muzzonigro, Rodolfo Montironi, Mario Castellucci International Journal of Cancer, 2013
Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus Ilkka Liikanen, Vladia Monsurrò, Laura Ahtiainen, Mari Raki, Tanja Hakkarainen, Iulia Diaconu, Sophie Escutenaire, Otto Hemminki, João D Dias, Vincenzo Cerullo, Anna Kanerva, Sari Pesonen, Daniela Marzioni, Marco Colombatti, Akseli Hemminki Molecular Therapy, 2011
Expression pattern alterations of the serine protease HtrA1 in normal human placental tissues and in gestational trophoblastic diseases Histology and Histopathology, 2009
PUNLMP or not PUNLMP? This is the problem Analytical and Quantitative Cytology and Histology, 2009
