Stress et cancer

Publications de l’équipe

Année de publication : 2016

Luciana Batista, Brigitte Bourachot, Bogdan Mateescu, Fabien Reyal, Fatima Mechta-Grigoriou (2016 Jan 5)

Regulation of miR-200c/141 expression by intergenic DNA-looping and transcriptional read-through.

Nature communications : 8959 : DOI : 10.1038/ncomms9959 En savoir plus
Résumé

The miR-200 family members have been implicated in stress responses and ovarian tumorigenesis. Here, we find that miR-200c/141 transcription is intimately linked to the transcription of the proximal upstream gene PTPN6 (SHP1) in all physiological conditions tested. PTPN6 and miR-200c/141 are transcriptionally co-regulated by two complementary mechanisms. First, a bypass of the regular PTPN6 polyadenylation signal allows the transcription of the downstream miR-200c/141. Second, the promoters of the PTPN6 and miR-200c/141 transcription units physically interact through a 3-dimensional DNA loop and exhibit similar epigenetic regulation. Our findings highlight that transcription of intergenic miRNAs is a novel outcome of transcriptional read-through and reveal a yet unexplored type of DNA loop associating two closely located promoters. These mechanisms have significant relevance in ovarian cancers and stress response, pathophysiological conditions in which miR-200c/141 exert key functions.

Replier

Année de publication : 2015

Tina Gruosso, Camille Garnier, Sophie Abelanet, Yann Kieffer, Vincent Lemesre, Dorine Bellanger, Ivan Bieche, Elisabetta Marangoni, Xavier Sastre-Garau, Virginie Mieulet, Fatima Mechta-Grigoriou (2015 Oct 13)

MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas.

Nature communications : 8583 : DOI : 10.1038/ncomms9583 En savoir plus
Résumé

Ovarian cancer is a silent disease with a poor prognosis that urgently requires new therapeutic strategies. In low-grade ovarian tumours, mutations in the MAP3K BRAF gene constitutively activate the downstream kinase MEK. Here we demonstrate that an additional MAP3K, MAP3K8 (TPL-2/COT), accumulates in high-grade serous ovarian carcinomas (HGSCs) and is a potential prognostic marker for these tumours. By combining analyses on HGSC patient cohorts, ovarian cancer cells and patient-derived xenografts, we demonstrate that MAP3K8 controls cancer cell proliferation and migration by regulating key players in G1/S transition and adhesion dynamics. In addition, we show that the MEK pathway is the main pathway involved in mediating MAP3K8 function, and that MAP3K8 exhibits a reliable predictive value for the effectiveness of MEK inhibitor treatment. Our data highlight key roles for MAP3K8 in HGSC and indicate that MEK inhibitors could be a useful treatment strategy, in combination with conventional chemotherapy, for this disease.

Replier

Année de publication : 2014

Benjamin G Cuiffo, Antoine Campagne, George W Bell, Antonio Lembo, Francesca Orso, Evan C Lien, Manoj K Bhasin, Monica Raimo, Summer E Hanson, Andriy Marusyk, Dorraya El-Ashry, Peiman Hematti, Kornelia Polyak, Fatima Mechta-Grigoriou, Odette Mariani, Stefano Volinia, Anne Vincent-Salomon, Daniela Taverna, Antoine E Karnoub (2014 Dec 18)

MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis.

Cell stem cell : 762-74 : DOI : 10.1016/j.stem.2014.10.001 En savoir plus
Résumé

Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer.

Replier

Année de publication : 2013

Ana Costa, Alix Scholer-Dahirel, Fatima Mechta-Grigoriou (2013 Jul 30)

The role of reactive oxygen species and metabolism on cancer cells and their microenvironment.

Seminars in cancer biology : 23-32 : DOI : 10.1016/j.semcancer.2013.12.007 En savoir plus
Résumé

Compelling evidence show that reactive oxygen species (ROS) levels are finely regulated in the cell and can act as « second messengers » in response to diverse stimuli. In tumor epithelial cells, ROS accumulate abnormally and induce signaling cascades that mediate the oncogenic phenotype. In addition to their impact on tumor epithelial cells, ROS also affect the surrounding cells that constitute the tumor microenvironment. Indeed, ROS production increases tumor angiogenesis, drives the onset of inflammation and promotes conversion of fibroblast into myofibroblasts. These cells, initially identified upon wound healing, exhibit similar properties to those observed in fibroblasts associated with aggressive adenocarcinomas. Indeed, analyses of tumors with distinct severity revealed the existence of multiple distinct co-existing subtypes of carcinoma-associated fibroblasts (CAFs), with specific marker protein profiling. Chronic oxidative stress deeply modifies the proportion of these different fibroblast subtypes, further supporting tumor growth and metastatic dissemination. At last, ROS have been implicated in the metabolic reprogramming of both cancer cells and CAFs, allowing an adaptation to oxidative stress that ultimately promotes tumorigenesis and chemoresistance. In this review, we discuss the role of ROS in cancer cells and CAFs and their impact on tumor initiation, progression, and metastasis.

Replier
Alix Scholer-Dahirel, Ana Costa, Fatima Mechta-Grigoriou (2013 Jun 28)

Control of cancer-associated fibroblast function by oxidative stress: A new piece in the puzzle.

Cell cycle (Georgetown, Tex.) : 2169 En savoir plus
Résumé

Replier
Francesco Paneni, Elena Osto, Sarah Costantino, Bogdan Mateescu, Sylvie Briand, Giuseppe Coppolino, Enrico Perna, Pavani Mocharla, Alexander Akhmedov, Ruslan Kubant, Lucia Rohrer, Tadeusz Malinski, Giovanni G Camici, Christian M Matter, Fatima Mechta-Grigoriou, Massimo Volpe, Thomas F Lüscher, Francesco Cosentino (2013 Feb 14)

Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction.

Circulation : 1229-40, e1-21 : DOI : 10.1161/CIRCULATIONAHA.112.000826 En savoir plus
Résumé

Reactive oxygen species are major determinants of vascular aging. JunD, a member of the activated protein-1 family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to reactive oxygen species homeostasis in the vasculature remains unknown.

Replier
Richard P Hull, Prashant K Srivastava, Zelpha D'Souza, Santosh S Atanur, Fatima Mechta-Grigoriou, Laurence Game, Enrico Petretto, H Terence Cook, Timothy J Aitman, Jacques Behmoaras (2013 Feb 13)

Combined ChIP-Seq and transcriptome analysis identifies AP-1/JunD as a primary regulator of oxidative stress and IL-1β synthesis in macrophages.

BMC genomics : 92 : DOI : 10.1186/1471-2164-14-92 En savoir plus
Résumé

The oxidative burst is one of the major antimicrobial mechanisms adopted by macrophages. The WKY rat strain is uniquely susceptible to experimentally induced macrophage-dependent crescentic glomerulonephritis (Crgn). We previously identified the AP-1 transcription factor JunD as a determinant of macrophage activation in WKY bone marrow-derived macrophages (BMDMs). JunD is over-expressed in WKY BMDMs and its silencing reduces Fc receptor-mediated oxidative burst in these cells.

Replier
L Batista, T Gruosso, F Mechta-Grigoriou (2013 Jan 9)

Ovarian cancer emerging subtypes: role of oxidative stress and fibrosis in tumour development and response to treatment.

The international journal of biochemistry & cell biology : 1092-8 : DOI : 10.1016/j.biocel.2013.03.001 En savoir plus
Résumé

Epithelial ovarian cancer is a silent disease of usually late diagnosis and poor prognosis. Currently treatment options are limited and mainly consist of surgery followed by taxol- and platinum-based chemotherapy. Patient response to treatment is difficult to predict and there is a serious need for anticipating tumour response and orientating medical choices. In that aim, recent researches have focused on molecular aspects of ovarian tumours that could help patient stratification. We review here published discoveries in that field. We emphasize that signatures, defined by combining miRNA and transcriptomic data, enlighten important aspects of ovarian cancer biology and reliably stratify patients. The miR-200-dependent « Oxidative stress » and « Fibrosis » signatures are promising in patient stratification for defining oriented therapeutic strategies. Indeed, the « Stress » patients survive longer than the « Fibrosis » patients, who exhibit partial debulking and incomplete response to chemotherapy. Interestingly, these two subgroups might benefit from specifically targeted therapeutic approaches, as discussed here.

Replier

Année de publication : 2011

H Terence Cook, Ruth Tarzi, Zelpha D'Souza, Gaelle Laurent, Wei-Chou Lin, Timothy J Aitman, Fatima Mechta-Grigoriou, Jacques Behmoaras (2011 Jun 7)

AP-1 transcription factor JunD confers protection from accelerated nephrotoxic nephritis and control podocyte-specific Vegfa expression.

The American journal of pathology : 134-40 : DOI : 10.1016/j.ajpath.2011.03.006 En savoir plus
Résumé

Genetic investigation of crescentic glomerulonephritis (Crgn) susceptibility in the Wistar Kyoto rat, a strain uniquely susceptible to nephrotoxic nephritis (NTN), allowed us to positionally clone the activator protein-1 transcription factor Jund as a susceptibility gene associated with Crgn. To study the influence of Jund deficiency (Jund(-/-)) on immune-mediated renal disease, susceptibility to accelerated NTN was examined in Jund(-/-) mice and C57BL/6 wild-type (WT) controls. Jund(-/-) mice showed exacerbated glomerular crescent formation and macrophage infiltration, 10 days after NTN induction. Serum urea levels were also significantly increased in the Jund(-/-) mice compared with the WT controls. There was no evidence of immune response differences between Jund(-/-) and WT animals because the quantitative immunofluorescence for sheep and mouse IgG deposition in glomeruli was similar. Because murine Jund was inactivated by replacement with a bacterial LacZ reporter gene, we then investigated its glomerular expression by IHC and found that the Jund promoter is mainly active in Jund(-/-) podocytes. Furthermore, cultured glomeruli from Jund(-/-) mice showed relatively increased expression of vascular endothelial growth factor A (Vegfa), Cxcr4, and Cxcl12, well-known HIF target genes. Accordingly, small-interfering RNA-mediated JUND knockdown in conditionally immortalized human podocyte cell lines led to increased VEGFA and HIF1A expression. Our findings suggest that deficiency of Jund may cause increased oxidative stress in podocytes, leading to altered VEGFA expression and subsequent glomerular injury in Crgn.

Replier
Bogdan Mateescu, Luciana Batista, Melissa Cardon, Tina Gruosso, Yvan de Feraudy, Odette Mariani, André Nicolas, Jean-Philippe Meyniel, Paul Cottu, Xavier Sastre-Garau, Fatima Mechta-Grigoriou (2011 Jan 12)

miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response.

Nature medicine : 1627-35 : DOI : 10.1038/nm.2512 En savoir plus
Résumé

Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.

Replier

Année de publication : 2008

Gaëlle Laurent, Florence Solari, Bogdan Mateescu, Melis Karaca, Julien Castel, Brigitte Bourachot, Christophe Magnan, Marc Billaud, Fatima Mechta-Grigoriou (2008 Feb 6)

Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling.

Cell metabolism : 113-24 : DOI : 10.1016/j.cmet.2007.12.010 En savoir plus
Résumé

JunD, a transcription factor of the AP-1 family, protects cells against oxidative stress. Here, we show that junD(-/-) mice exhibit features of premature aging and shortened life span. They also display persistent hypoglycemia due to enhanced insulin secretion. Consequently, the insulin/IGF-1 signaling pathways are constitutively stimulated, leading to inactivation of FoxO1, a positive regulator of longevity. Hyperinsulinemia most likely results from enhanced pancreatic islet vascularization owing to chronic oxidative stress. Indeed, accumulation of free radicals in beta cells enhances VEGF-A transcription, which in turn increases pancreatic angiogenesis and insulin secretion. Accordingly, long-term treatment with an antioxidant rescues the phenotype of junD(-/-) mice. Indeed, dietary antioxidant supplementation was protective against pancreatic angiogenesis, hyperinsulinemia, and subsequent activation of insulin signaling cascades in peripheral tissues. Taken together, these data establish a pivotal role for oxidative stress in systemic regulation of insulin and define a key role for the JunD protein in longevity.

Replier