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EBioMedicine ; 46: 79-93, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31303496


BACKGROUND: Metastatic colorectal cancer (CRC) remains a deadly disease. Identifying locally advanced CRC patients with high risk of developing metastasis and improving outcome of metastatic CRC patients require discovering master regulators of metastasis. In this context, the non-coding part of the human genome is still largely unexplored. METHODS: To interrogate the non-coding part of the human genome and disclose regulators of CRC metastasis, we combined a transposon-based forward genetic screen with a novel in vitro assay, which forces cells to grow deprived of cell-substrate and cell-cell contacts (i.e. forced single cell suspension assay - fSCS). FINDINGS: We proved that fSCS selects CRC cells with mesenchymal and pro-metastatic traits. Moreover, we found that the transposon insertions conferred CRC cells resistance to fSCS and thus metastatic advantage. Among the retrieved transposon insertions, we demonstrated that the one located in the 3'UTR of BTBD7 disrupts miR-23b::BTBD7 interaction and contributes to pro-metastatic traits. In addition, miR-23b and BTBD7 correlate with CRC metastasis both in preclinical experiments and in clinical samples. INTERPRETATION: fSCS is a simple and scalable in vitro assay to investigate pro-metastatic traits and transposon-based genetic screens can interrogate the non-coding part of the human genome (e.g. miRNA::target interactions). Finally, both Btbd7 and miR-23b represent promising prognostic biomarkers and therapeutic targets in CRC. FUND: This work was supported by Marie Curie Actions (CIG n. 303877) and Friuli Venezia Giulia region (Grant Agreement n°245574), Italian Association for Cancer Research (AIRC, MFAG n°13589), Italian Ministry of Health (GR-2010-2319387 and PE-2016-02361040) and 5x1000 to CRO Aviano.

Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Interferencia de ARN , Comunicación Celular , Línea Celular Tumoral , Proliferación Celular , Transición Epitelial-Mesenquimal/genética , Matriz Extracelular/metabolismo , Pruebas Genéticas , Humanos , Metástasis de la Neoplasia , Estadificación de Neoplasias
Int Rev Cell Mol Biol ; 333: 173-228, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28729025


Approximately a decade ago the first MicroRNAs (MiRNAs) participating in cancer metastasis were identified and metastmiRs were initially only a handful. Since those first reports, MiRNA research has explosively thrived, mainly due to their revolutionary mechanism of action and the hope of having at hand a novel tool to control cancer aggressiveness. This has ultimately led to delineate an almost impenetrable regulatory network: hundreds of MiRNAs transversally dominating every aspect of normal and cancer biology, each MiRNA having hundreds of targets and context-dependent activity. Providing a comprehensive description of MiRNA roles in cancer metastasis is a daunting task; nevertheless, we still believe that grasping the big picture of MiRNAs in cancer metastasis can give a different perspective on the potential insights and approaches that MiRNAs can offer to understand cancer complexity (e.g., as predictive and prognostic markers) and to tackle cancer metastasis (e.g., as therapeutic targets or tools). This chapter presents a schematic overview of the role of MiRNAs in governing cancer metastasis, describing step by step the cellular and molecular processes whereby cancer cells conquer distant organs and can grow as secondary tumors at different distant sites, and for each step, we will introduce how MiRNAs impinge on each one of them. We deeply apologize with our colleagues for any of their research work that, for clarity, for our effort to streamline and due to space limitations, we did not cite.

MicroARNs/metabolismo , Metástasis de la Neoplasia/genética , Neoplasias/metabolismo , Animales , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias/genética , Neoplasias/patología , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo
Cell Death Dis ; 7(9): e2374, 2016 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-27899818


Rs3814113 is the single-nucleotide polymorphism (SNP) showing the strongest association with high-grade serous ovarian carcinoma (HGSOC) incidence and is located in an intergenic region about 44 kb downstream of basonuclin 2 (BNC2) gene. Lifetime number of ovulations is associated with increased risk to develop HGSOC, probably because of cell damage of extrauterine Müllerian epithelium by ovulation-induced oxidative stress. However, the impact of low-penetrance HGSOC risk alleles (e.g. rs3814113) on the damage induced by oxidative stress remains unclear. Therefore, the purpose of this study was to investigate whether rs3814113 genetic interval regulates BNC2 expression and whether BNC2 expression levels impact on cell survival after oxidative stress. To do this, we analyzed gene expression levels of BNC2 first in HGSOC data sets and then in an isogenic cell line that we engineered to carry a 5 kb deletion around rs3814113. Finally, we silenced BNC2 and measured surviving cells after hydrogen peroxide (H2O2) treatment to simulate oxidative stress after ovulation. In this paper, we describe that BNC2 expression levels are reduced in HGSOC samples compared with control samples, and that BNC2 expression levels decrease following oxidative stress and ovulation in vitro and in vivo, respectively. Moreover, deletion of 5 kb surrounding rs3814113 decreases BNC2 expression levels in an isogenic cell line, and silencing of BNC2 expression levels increases cell survival after H2O2 treatment. Altogether, our findings suggest that the intergenic region located around rs3814113 regulates BNC2 expression, which in turn affects cell survival after oxidative stress response. Indeed, HGSOC samples present lower BNC2 expression levels that probably, in the initial phases of oncogenic transformation, conferred resistance to oxidative stress and ultimately reduced the clearance of cells with oxidative-induced damages.

Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Proteínas de Unión al ADN/genética , Genes Supresores de Tumor , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Estrés Oxidativo , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Ligamiento Genético , Genoma Humano , Humanos , Peróxido de Hidrógeno/toxicidad , Ratones , Clasificación del Tumor , Estrés Oxidativo/genética , Polimorfismo de Nucleótido Simple/genética