Suchergebnisse

The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger. © 2013 The Anatomical Society and John Wiley & Sons Ltd. ; This work was supported by grants SAF2009-09031 and SAF2012-32117 from the Spanish Government to IP, and core support from MRCand grants from MRCT, CRUK, AICR, and the EMBO Young Investigator Programme to JG. We are grateful to Manuel Serrano and Daniel Peeperfor reagents and advice, and to Pablo Huertas for help with DDR assays. ; Peer Reviewed

Six1 is a developmental transcriptional regulator frequently overexpressed in human tumors. Recent results show that SIX1 also acts as a repressor of cell senescence, an antiproliferative response with a key role in tumor suppression, among other physiological and pathological settings. Here, we set to study the impact of SIX1 gain of function in transformation and tumorigenesis of fibroblasts, in connection with senescence. Using transcriptomic, histological, and functional analyses in murine tumors and cells of fibroblast origin, we show that SIX1 has a strong pro-tumorigenic action in this model, linked to the repression of a senescence-related gene signature and the induction of an undifferentiated phenotype mediated, at least in part, by the regulation of the stemness factor Sox2. Moreover, functional analyses with human glioma cell lines also show that SIX1 controls SOX2 expression, senescence and self-renewal in this model. Collectively, our results support a general link of SIX1 with senescence and SOX2-mediated cell plasticity in tumors. ; This work was supported by grants SAF2015-65960P (MINECO-FEDER) to IP, and CP16/00039, PI16/01580 (Instituto Salud Carlos III-FEDER) to AM. JA-I is the recipient of a predoctoral fellowship (PRE20160375) from the Department of Education, University and Research of the Basque Government. ; Peer reviewed

© 2021 The Authors. ; Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness. ; This work was supported by grants to E. González-Suárez by the Agencia Estatal de Investigación (AEI) (SAF2014-55997-R, SAF2017-86117-R) co-funded by FEDER funds/European Regional Development Fund (ERDF) (a way to build Europe), by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 682935), and by the Fundació La Marató de TV3. We thank CERCA Programme/Generalitat de Catalunya for institutional support. S. Benítez was a recipient of an FPI, A. Collado-Solé holds an FPU from the MICINN and J Redondo-Pedraza is a recipient of an FPI Severo Ochoa Fellowship. We are grateful to Amgen for providing Rankl and Rankt+/tg mice.