Publications by authors named "Camille Jacques"

13 Publications

  • Page 1 of 1

Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas.

Cells 2020 03 27;9(4). Epub 2020 Mar 27.

INSERM, Bone sarcomas and remodeling of calcified tissues, Nantes Université, UMR 1238, F-44000 Nantes, France.

The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression.
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http://dx.doi.org/10.3390/cells9040810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226610PMC
March 2020

Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme.

Mol Cancer 2020 02 25;19(1):36. Epub 2020 Feb 25.

CRCINA, INSERM, Université de Nantes, Nantes, France.

Background: Literature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM).

Methods: RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3'UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints.

Results: Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients.

Conclusion: Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.
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http://dx.doi.org/10.1186/s12943-020-01155-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041276PMC
February 2020

BET bromodomains' functions in bone-related pathologies.

Epigenomics 2020 01 18;12(2):127-144. Epub 2019 Dec 18.

Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France.

Throughout life, bones are subjected to the so-called 'bone-remodeling' process, which is a balanced mechanism between the apposition and the resorption of bone. This remodeling process depends on the activities of bone-specialized cells, namely the osteoblasts and the osteoclasts. Any deregulation in this process results in bone-related pathologies, classified as either metabolic nonmalignant diseases (such as osteoporosis) or malignant primary bone sarcomas. As these pathologies are not characterized by common targetable genetic alterations, epigenetic strategies could be relevant and promising options. Recently, targeting epigenetic regulators such as the bromodomains and extraterminal domains (BET) readers have achieved success in numerous other pathologies, including cancers. In this review, we highlight the current state of the art in terms of the diverse implications of BET bromodomain proteins in the bone's biology and its defects. Consequently, their role in bone-related pathologies will also be developed, especially in the context of the primary bone sarcomas.
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http://dx.doi.org/10.2217/epi-2019-0172DOI Listing
January 2020

Murine Models of Bone Sarcomas.

Methods Mol Biol 2019 ;1914:331-342

Institut de Cancérologie de l'Ouest, INSERM, UMR1232, Université de Nantes, Université d'Angers, Tumour Heterogeneity and Precision Medicine, Nantes, France.

This chapter describes the procedures for inducing bone sarcoma in mice. Two models based on inoculation of cancer cells in paraosseous and intraosseous site will be described. In addition to providing technical aspects of anesthesia and surgical options, key information of cell preparation and postoperative follow-up will be discussed.
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http://dx.doi.org/10.1007/978-1-4939-8997-3_18DOI Listing
June 2019

Analysis of mRNA, miRNA, and DNA in Bone Cells by RT-qPCR and In Situ Hybridization.

Methods Mol Biol 2019 ;1914:169-196

INSERM, UMR1238, Bone Sarcoma and Remodeling of Calcified Tissues, Université de Nantes, Nantes Atlantique Universités, Nantes, France.

The aim of this chapter is to describe a method used to evaluate gene expression and microRNAs (miRNAs) in bone cells or tissue using Reverse transcription and quantitative Polymerase Chain Reaction (RT-qPCR), and a method to assess chromogenic in situ hybridization (CISH) on Formalin Fixed Paraffin Embedded (FFPE ) mouse bone tissue to detect both DNA and mRNA transcripts using the double digoxigenin (DIG) locked nucleic acid (LNA™) probes .
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http://dx.doi.org/10.1007/978-1-4939-8997-3_9DOI Listing
June 2019

Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma.

Oncotarget 2018 Nov 6;9(87):35726-35741. Epub 2018 Nov 6.

INSERM, UMR-S 1238, Nantes 44035, France.

The metastatic dissemination is a complex multistep process by which tumor cells from a primary site enter into the systemic circulation to finally spread at distant sites. Even if this mechanism is rare at the tumor level, it remains the major cause of Osteosarcoma-patients' relapse and mortality. MicroRNAs (miRNAs) have recently been described as novel epigenetics' genes' expression regulators actively implicated in cancer progression and dissemination. The understanding of their implication in the metastatic spreading could help clinicians to improve the outcome of osteosarcoma. We established the miRNA's expression-profile between primary bone-tumors (PTs), circulating tumor cells (CTCs) and lung metastatic (META) samples from mice xenograft models. Our results show that the expression level of the miR-198 and -206 was decreased in META samples, in which the expression of the metastasis-related receptor C-Met was up-regulated. Those expression variations were validated in osteosarcoma patient biopsies from matching primary tumors and lung metastasis. We validated the endogenous miRNAs inhibitory effects on both migration and invasion, as well as we confirmed by luciferase assays that the C-Met receptor is one of their targets. The anti-metastatic effect of these miRNAs was also validated , as their direct injections into the tumors reduce the number of lung-metastases and prolongs the overall survival of the treated animals. All together, our results suggest the absence of the miR-198 and -206 as powerful predictive biomarkers of the tumor cell dissemination and the rationale of their potential therapeutic use in the treatment of Osteosarcoma.
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http://dx.doi.org/10.18632/oncotarget.26284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254661PMC
November 2018

Small animal models for the study of bone sarcoma pathogenesis:characteristics, therapeutic interests and limitations.

J Bone Oncol 2018 Sep 21;12:7-13. Epub 2018 Feb 21.

University of Sheffield, Medical School, Dept of Oncology and Metabolism. INSERM, European Associated laboratory «Sarcoma Research Unit», Beech Hill Road, S10 2RX Sheffield, UK.

Osteosarcoma, Ewing sarcoma and chondrosarcoma are the three main entities of bone sarcoma which collectively encompass more than 50 heterogeneous entities of rare malignancies. In contrast to osteosarcoma and Ewing sarcoma which mainly affect adolescents and young adults and exhibit a high propensity to metastasise to the lungs, chondrosarcoma is more frequently observed after 40 years of age and is characterised by a high frequency of local recurrence. The combination of chemotherapy, surgical resection and radiotherapy has contributed to an improved outcome for these patients. However, a large number of patients still suffer significant therapy related toxicities or die of refractory and metastatic disease. To better delineate the pathogenesis of bone sarcomas and to identify and test new therapeutic options, major efforts have been invested over the past decades in the development of relevant pre-clinical animal models. Nowadays, in vivo models aspire to mimic all the steps and the clinical features of the human disease as accurately as possible and should ideally be manipulable. Considering these features and given their small size, their conduciveness to experiments, their affordability as well as their human-like bone-microenvironment and immunity, murine pre-clinical models are interesting in the context of these pathologies. This chapter will provide an overview of the murine models of bone sarcomas, paying specific attention for the models induced by inoculation of tumour cells. The genetically-engineered mouse models of bone sarcoma will also be summarized.
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http://dx.doi.org/10.1016/j.jbo.2018.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966525PMC
September 2018

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis.

Bone 2017 01 23;94:10-21. Epub 2016 Sep 23.

INSERM, UMR 957, équipe labellisée ligue 2012, 1 Rue Gaston Veil, 44035 Nantes, France; Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, 44035 Nantes, France. Electronic address:

Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis.
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http://dx.doi.org/10.1016/j.bone.2016.09.020DOI Listing
January 2017

miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors.

Oncotarget 2016 Aug;7(34):54503-54514

INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.

Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73β, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73β. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73β axis in the context of these malignancies.
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http://dx.doi.org/10.18632/oncotarget.10950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342358PMC
August 2016

Targeting the epigenetic readers in Ewing sarcoma inhibits the oncogenic transcription factor EWS/Fli1.

Oncotarget 2016 Apr;7(17):24125-40

INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.

Ewing Sarcoma is a rare bone and soft tissue malignancy affecting children and young adults. Chromosomal translocations in this cancer produce fusion oncogenes as characteristic molecular signatures of the disease. The most common case is the translocation t (11; 22) (q24;q12) which yields the EWS-Fli1 chimeric transcription factor. Finding a way to directly target EWS-Fli1 remains a central therapeutic approach to eradicate this aggressive cancer. Here we demonstrate that treating Ewing Sarcoma cells with JQ1(+), a BET bromodomain inhibitor, represses directly EWS-Fli1 transcription as well as its transcriptional program. Moreover, the Chromatin Immuno Precipitation experiments demonstrate for the first time that these results are a consequence of the depletion of BRD4, one of the BET bromodomains protein from the EWS-Fli1 promoter. In vitro, JQ1(+) treatment reduces the cell viability, impairs the cell clonogenic and the migratory abilities, and induces a G1-phase blockage as well as a time- and a dose-dependent apoptosis. Furthermore, in our in vivo model, we observed a tumor burden delay, an inhibition of the global vascularization and an increase of the mice overall survival. Taken together, our data indicate that inhibiting the BET bromodomains interferes with EWS-FLi1 transcription and could be a promising strategy in the Ewing tumors context.
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http://dx.doi.org/10.18632/oncotarget.8214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029689PMC
April 2016

ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis.

Cancer Res 2016 06 17;76(11):3236-51. Epub 2016 Mar 17.

INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.

Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ΔNp63α, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ΔNp63α-expressing cells within a TGFβ-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ΔNp63α-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ΔNp63α repressed miR-527 and miR-665, leading to the upregulation of two TGFβ effectors, SMAD4 and TβRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound-healing response. We show that ΔNp63α-mediated repression of miR-527/665 controls a TGFβ-dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236-51. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891241PMC
June 2016

Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle.

Nat Commun 2014 Mar 19;5:3511. Epub 2014 Mar 19.

1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France.

The vicious cycle established between bone-associated tumours and bone resorption is the central problem with therapeutic strategies against primary bone tumours and bone metastasis. Here we report data to support inhibition of BET bromodomain proteins as a promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a BET bromodomain inhibitor, reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation both in vitro and in vivo. These effects are associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibits osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicate that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumour development.
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http://dx.doi.org/10.1038/ncomms4511DOI Listing
March 2014

Phytochemicals isolated from leaves of Chromolaena odorata: impact on viability and clonogenicity of cancer cell lines.

Phytother Res 2013 Jun 16;27(6):835-40. Epub 2012 Aug 16.

Elucidation of Biosynthesis by Isotopic Spectrometry Group, CEISAM, University of Nantes-CNRS UMR6230, Nantes, France.

The leaves of Chromolaena odorata (Asteraceae) are exploited extensively in West and Central African ethnopharmacy for the treatment of a wide range of conditions, despite this being a non-native species established in the last 50 years. With the objective of seeking bioactive principles, the nonvolatile compounds, an ethanolic (80% v/v) extract was made and fractionated. From the hexane-soluble fraction, three compounds were isolated. Two of these, 5-hydroxy-7,4'-dimethoxyflavanone and 2'-hydroxy-4,4',5',6'-tetramethoxychalcone, have previously been identified in C. odorata leaves. The third was fully characterised spectroscopically and found to be 1,6-dimethyl-4-(1-methylethyl)naphthalene (cadalene), not previously isolated from the Asteraceae. All three compounds were tested for their cytotoxicity and anticancer properties. 2'-Hydroxy-4,4',5',6'-tetramethoxychalcone was found to be both cytotoxic and anticlonogenic at 20 µm in cell lines Cal51, MCF7 and MDAMB-468, and to act synergistically with the Bcl2 inhibitor ABT737 to enhance apoptosis in Cal51 breast cancer cells.
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http://dx.doi.org/10.1002/ptr.4787DOI Listing
June 2013