Biology subjects

Penzo, M.

Publications and source records attributed to Penzo, M..

7 recordsLinked to original sources

bioRxiv2026

Landscape of 8q24.3-Encoded microRNAs and Their Prognostic Impact in Ovarian Cancer

Ovarian cancer is the most lethal gynecological malignancy, largely because of late diagnosis and marked genomic instability, with high-grade serous ovarian cancer (HGSOC) representing its most common and aggressive subtype. Amplification of chromosome 8q24.3 is a recurrent event in HGSOC, yet the regulation and clinical relevance of the non-coding RNA output from this locus remain poorly defined. Here, we performed an integrative analysis of 8q24.3-encoded miRNAs in ovarian cancer using copy-number, transcriptomic, isoform-resolved, and clinical data from TCGA and NCBI datasets. We identified pronounced heterogeneity in miRNA abundance and strand usage across this locus. Copy-number gain broadly associated with increased miRNA expression, although this effect was not uniform across all candidates. Intronic miRNAs showed variable coupling with their host genes, indicating that mature miRNA output is shaped by both genomic dosage and post-transcriptional regulation. Isoform-level analysis revealed marked strand asymmetry and regulatory complexity, but did not strengthen copy-number or histotype associations compared with total miRNA measurements. Clinically, higher expression of miR-937, miR-4664, and miR-6849 was associated with improved overall survival in HGSOC. Functional enrichment of validated targets highlighted pathways related to cellular stress responses, senescence, p53 signaling, endocytosis, and metabolic adaptation. Together, these findings define 8q24.3 as a heterogeneous non-coding regulatory hub in ovarian cancer and provide a basis for future mechanistic and biomarker studies.

bioinformatics↗

bioRxiv2025

miR-6850 Drives Phenotypic Changes and Signaling in High Grade Serous Ovarian Cancer

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression, and their dysregulation is closely linked to cancer development. Ovarian cancer (OC), particularly the high-grade serous ovarian carcinoma (HGSOC) subtype, is the most lethal gynecological malignancy, primarily due to late-stage diagnosis and limited treatment options. Among the miRNAs encoded at the often amplified 8q24.3 region, miR-6850 has emerged as a potential candidate target owing to its genomic positioning inside this hotspot and its unexpectedly low expression in HGSOC tissues and cell lines. In silico investigations indicated that, despite the gain in MIR6850 copy number, its mature products, miR-6850-5p and miR-6850-3p, were expressed at low levels; notably, MIR6850 gene amplification was associated with enhanced disease-specific survival. Functional studies revealed that ectopic production of both isoforms in SKOV-3 and NIH:OVCAR3 cells inhibited proliferation, compromised clonogenic capacity, and disturbed cell cycle progression. Moreover, miR-6850 altered cell phenotype by facilitating mesenchymal-to-epithelial transition (MET), as shown by the overexpression of E-cadherin and {beta}-catenin and the downregulation of Slug and Vimentin. It also regulated cell adhesion and migration while reducing global protein synthesis via the downregulation of the PI3K/Akt/mTOR pathway. Our results together identify miR-6850 as a tumor-suppressive miRNA in HGSOC, demonstrating its diverse anti-oncogenic actions and underscoring its potential as a prognostic biomarker and therapeutic target in ovarian cancer.

cancer biology↗

bioRxiv2025

Ribosomal protein L5 (RPL5/uL18) I60V mutation is associated to increased translation and modulates drug sensitivity in T-cell acute lymphoblastic leukemia cells

Somatic mutations in ribosomal proteins (RPs), including RPL5, have been reported in approximately 10% of pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL). In cancer, the incorporation of mutant RPs into ribosomes often disrupts canonical ribosome function, thereby contributing to disease development. In this study, we aimed to characterize the effects of the RPL5-I60V mutation in the context of T-ALL, focusing on its impact on translation and cellular responses to a panel of compounds in vitro. Using CRISPR-Cas9, we generated a homozygous knock-in mutant in Jurkat cells and investigated its effects on ribosome biogenesis. We observed both quantitative and qualitative alterations in the production of the large ribosomal subunit. Ribosomes containing the mutant RPL5 protein exhibited intrinsically increased protein synthesis activity, which correlated with enhanced cellular proliferation. We then evaluated the response of these mutant cells to a panel of compounds targeting protein synthesis at various levels--including an MNK1 inhibitor, metformin, silvestrol, homoharringtonine, anisomycin, resveratrol, and hygromycin B--as well as cytarabine, a chemotherapeutic agent commonly used in T-ALL treatment. Our results showed that the RPL5-I60V mutation confers increased sensitivity to most of these compounds, with the exception of hygromycin B. This study advances our understanding of how oncoribosomes contribute to cancer pathogenesis and highlights the therapeutic potential of directly or indirectly targeting altered ribosomes, offering insights for the development of personalized treatment strategies. HighlightsO_LIRPL5 mutations have been reported in T-ALL C_LIO_LIRibosomes containing the RPL5 I60V mutation exhibit increased translational activity C_LIO_LIIncreased proliferation is observed in cells harboring the RPL5-I60V mutation C_LIO_LIRPL5-I60V confers a specific drug sensitivity profile C_LI Statements and DeclarationsCompeting interests: The authors declare that they have no conflict of interest.

cancer biology↗

bioRxiv2025

From Flies to Humans: Conserved Roles of CEBPZ, NOC2L, and NOC3L in rRNA Processing and Tumorigenesis

NOC1, NOC2, and NOC3 are evolutionarily conserved nucleolar proteins that play an essential role in the maturation and processing of ribosomal RNA (rRNA). NOC1, in Drosophila is necessary to sustain rRNA processing, whereas its depletion leads to impaired polysome formation, reduced protein synthesis, and induces apoptosis. In this study, we demonstrated that the RNA-regulatory functions of NOC1 are conserved in vertebrates, where the reduction of the CEBPZ homolog of NOC1 leads to the accumulation of unprocessed 45S pre-rRNA, a reduction in protein synthesis, and inhibition of cell growth. Gene Ontology and bioinformatic analyses of CEBPZ, NOC2L, and NOC3L in tumors highlight a significant correlation between their expression and processes that regulate rRNA processing and ribosomal maturation. Moreover, comparative analysis of TCGA datasets from tumor databases revealed that CEBPZ, NOC2L, and NOC3L exhibit contrasting expression patterns across tumor types. This context-dependent behavior suggests that overexpression of these proteins may promote tumor growth, whereas reduced expression could exert tumor-suppressive effects, underscoring their complex and unexpected regulatory roles in cancer. Summary StatementNOC1, NOC2, and NOC3 are conserved nucleolar proteins essential for rRNA processing. Their reduction impairs rRNA maturation, decreases protein synthesis, and induces cell death. CEBPZ, NOC2L, and NOC3L show context-dependent expression in tumors, suggesting dual roles in cancer progression and suppression.

cancer biology↗

bioRxiv2023

Dissociable encoding of motivated behavior by parallel thalamo-striatal projections

The successful pursuit of goals requires the coordinated execution and termination of actions that lead to positive outcomes. This process is thought to rely on motivational states that are guided by internal drivers, such as hunger or fear. However, the mechanisms by which the brain tracks motivational states to shape instrumental actions are not fully understood. The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus that shapes motivated behaviors via its projections to the nucleus accumbens (NAc)1-8 and monitors internal state via interoceptive inputs from the hypothalamus and brainstem3,9-14. Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVTD2(+) and PVTD2(-), which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc4,15,16. In this study, we used fiber photometry to investigate the in vivo dynamics of these two distinct PVT neuronal types in mice performing a reward foraging-like behavioral task. We discovered that PVTD2(+) and PVTD2(-) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVTD2(-) neurons, also mirrored some of these parameters but to a much lesser extent. Importantly, these features were largely preserved when activity in PVT projections to the NAc was selectively assessed. Collectively, our results highlight the existence of two parallel thalamo-striatal projections that participate in the dynamic regulation of goal pursuits and provide insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.

animal behavior and cognition↗

bioRxiv2021

Nucleolar NOC1 controls protein synthesis and cell competition in Drosophila

NOC1 is a nucleolar protein necessary in yeast for both transport and maturation of ribosomal subunits. Here we show that in Drosophila NOC1 is essential for the correct animal development, and that its ubiquitous downregulation results in small larvae with reduced polysome abundance and decreased protein synthesis. NOC1 expression in multiple organs, such as the prothoracic gland and the fat body, is necessary for proper organ functioning. Reduction of NOC1 in clones from the imaginal discs results in small clones with cells that die by apoptosis, an event that is partially rescued using a M/+ background, suggesting that reduction of NOC1 causes the cells to acquire a loser state. This event was supported also by an increase in the transcription of Xrp1 and by activation of the pro-apoptotic eiger-JNK pathway, resulting in the upregulation of DILP8 as an indication of cellular damage. Here, we show that Drosophila NOC1 is important in the control of pre-rRNAs maturation and essential step in the regulation of ribosome biogenesis and its downregulation results in defects in growth and in cell competition, highlighting its novel function in this field. summary statementNOC1 is a nucleolar protein necessary for protein synthesis and ribosomal assembling. Its modulation induces cell competition and affects animal growth.

cell biology↗

bioRxiv2021

The pseudouridine synthase dyskerin binds to cytoplasmic H/ACA-box snoRNA retaining transcripts affecting nuclear hormone receptor dependence

Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. Since its defective function induces specific alterations in gene expression, we sought to unbiasedly identify mRNAs regulated by dyskerin. We found that dyskerin depletion affects the expression or the association with polysomes of selected mRNA isoforms characterized by the retention of H/ACA box snoRNA-containing introns. These snoRNA retaining transcripts (snoRTs) are bound by dyskerin and can interact with cytoplasmic ribosomes. We then characterized the cytoplasmic dyskerin RNA interactome finding both H/ACA box snoRTs and protein-coding transcripts. Since a fraction of these latter transcripts is involved in the nuclear hormone receptor binding, we tested to see if this specific activity is affected by dyskerin. Results indicate that dyskerin dysregulation may alter the dependence on nuclear hormone receptor ligands in breast cancer. Our work suggests a cytoplasmic function for dyskerin which could affect mRNA post-transcriptional networks relevant for nuclear hormone receptor functions.

molecular biology↗