Éditeur(s) : HAL CCSD INVS
Résumé : National audience
Context – Cervical cancer is the second most frequent cancer of women in French Guiana. Studies have shown that populations living in remote villages in the interior of the territory have early sexual relations and that multiple sexual partnerships are frequent. Hence, the main objective of the study was to determine the prevalence of Human Papilloma Virus (HPV) in these areas.Methods – This multicentric cross sectional study was conducted in women aged 20 to 65 years, living in theremote villages along the Maroni and Oyapock rivers. Women were included on a voluntary basis after beinginformed of the study team schedule through radio address and key opinion leaders.The search for HPV and cytologic examinations were performed on each sample. HPV infection was defined bythe detection of viral DNA using the Greiner Bio One® kit. Cytologic analyses were performed using the 2001Bethesda classification.Results – Overall, 643 women were included in the study. Age-standardized HPV prevalence was 35%. Theprevalence curve by age group showed a U-shaped pattern: women over 50 years had the highest risk of being infected by HPV, followed by women aged 20-29 years. In addition, 26.1% of women with a normal smear test had HPV infection. The most frequent genotypes were HPV52, HPV58, and HPV16. On interpretable smears 1.16% of women had high grade superficial intra-epithelial (HSIL) lesions.Conclusions – The standardized prevalence of HPV in French Guiana is among the highest in the world. HSILcytological lesions were nearly 4 times more frequent than in the Île-de-France region. Given the importance of the incidence of cervical cancer in French Guiana, these results suggest it may be preferable to use HPV testing than cytology. Vaccination against HPV, preferably with the new nonavalent vaccine seems an appropriate prevention measure. However, this intervention will be a challenge to implement in this region where a significant proportion of the population is not covered by health insurance.
Contexte – Le cancer du col de l’utérus est le deuxième cancer féminin le plus fréquent en Guyane française.Des études ont montré que les populations résidant dans les communes isolées de l’intérieur du départementdébutent leur vie sexuelle de façon précoce et que le multipartenariat sexuel y est fréquent. Dans ce contexte, l’objectif principal de cette étude était de déterminer la prévalence de l’infection à papillomavirus humains (HPV) dans ces zones.Méthodes – Cette étude transversale multicentrique a été conduite auprès des femmes âgées de 20 à 65 ansrésidant dans les communes isolées des fleuves Maroni et Oyapock. Les femmes étaient incluses sur la basedu volontariat après avoir été informées du passage de l’équipe de l’étude via la radio locale et par les leadersd’opinion. La recherche d’infection à HPV et les analyses cytologiques ont été réalisées sur chaque prélèvement. L’infection à HPV était définie par la détection d’ADN viral par le kit de dépistage Greiner Bio One®. Les analyses cytologiques ont été décrites selon la classification de Bethesda 2001.Résultats – Au total, 643 femmes ont été incluses. La prévalence de l’infection à HPV, standardisée sur l’âge,était de 35%. La courbe de prévalence par classe d’âge présentait une forme en U : les femmes de plus de50 ans avaient le plus haut risque d’être infectées par HPV, suivies par les femmes âgées de 20 à 29 ans.Par ailleurs, 26,1% des femmes ayant un frottis normal étaient infectées par le HPV. Les génotypes les plusfréquents étaient HPV52, HPV58 et HPV16. Sur les frottis interprétables, 1,16% des femmes avaient des lésions de haut grade (type HSIL).Conclusions – Le taux standardisé de prévalence de l’infection par le HPV en Guyane est parmi les plus élevésau monde. Les lésions cytologiques de type HSIL étaient près de 4 fois plus fréquentes qu’en Île-de-France.Étant donné l’importance de l’incidence du cancer du col de l’utérus en Guyane, ces résultats montrent qu’il est peut être préférable d’utiliser le test HPV plutôt que la cytologie. La vaccination anti-HPV, de préférence avec le nouveau vaccin nonavalent, semble être une mesure de prévention appropriée. Pour autant, cela reste un challenge de mettre en oeuvre ces interventions dans cette région où une part importante de la population n’a pas d’assurance maladie.
ISSN: 1953-8030

Droits : info:eu-repo/semantics/OpenAccess
inserm-01407222
http://www.hal.inserm.fr/inserm-01407222
http://www.hal.inserm.fr/inserm-01407222/document
http://www.hal.inserm.fr/inserm-01407222/file/2016%2C%20Dufit%20et%20al.pdf

Éditeur(s) : HAL CCSD John Libbey Eurotext
Résumé : International audience
Prostate cancer is the most frequent cancer affecting men in most Western countries. Certain risk factors have been identified (age, family history, ethnic origin), but the aetiology of this cancer remains largely unknown. However, a role for environmental factors is strongly suspected. Questions have been raised concerning the role of the chemical substances generated by human activities in the occurrence of this disease. Diverse studies have consistently demonstrated a higher risk of prostate cancer in agricultural populations than in the general population. The hypothesis that this higher risk is linked to the use of pesticides has been tested in a number of studies, mostly in North America and Europe. However, to date, with a few possible exceptions, it has been impossible to demonstrate a significant association between exposure to pesticides or a chemical family of pesticides and prostate cancer. In the face of these uncertainties, rigorous studies are required, with objective measurements of exposure, taking into account confounding factors and individual risk factors, making it possible to assess gene-environment interactions.
ISSN: 0007-4551

inserm-00504733
http://www.hal.inserm.fr/inserm-00504733
DOI : 10.1684/bdc.2008.0812
PUBMED : 19258224

Éditeur(s) : HAL CCSD Cancer Research UK
Résumé : International audience
BACKGROUND: Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent. METHODS: Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells. RESULTS: Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells. CONCLUSION: These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.
ISSN: 0007-0920

hal-00684528
https://hal.archives-ouvertes.fr/hal-00684528
DOI : 10.1038/bjc.2012.6
PUBMED : 22294184

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Development of hepatocellular carcinoma (HCC) is a complex and progressive disease that involves cycles of liver cell death, inflammation, and tissue regeneration/remodelling. Chemokines and chemokine receptors play numerous and integral roles in the disease progression of HCC. Here we investigated the novel chemokine receptor CXCR7/RDC1 in HCC progression, its two known ligands CXCL12 and CXCL11, as well as the other CXCL12 receptor, CXCR4. Our results show that in a cohort of 408 human HCCs, CXCR7 and CXCL11 were significantly higher in tumours compared to normal liver controls (5- and 10-fold, respectively). Immunohistochemical (IHC) staining on human HCC sections confirmed that both CXCL11 and CXCR7 were much higher in cancer tissues. Furthermore, IHC staining revealed that CXCR7 protein was only expressed in endothelial cells whereas CXCL11 exhibited a much broader tissue expression. At the cellular level we observed that in vitro, human microvascular endothelial cells (HMEC-1) up-regulated CXCR7 under hypoxic and acidic pH conditions, which are well known characteristics of the HCC tumour micro-environment. As for its ligand, we observed that IFNγ robustly induced CXCL11 in hepatic stellate cells, hepatocytes, and HMEC-1s. In addition, in the mouse Diethylnitrosamine model of hepatocarcinogenesis we observed a very strong induction of CXCR7 and CXCL11 transcripts, confirming that CXCR7/CXCL11 up-regulation is conserved between human and mice liver cancer. Altogether, our results strongly support the hypothesis that the CXCL11/CXCR7 pathway is involved HCC progression.
ISSN: 0959-8049

hal-00682463
https://hal.archives-ouvertes.fr/hal-00682463
DOI : 10.1016/j.ejca.2011.06.044
PUBMED : 21778049

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Seventy percent of breast tumors express the estrogen receptor (ER), which is generally considered to predict a better outcome relative to ER-negative tumors, as they often respond to antiestrogen therapies. During cancer progression, mammary tumors can escape from estrogen control, resulting in the acquisition of invasive properties and resistance to treatment. ER expression is a dynamic phenomenon and is finely regulated at numerous levels, including the gene, mRNA, and protein levels. As a consequence, many molecular mechanisms have been implicated in modulating ER activity and estrogen signaling in mammary cancer. In fact, one-third of ER-positive breast cancer cells do not respond to first-line endocrine therapies, and a large subset of relapsing tumors retain ER expression. Increased knowledge of these mechanisms has led to the development of better prognostic methods and targeted therapies for patients; however, additional research is still needed to improve patient survival. In this chapter, we focus on the signaling pathways leading to changes in or loss of ER activity in breast cancer progression.
ISSN: 0083-6729

hal-00874313
https://hal.archives-ouvertes.fr/hal-00874313
DOI : 10.1016/B978-0-12-416673-8.00004-6
PUBMED : 23810005

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas.
ISSN: 1932-6203

hal-00873684
https://hal.archives-ouvertes.fr/hal-00873684
https://hal.archives-ouvertes.fr/hal-00873684/document
https://hal.archives-ouvertes.fr/hal-00873684/file/Functional_Characterization-accepted.pdf
DOI : 10.1371/journal.pone.0054000

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
ISSN: 2045-2322

Droits : http://creativecommons.org/licenses/by/
hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/file/The%20environmental%20carcinogen-CCBY%20%281%29.pdf
DOI : 10.1038/srep30776

Éditeur(s) : HAL CCSD
Résumé : TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a well-known apoptosis inducer, which activates the extrinsic death pathway. TRAIL is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by cell resistance to cell death which occurs in approximately 50% of cancer cells. Short Chain Fatty Acids (SCFA) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate and acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. Indeed, we hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, increased pro-apoptotic gene expression (TRAIL-R2/DR5) and decreased anti-apoptotic gene expression (FLIP, XIAP) in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on both death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and caspases (caspase-8, -9 and -3) activation, was lethal on cancer cells but not on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented by P. freudenreichii induced HT29 cells apoptosis and enhanced TRAIL cytotoxic activity, as did P. freudenreichii DMEM culture supernatants or its SCFA metabolites. These results open new perspectives for food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer.
4 . International Symposium on Propionibacteria and Bibfidobacteria
Cork, Ireland

hal-01372131
https://hal.archives-ouvertes.fr/hal-01372131
PRODINRA : 371605

Éditeur(s) : HAL CCSD
Résumé : International audience
Fucoxanthin is a carotenoid present in brown micro-and macro algae, that induces apoptosis or autophagy in cancer cells grown in vitro. In vivo studies confirmed its interest as a natural anticancer compound, as it exerts antitumoral, antimetastatic and antiangiogenic activities in animal models. Studies focused on the pharmacology of fucoxanthin in cancer cells and tumors have revealed that it affects a wide panel of cellular, molecular and tissular processes, suggesting that its biological activity may be related in part to a nonspecific integration in cell membranes, and possible interaction with lipid rafts. Thus, preliminary data confirming this interaction of fucoxanthin with lipid rafts were obtained in mast cells and hepatoma WIF-B9 cells. We here discuss this hypothesis, in view of the critical function of lipid rafts in cancer cell survival, invasivity and communication with the tumoral microenvironment.
ISSN: 2141-2294

hal-01391001
https://hal.archives-ouvertes.fr/hal-01391001
https://hal.archives-ouvertes.fr/hal-01391001/document
https://hal.archives-ouvertes.fr/hal-01391001/file/could-fucoxanthin-interaction-with-lipid-rafts-mediate-its-cytotoxicity-incancer-cells-.pdf
DOI : 10.4172/jomr.1000144

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as a model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases.
ISSN: 0041-008X

hal-01558816
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01558816
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01558816/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01558816/file/Lecomte%20et%20al.%20-%20Assessment%20of%20the%20potential%20activity%20of%20major%20diet.pdf
DOI : 10.1016/j.taap.2017.04.005

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology
ISSN: 0022-2623

hal-01187307
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187307
DOI : 10.1021/acs.jmedchem.5b00991
PUBMED : 26237138

Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences
Résumé : International audience
BACKGROUND: Women of reproductive age can be exposed to endocrine-disrupting chemicals (EDCs) at work, and exposure to EDCs in pregnancy may affect fetal growth. OBJECTIVES: We assessed whether maternal occupational exposure to EDCs during pregnancy as classified by application of a job exposure matrix was associated with birth weight, term low birth weight (LBW), length of gestation, and preterm delivery. METHODS: Using individual participant data from 133,957 mother-child pairs in 13 European cohorts spanning births from 1994 through 2011, we linked maternal job titles with exposure to 10 EDC groups as assessed through a job exposure matrix. For each group, we combined the two levels of exposure categories (possible and probable) and compared birth outcomes with the unexposed group (exposure unlikely). We performed meta-analyses of cohort-specific estimates. RESULTS: Eleven percent of pregnant women were classified as exposed to EDCs at work during pregnancy, based on job title. Classification of exposure to one or more EDC group was associated with an increased risk of term LBW [odds ratio (OR) = 1.25; 95% CI: 1.04, 1.49], as were most specific EDC groups; this association was consistent across cohorts. Further, the risk increased with increasing number of EDC groups (OR = 2.11; 95% CI: 1.10, 4.06 for exposure to four or more EDC groups). There were few associations (p < 0.05) with the other outcomes; women holding job titles classified as exposed to bisphenol A or brominated flame retardants were at higher risk for longer length of gestation. CONCLUSION: Results from our large population-based birth cohort design indicate that employment during pregnancy in occupations classified as possibly or probably exposed to EDCs was associated with an increased risk of term LBW.
ISSN: 0091-6765

hal-01405823
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01405823
DOI : 10.1289/EHP208
PUBMED : 27152464

Éditeur(s) : HAL CCSD MDPI
Résumé : International audience
The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen-like compounds. Estrogen receptors alpha (ERα) and beta (ERβ) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERα-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen-like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens.
ISSN: 2073-4425

hal-01616486
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616486
DOI : 10.3390/genes8090229
PUBMED : 28914763
PUBMEDCENTRAL : PMC5615362

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Cell proliferation is a hallmark of cancer and depends on complex signaling networks that are chiefly supported by protein kinase activities. Therapeutic strategies have been used to target specific kinases but new methods are required to identify combined targets and improve treatment. Here, we propose a small interfering RNA genetic screen and an integrative approach to identify kinase networks involved in the proliferation of cancer cells. The functional siRNA screen of 714 kinases in HeLa cells identified 91 kinases implicated in the regulation of cell growth, most of them never being reported in previous whole-genome siRNA screens. Based on gene ontology annotations, we have further discriminated between two classes of kinases that, when suppressed, result in alterations of the mitotic index and provoke cell-cycle arrest. Extinguished kinases that lead to a low mitotic index mostly include kinases implicated in cytosolic signaling. In contrast, extinguished kinases that result in a high mitotic index mostly include kinases implicated in cell division. By mapping hit kinases in the PhosphPOINT phosphoprotein database, we generated scale-free networks consisting of 449 and 661 protein-protein interactions for kinases from low MI and high MI groups, respectively. Further analyses of the kinase interactomes revealed specific modules such as FER- and CRKL-containing modules that connect three members of the epidermal growth factor receptor (EGFR) family, suggesting a tight control of the mitogenic EGF-dependent pathway. Based on experimental studies, we confirm the involvement of these two kinases in the regulation of tumor cell growth. Based on a combined approach of large kinome-wide siRNA screens and ontology annotations, our study identifies for the first time two kinase groups differentially implicated in the control of cell proliferation. We further demonstrate that integrative analysis of the kinase interactome provides key information which can be used to facilitate or optimize target design for new therapeutic strategies. The complete list of protein-protein interactions from the two functional kinase groups will provide a useful database for future investigations.
ISSN: 1471-2164

hal-01118475
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118475
DOI : 10.1186/1471-2164-15-1169
PUBMED : 25540073

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
BACKGROUND: Deletions of the glutathione S-transferase genes M1 and T1 (GSTM1 and GSTT1) have been studied as potential risk factors for prostate cancer. Conflicting results have been obtained. Moreover, most such studies could not discriminate heterozygous from homozygous carriers of the non-deleted alleles. OBJECTIVE: We investigated whether copy number variation (CNV) of the GSTM1 and/or GSTT1 genes contribute to the risk of prostate cancer in the Caribbean population of African descent of Guadeloupe. METHODS: In a population-based case-control study, we compared 629 prostate cancer patients and 622 control subjects. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Exact copy numbers of GSTM1 and GSTT1 were determined by real-time PCR. RESULTS: A higher copy number of GSTM1 was marginally associated with prostate cancer risk. Men with 2 and 3 or more GSTT1 genes were at higher risk of prostate cancer (OR: 1.55, 95% CI: 1.11-2.16 and OR: 4.89, 95% CI: 1.71-13.99, respectively; Ptrend extless0.001). Men with 3, 4 and 5 or more copies of both GSTM1 and GSTT1 genes were at higher risk of prostate cancer (OR: 2.18, 95% CI: 1.21-3.91, OR: 3.24, 95% CI: 1.63-6.46, and OR: 5.77, 95% CI: 1.40-23.84, respectively; Ptrend extless0.001). CONCLUSIONS: Copy number of GSTT1 and combined GSTM1/GSTT1 appear to be associated with prostate cancer risk in our population study with gene dose relationship. Our results support the hypothesis that variations in copy number of GSTT1 modulate the risk of prostate cancer.
ISSN: 1932-6203

hal-01063905
https://hal.archives-ouvertes.fr/hal-01063905
DOI : 10.1371/journal.pone.0107275
PUBMED : 25198353

Éditeur(s) : HAL CCSD Cambridge University Press (CUP)
Résumé : International audience
Cervical cancer is the second most frequent cancer in women in French Guiana. Studies have shown that populations living in the remote areas of the interior have early sexual debut and that multiple sexual partnerships are common. The objective of the present study was thus to determine the prevalence of human papillomavirus (HPV) infection in these areas. A study was conducted in women aged 20-65 years with previous sexual activity. Women were included on a voluntary basis after using local media and leaders to inform them of the visit of the team. HPV infection was defined by the detection of HPV DNA using the Greiner Bio-One kit. In addition to HPV testing cytology was performed. The overall age-standardized prevalence rate was 35%. There was a U-shaped evolution of HPV prevalence by age with women aged >50 years at highest risk for HPV, followed by the 20-29 years group. Twenty-seven percent of women with a positive HPV test had normal cytology. Given the high incidence of cervical cancer in French Guiana and the high prevalence of HPV infections the present results re-emphasize the need for screening for cervical cancer in these remote areas. Vaccination against HPV, preferably with a nonavalent vaccine, also seems an important prevention measure. However, in this region where a large portion of the population has no health insurance, this still represents a challenge.
ISSN: 0950-2688

inserm-01476015
http://www.hal.inserm.fr/inserm-01476015
http://www.hal.inserm.fr/inserm-01476015/document
http://www.hal.inserm.fr/inserm-01476015/file/High%20prevalence%20HPV%20infection%20in%20women%20living%20in%20the%20remote%20territories%20of%20French%20Guiana%20STD.pdf
http://www.hal.inserm.fr/inserm-01476015/file/Table%203.pdf

Éditeur(s) : HAL CCSD American Association for Cancer Research
Résumé : International audience
Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here we report that serum levels of CD95L are higher in TNBC patients compared to other breast cancer patients. Metalloprotease-mediated cleavage of CD95L expressed by endothelial cells surrounding tumors generates a gradient that promotes cell motility, due to formation of an unconventional CD95-containing receptosome termed the motility-inducing signaling complex. Formation of this complex was instrumental for Nox3-driven ROS generation. Mechanistic investigations revealed a Yes-Orai1-EGFR-PI3K pathway that triggered migration of TNBC cells exposed to CD95L. Our findings establish a pro-metastatic function for metalloprotease-cleaved CD95L in triple-negative breast cancers, revisiting its role in carcinogenesis.
ISSN: 0008-5472

hal-00873634
https://hal.archives-ouvertes.fr/hal-00873634
PUBMED : 24072745
DOI : 10.1158/0008-5472.CAN-13-1794

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Ro 31-8220 is a potent protein kinase C (PKC) inhibitor belonging to the chemical class of bisindolylmaleimides (BIMs). Various PKC-independent effects of Ro 31-8220 have however been demonstrated, including inhibition of the ATP-binding cassette drug transporter breast cancer resistance protein. In the present study, we reported that the BIM also blocks activity of the solute carrier organic cation transporter (OCT) 1, involved in uptake of marketed drugs in the liver, in a PKC-independent manner. Ro 31-8220, in contrast to other pan-PKC inhibitors such as staurosporine and chelerythrine, was thus shown to cis-inhibit uptake of the reference OCT1 substrate tetraethylammonium in OCT1-transfected HEK293 cells in a concentration-dependent manner (IC50 = 0.18 μM) and without altering membrane expression of OCT1. This blockage of OCT1 was also observed in human hepatic HepaRG cells that constitutionally express OCT1. It likely occurred through a mixed mechanism of inhibition. Ro 31-8220 additionally trans-inhibited TEA uptake in OCT1-transfected HEK293 cells, which likely discards a transport of Ro 31-8220 by OCT1. Besides Ro 31-8220, 7 additional BIMs, including the PKC inhibitor LY 333531, inhibited OCT1 activity, whereas 4 other BIMs were without effect. In silico analysis of structure-activity relationships next revealed that various molecular descriptors, especially 3D-WHIM descriptors related to total size, correspond to key physico-chemical parameters for inhibition of OCT1 activity by BIMs. In addition to activity of OCT1, Ro 31-8220 inhibited those of other organic cation transporters such as multidrug and toxin extrusion protein (MATE) 1 and MATE2-K, whereas, by contrast, it stimulated that of OCT2. Taken together, these data extend the nature of cellular off-targets of the BIM Ro 31-8220 to OCT1 and other organic cation transporters, which has likely to be kept in mind when using Ro 31-8220 and other BIMs as PKC inhibitors in experimental or clinical studies
ISSN: 1932-6203

hal-01255837
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01255837
DOI : 10.1371/journal.pone.0144667
PUBMED : 26657401
PUBMEDCENTRAL : PMC4675551

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Chlordecone (Kepone) is an organochlorine insecticide that has been used as insecticide and fungicide. In the French West Indies, Guadeloupe and Martinique, it was intensively applied to banana fields from 1973 to 1993 to control root borers. This pesticide undergoes no significant biotic or abiotic degradation in the environment and is still present in soils where it was applied. It was only in 1999 that health and environmental authorities became aware of the extent of the chlordecone pollution of environmental media, including soils, waterways, and the food chain. Earlier observations and toxicological studies have demonstrated that chlordecone is a reproductive and developmental toxicant, neurotoxic and carcinogenic in rodents, and is an endocrine-disrupting chemical because of its estrogenic properties both in vitro and in vivo. Several surveys have confirmed that the French West Indian population continues to be exposed to this chemical though consumption of contaminated foodstuffs. Here, we report the findings of various epidemiological studies conducted in the French West Indies to assess the impact of environmental exposure to chlordecone on the health of the population.
ISSN: 0944-1344

hal-01150382
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01150382/file/Chlordecone%20exposure%20and%20adverse%20effects%20in%20French%20West.pdf
DOI : 10.1007/s11356-015-4621-5

Éditeur(s) : HAL CCSD Society for the Study of Reproduction
Résumé : International audience
Matrix-assisted laser desorption/ionization (MALDI) tissue imaging mass spectrometry is particularly promising among the numerous applications of mass spectrometry. It is used for probing and analyzing the spatial arrangement of a wide range of molecules, including proteins, peptides, lipids, drugs, and metabolites, directly in thin slices of tissue. In the field of proteomics, the technology avoids tedious and time-consuming extraction and fractionation steps classically required for sample analysis. MALDI imaging mass spectrometry is increasingly recognized as a powerful method for clinical proteomics, particularly in cancer research. The technology has particular potential for the discovery of new tissue biomarker candidates, classification of tumors, early diagnosis or prognosis, elucidating pathogenesis pathways, and therapy monitoring. Over recent years, MALDI imaging mass spectrometry has been used for molecular profiling and imaging directly in male and female reproductive tissues. This review will consider some of the recent publications in the field, addressing a range of issues covering embryo development, gene expression product profiling during gametogenesis, and seeking and identifying biomarkers of reproductive cancers. The wealth of advances in mass spectrometry imaging will inevitably attract biologists and clinicians as the advantages and power of this technology become more widely known. This review will also discuss bottlenecks and the many technical issues that remain to be resolved before laboratories in the field can adopt the technology. We foresee that MALDI imaging mass spectrometry will have a major impact in reproductive research by opening new avenues to the understanding of various molecular mechanisms and the diagnosis of reproductive pathologies.
ISSN: 0006-3363

hal-00877851
https://hal.archives-ouvertes.fr/hal-00877851
DOI : 10.1095/biolreprod.111.094896
PUBMED : 22156474