Giulia Fontemaggi

Istituti di Ricovero e Cura a Carattere Scientifico

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Giovanni Blandino

Istituti di Ricovero e Cura a Carattere Scientifico

Sabrina Strano

Istituti di Ricovero e Cura a Carattere Scientifico

Federica Ganci

Istituti di Ricovero e Cura a Carattere Scientifico

Andrea Sacconi

Istituti di Ricovero e Cura a Carattere Scientifico

Paola Muti

Istituti di Ricovero e Cura a Carattere Scientifico

Valentina Manciocco

Istituti Fisioterapici Ospitalieri

Francesco Fazi

Sapienza University of Rome

Chiara Turco

Istituti di Ricovero e Cura a Carattere Scientifico

Giuseppe Spriano

Humanitas University

Renato Covello

Istituti di Ricovero e Cura a Carattere Scientifico

Cooperative Institutions

Istituti di Ricovero e Cura a Carattere Scientifico

Sapienza University of Rome

National Cancer Institute

Instituto Nazionale Tumori Regina Elena

Istituti Fisioterapici Ospitalieri

Weizmann Institute of Science

Tumori Foundation

Istituto Pasteur

University of Rome Tor Vergata

Fondazione IRCCS Istituto Nazionale dei Tumori

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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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Identification of post-transcriptional regulatory networks during myeloblast-to-monocyte differentiation transition

Italian Journal of Anatomy and Embryology (2015)

Teresa Bellissimo Giulia Fontemaggi Sara Donzelli Ilaria Iosue Barbara Benassi

During hematopoiesis it is clearly emerging that microRNAs are integrated with target genes in regulatory circuitries involved in the decisions regarding the ability to self-renew and to generate a differentiated progeny in hematopoietic cells including myeloid cells (1). microRNAs are able to modulate genes expression mainly by tuning the rate of proteins’ synthesis inhibiting the initiation or later stages of translation. A change in the association of an mRNA with polysomes is indicative of changes in its translation state. For instance, a block in translational initiation would result in reduced ribo- some density on the affected mRNA and a shift toward the lower-density fractions of the gradient (2). Prediction algorithms usually provide hundreds of target genes for each microRNA and the identification of reliable target genes is feasible only through single-gene approaches. To identify microRNA-mRNA networks relevant for the transition from myeloblasts to monocytes, we here evaluated the localization of microRNAs and mRNAs in ribosomal/polysomal cell fractions obtained by sucrose density gradient centrifugation from the myeloblastic cell line HL60 induced or not to differentiate by 1,25-dihydroxyvitamin D3 treatment to induce monocyte/macrophage differentiation. The co-localization of miRNAs and predicted target mRNAs in low-density riboso- mal fractions is strongly indicative of their functional interaction. Intersection between mRNAs shifted across the fractions after treatment with putative target genes of modulated microRNAs showed a series of molecular net- works relevant for the monocyte cell fate determination, as for example the post-tran- scriptional regulation of the Polo-like kinase 1 (PLK1) by miR-22-3p and let-7e-5p. The disclosing of new molecular players involved in myeloid cell fate determina- tion paves the way for the identification of new potentially interesting molecular tar- gets for the treatment of acute myeloid leukemia cells.

Polysome

10.13128/ijae-16967

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Expression of TP53 mutation-associated microRNAs predicts clinical outcome in head and neck squamous cell carcinoma patients

Annals of Oncology (2013)

Federica Ganci Andrea Sacconi Noa Bossel Ben‐Moshe Valentina Manciocco Isabella Sperduti

10.1093/annonc/mdt380

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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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The locus of microRNA-10b

Cell Cycle (2013)

Francesca Biagioni Noa Bossel Ben‐Moshe Giulia Fontemaggi Yosef Yarden Eytan Domany

Contemporary microRNA research has led to significant advances in our understanding of the process of tumorigenesis. MicroRNAs participate in different events of a cancer cell's life, through their ability to target hundreds of putative transcripts involved in almost every cellular function, including cell cycle, apoptosis, and differentiation. The relevance of these small molecules is even more evident in light of the emerging linkage between their expression and both prognosis and clinical outcome of many types of human cancers. This identifies microRNAs as potential therapeutic modifiers of cancer phenotypes. From this perspective, we overview here the miR-10b locus and its involvement in cancer, focusing on its role in the establishment (miR-10b*) and spreading (miR-10b) of breast cancer. We conclude that targeting the locus of microRNA 10b holds great potential for cancer treatment.

10.4161/cc.25380

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Abstract 3010: The advent of miRNAs in the molecular taxonomy of breast cancer

Cancer Research (2010)

Francesca Biagioni Noa Bossel Ben‐Moshe Giulia Fontemaggi Barbara Antoniani Anna Di Benedetto

Abstract Breast cancer (BC) is the most common malignancy in women; worldwide, it is the second most common type of cancer after lung cancer and the fifth most common cause of cancer death. BC progresses as a multi-step process encompassing progressive changes. Although the majority of concepts related to morphologically-defined breast precursor lesions remain valid, molecular genetics and tumor phenotypic characterization have changed the way that the BC multi-step model is viewed. More recently, profiling BC using expression array technology has unravelled a novel molecular taxonomy which classifies BC in three main groups: Luminal, Basal-like and HER2, thereby further extending our knowledge regarding BC biology. microRNA is a new class of small molecules that has been linked to the regulation of proliferation, differentiation, apoptosis and even exocytosis. Accumulating evidence indicates that miRNAs are critical in the control of cell proliferation and survival. In particular, miRNAs show altered expression in cancers, in relation to that shown in normal tissue, which distinguishes cancers arising in different physiological sites. Some miRNAs exhibit differential expression levels in cancer and have demonstrated capability to affect cellular transformation, carcinogenesis and metastasis by acting either as oncogenes or tumor suppressors. Although microRNAs were discovered in humans a mere eight years ago, a host of promising potential applications in the diagnosis, prognoses and therapy of cancer is emerging at a rapid pace. Indeed, specific miRNA expression signatures could have a prognostic value, indicating that miRNAs are determinants of clinical aggressiveness. In this context, newly developed technology like microRNA profiling could have not only the potential to classify tumors but also to predict patient outcome with a high accuracy. In our study we analyzed the three main groups of breast cancer (BC) subtypes: Luminal, Basal-like and HER2. Two biopsies, from the tumor itself and from the peri-tumoral area, were obtained from each patient included in the study. In addition, biopsies from some healthy tissues (reductive mammoplasty) were also analyzed. We extracted RNA using TriZOL reagent and then checked, with the Agilent bioanalyzer, the quality of the samples. We performed the hybridization on Human miRNA Microarray from Agilent that contained probes for 723 human and 76 human viral microRNAs from the Sanger database v.10.1. The bioinformatic analysis revealed distinct groups of miRNAs that were selectively modulated by comparing tumor and peritumoral samples. Experimental work aimed at dissecting the functional role of microRNAs in breast cancer model is in progress. We believe that our work could contribute to a better understanding of the oncogenic potential of a specific subset of miRs and in general help to clarify the role of these microRNAs in the tumorigenic process of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3010.

10.1158/1538-7445.am10-3010

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Supplementary Figure 6 from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Federica Ganci Claudio Pulito Sara Valsoni Andrea Sacconi Chiara Turco

<p>Supplementary Figure 6</p>

Gain of function

10.1158/1078-0432.22477313.v1

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Supplementary Data from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Federica Ganci Claudio Pulito Sara Valsoni Andrea Sacconi Chiara Turco

<p>Supplementaty tables</p>

Gain of function

10.1158/1078-0432.22477334.v1

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Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells

Oncogene (2013)

Silvia Masciarelli Giulia Fontemaggi Silvia Di Agostino Sara Donzelli Elena Carcarino

10.1038/onc.2013.106

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Citations (127)

Mutant p53 oncogenic functions are sustained by Plk2 kinase through an autoregulatory feedback loop

Cell Cycle (2011)

Fabio Valenti Francesca Fausti Francesca Biagioni Tal Shay Giulia Fontemaggi

AbstractAberrant activation of kinases has emerged to be a key event along with tumor progression, maintenance of tumor phenotype and response to anticancer treatments. This study documents the existence of an oncogenic auto-regulatory feedback loop that includes the Polo-like kinase-2 (Snk/Plk2) and mutant p53 proteins. Plk2 protein binds to and phosphorylates mutant p53, thereby potentiating its oncogenic activities. Phosphorylated mutant p53 binds more efficiently to p300 consequently strengthening its own transcriptional activity. Plk2 gene is regulated at a transcriptional level by both wt- and mutant p53 proteins. This leads to growth suppression or enhanced cell proliferation and chemo-resistance, respectively. In turn, the siRNA-mediated knock down of either mutant p53 or Plk2 proteins significantly curtails the growth properties of tumor cells and their chemo-resistance to anticancer treatments. Therefore, this paper identifies a novel tumor network including Plk2 and mutant p53 proteins whose triggering in response to DNA damage might disclose important implications for the treatment of human cancers.

10.4161/cc.10.24.18682

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Citations (64)