Biology subjects

Florio, T.

Publications and source records attributed to Florio, T..

3 recordsLinked to original sources

bioRxiv2025

Synergic microRNAs suppress human glioblastoma progression by modulating clinically relevant targets

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by therapy-resistant glioma stem-like cells (GSCs) and extensive infiltration into surrounding brain tissue. MicroRNAs (miRNAs) are post-transcriptional regulators of oncogenic pathways, but their tumor-suppressive function is frequently lost in GBM. This study explores a multimodal therapeutic approach by restoring a combination of miRNAs to exploit their synergistic effects against GBM. Using patient-derived GBM cells cultured under stem cell-permissive conditions, we demonstrate that miRNA restoration reduces tumor growth, limits invasiveness, stemness and enhances sensitivity to temozolomide. In vivo studies in an orthotopic xenograft mouse model of GBM confirm the therapeutic efficacy and low toxicity of the nanoformulated miRNAs, following local injection. Multi-omics and computational analyses on different GBM subtypes reveal that these miRNAs synergistically suppress tumor-promoting extracellular matrix interactions, particularly through the collagen pathway, and downregulate genes associated with GBM progression. The identified miRNA targets correlate with glioma grade and poor patient prognosis, further underscoring their therapeutic potential. These findings highlight the promise of combinatorial miRNA therapy as a novel strategy for GBM treatment and suggest new molecular targets for theragnostic development.

cancer biology↗

bioRxiv2022

Metformin antiproliferative activity is exclusively mediated by the membrane functional expression of the Chloride Intracellular Channel 1 in glioblastoma stem cells

Metformin is the first-line drug for type-2 diabetes. Retrospective analyses, based on diabetic patients clinical data, demonstrate that daily assumption of metformin reduces the incidence of several kinds of solid tumors. Even though it is widely agreed that metformin must be internalized to accomplish its pharmacological activity, direct evidence about metformin membrane permeability and/or the presence of a specific membrane receptor in cancer cells is still missing. Here, we show that the transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1) works as a privileged metformin receptor in glioblastoma stem-like cells. We found that metformin impairs tmCLIC1 activity by a specific binding coordinated by arginine 29. Its mutation, preventing metformin to bind and block tmCLIC1, abolishes the biguanide inhibition of glioblastoma cell proliferation in 2D and 3D models and metformin dependent effect on mitochondrial respiration. In addition, we demonstrate the direct binding between the drug and its target, and by in vivo experiments on zebrafish embryos and mice orthotopically engrafted with glioblastoma cells and treated with metformin, we prove that metformin binding to tmCLIC1 is crucial for metformin antineoplastic effect. Considering tmCLIC1s contribution to glioblastoma progression, the present work provides the fundaments for future development of strategies aimed at improving metformin-tmCLIC1 interaction to further increase metformin therapeutic potential.

cancer biology↗

bioRxiv2020

Increased and ectopic expression of Triticum polonicum VRT-A2 underlies elongated glumes and grains in hexaploid wheat in a dosage-dependent manner

Flower development is a major determinant of yield in crops. In wheat, natural variation for the size of spikelet and floral organs is particularly evident in Triticum polonicum, a tetraploid subspecies of wheat with long glumes, lemmas, and grains. Using map-based cloning, we identified VRT2, a MADS-box transcription factor belonging to the SVP family, as the gene underlying the T. polonicum long-glume (P1) locus. The causal P1 mutation is a sequence re-arrangement in intron-1 that results in both increased and ectopic expression of the T. polonicum VRT-A2 allele. Based on allelic variation studies, we propose that the intron-1 mutation in VRT-A2 is the unique T. polonicum species defining polymorphism, which was later introduced into hexaploid wheat via natural hybridizations. Near-isogenic lines differing for the P1 locus revealed a gradient effect of P1 across florets. Transgenic lines of hexaploid wheat carrying the T. polonicum VRT-A2 allele show that expression levels of VRT-A2 are highly correlated with spike, glume, grain, and floral organ length. These results highlight how changes in expression profiles, through variation in cis-regulation, can impact on agronomic traits in a dosage-dependent manner in polyploid crops. One-sentence summaryAn intron-1 rearrangement in the MADS-box transcription factor VRT-A2 leads to its misexpression and defines the long-glume phenotype of Polish wheat (T. polonicum).

plant biology↗