Publications by authors named "Nhung Vuong"

8 Publications

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A hydride transfer complex reprograms NAD metabolism and bypasses senescence.

Mol Cell 2021 09;81(18):3848-3865.e19

CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada. Electronic address:

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.
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http://dx.doi.org/10.1016/j.molcel.2021.08.028DOI Listing
September 2021

Maternal physical activity significantly alters the placental transcriptome.

Placenta 2020 10 23;100:111-121. Epub 2020 Aug 23.

Faculty of Health Sciences, School of Human Kinetics, University of Ottawa, Canada. Electronic address:

Introduction: Maternal lifestyle, in particular physical activity (PA), influences many of the physiological adaptations during pregnancy associated with feto-placental development and growth. There is limited to no information on the link between PA during pregnancy and the molecular mechanisms governing placental function. The aim of this study was to investigate the molecular mechanisms through which maternal PA may influence placental function.

Methods: The level of PA was measured by accelerometry and gene expression was measured in term placenta with custom polymerase chain reaction (PCR) arrays and microarray analysis followed by a pathway analyses on significantly differentially expressed genes (DEGs).

Results: Microarray analysis showed 43 significantly DEGs between active and non-active participants. RT-qPCR validation of a sub-sample of DEGs revealed significant changes in the level of expression between active and non-active moms (student's t-test, p < 0.05, n = 11). Genes involved in transport of water (p = 0.00236) and uptake of glycerol (p = 0.00219) were enriched in active moms. PA was also associated with the alteration of alternative splicing patters. The most consistent splicing changes were observed for AQP9 where active moms lacked exon 2.

Discussion: Variations in maternal PA influences placental gene. We show significant expression changes of genes that are involved in transport and localization between active and non-active women. Most notably, the expression of the aquaporin family of genes (e.g. AQP1 and AQP9) were found to be significantly higher in the placentas of active women suggesting an adaptive response for the transport of water and glycerol in this population.
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http://dx.doi.org/10.1016/j.placenta.2020.08.016DOI Listing
October 2020

Physical Activity During Pregnancy Is Associated with Increased Placental FATP4 Protein Expression.

Reprod Sci 2020 10 9;27(10):1909-1919. Epub 2020 Jun 9.

Faculty of Health Sciences, School of Human Kinetics, University of Ottawa, 200 Lees Avenue, Building E, Room E250F, Ottawa, Ontario, K1N 6N5, Canada.

Placental function is of utmost importance to ensure proper fetal development in utero. Among the placenta's many roles includes the passage of sufficient macronutrients, such as glucose, amino acids, and fatty acids, to the fetus. Macronutrients are carried from maternal circulation to the fetus across transporters within the placenta. The objective of this study was to examine the impact of (i) an acute bout of exercise and (ii) chronic exercise participation on placenta nutrient transporter expression and localization. To investigate the effect of acute exercise, pre- and post-exercise serum was collected from pregnant (n = 5) and non-pregnant (n = 5) women who underwent a moderate-intensity exercise session and used to treat BeWo cells. To assess chronic physical activity, we analyzed term placenta from women categorized as active (n = 10) versus non-active (n = 10). Protein expression and localization for the transporters GLUT1, SNAT1, and FATP4 were examined for both groups. GLUT1 expression in BeWo cells treated with serum from pregnant women was higher compared with that from non-pregnant, independent of exercise. FATP4 protein expression was elevated in the term placenta of active women. Immunohistochemistry analysis of term placenta illustrated increased staining of FATP4 in placental tissue from active women and differential staining pattern of GLUT1 depending on physical activity status. Chronic exercise during pregnancy increases the expression of placental FATP4 in vivo, suggesting greater metabolism and usage of fatty acids. Additionally, serum from pregnant women could contain factors that increase GLUT1 protein expression in vitro. BeWo cells treated with pre- and post-exercise serum from pregnant women resulted in greater GLUT1 expression compared with those treated with pre- and post-exercise serum from non-pregnant women. Physical activity appears to differentially impact key placental transporters involved in the transfer and availability of nutrients from mother to fetus. Future research ought to examine the mechanisms involved in regulating these changes and their impact on fetal growth and health.
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http://dx.doi.org/10.1007/s43032-020-00210-wDOI Listing
October 2020

COX2 is induced in the ovarian epithelium during ovulatory wound repair and promotes cell survival†.

Biol Reprod 2019 11;101(5):961-974

Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

The ovarian surface epithelium (OSE) is a monolayer of cells surrounding the ovary that is ruptured during ovulation. After ovulation, the wound is repaired, however, this process is poorly understood. In epithelial tissues, wound repair is mediated by an epithelial-to-mesenchymal transition (EMT). Transforming Growth Factor Beta-1 (TGFβ1) is a cytokine commonly known to induce an EMT and is present throughout the ovarian microenvironment. We, therefore, hypothesized that TGFβ1 induces an EMT in OSE cells and activates signaling pathways important for wound repair. Treating primary cultures of mouse OSE cells with TGFβ1 induced an EMT mediated by TGFβRI signaling. The transcription factor Snail was the only EMT-associated transcription factor increased by TGFβ1 and, when overexpressed, was shown to increase OSE cell migration. A polymerase chain reaction array of TGFβ signaling targets determined Cyclooxygenase-2 (Cox2) to be most highly induced by TGFβ1. Constitutive Cox2 expression modestly increased migration and robustly enhanced cell survival, under stress conditions similar to those observed during wound repair. The increase in Snail and Cox2 expression with TGFβ1 was reproduced in human OSE cultures, suggesting these responses are conserved between mouse and human. Finally, the induction of Cox2 expression in OSE cells during ovulatory wound repair was shown in vivo, suggesting TGFβ1 increases Cox2 to promote wound repair by enhancing cell survival. These data support that TGFβ1 promotes ovulatory wound repair by induction of an EMT and activation of a COX2-mediated pro-survival pathway. Understanding ovulatory wound repair may give insight into why ovulation is the primary non-hereditary risk factor for ovarian cancer.
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http://dx.doi.org/10.1093/biolre/ioz134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877777PMC
November 2019

Single-cell RNA-sequencing reveals transcriptional dynamics of estrogen-induced dysplasia in the ovarian surface epithelium.

PLoS Genet 2018 11 12;14(11):e1007788. Epub 2018 Nov 12.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.

Estrogen therapy increases the risk of ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. Both in vivo and in vitro, ovarian surface epithelial (OSE) cells exposed to estradiol develop a subpopulation that loses cell polarity, contact inhibition, and forms multi-layered foci of dysplastic cells with increased susceptibility to transformation. Here, we use single-cell RNA-sequencing to characterize this dysplastic subpopulation and identify the transcriptional dynamics involved in its emergence. Estradiol-treated cells were characterized by up-regulation of genes associated with proliferation, metabolism, and survival pathways. Pseudotemporal ordering revealed that OSE cells occupy a largely linear phenotypic spectrum that, in estradiol-treated cells, diverges towards cell state consistent with the dysplastic population. This divergence is characterized by the activation of various cancer-associated pathways including an increase in Greb1 which was validated in fallopian tube epithelium and human ovarian cancers. Taken together, this work reveals possible mechanisms by which estradiol increases epithelial cell susceptibility to tumour initiation.
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http://dx.doi.org/10.1371/journal.pgen.1007788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258431PMC
November 2018

GREB1 is an estrogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer.

Oncogene 2018 11 4;37(44):5873-5886. Epub 2018 Jul 4.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.

Estrogenic hormone replacement therapy increases the risk of developing ovarian cancer, and estrogen promotes tumour initiation and growth in mouse models of this disease. GREB1 (Growth regulation by estrogen in breast cancer 1) is an ESR1 (estrogen receptor 1)-upregulated protein which may mediate estrogen action. GREB1 knockdown prevents hormone-driven proliferation of several breast and prostate cancer cell lines and prolongs survival of mice engrafted with ovarian cancer cells, but its mechanism of action remains unclear. In this study, we explored GREB1 function in ovarian cancer. GREB1 overexpression in ovarian cancer cell lines increased cell proliferation and migration and promoted a mesenchymal morphology associated with increased Col1a2, which encodes a collagen I subunit. GREB1 knockdown inhibited proliferation and promoted an epithelial morphology associated with decreased Col1a2. In human tissues, GREB1 was expressed in all ESR1-expressing tissues throughout the normal female reproductive tract, in addition to several tissues that did not show ESR1 expression. In a TMA of ovarian cancer cases, GREB1 was expressed in 75-85% of serous, endometrioid, mucinous, and clear cell carcinomas. Serous, endometrioid, and mucinous ovarian cancers were almost always positive for either ESR1 or GREB1, suggesting a possible reliance on signalling through ESR1 and/or GREB1. Targeting GREB1 may inhibit tumour-promoting pathways both downstream and independent of ESR1 and is therefore a possible treatment strategy worthy of further investigation.
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http://dx.doi.org/10.1038/s41388-018-0377-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212416PMC
November 2018

17β-Estradiol sensitizes ovarian surface epithelium to transformation by suppressing Disabled-2 expression.

Sci Rep 2017 12 1;7(1):16702. Epub 2017 Dec 1.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.

Estrogen replacement therapy increases the risk of human ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. This study uses primary cultures of mouse ovarian surface epithelium (OSE) to demonstrate that one possible mechanism by which estrogen accelerates the initiation of ovarian cancer is by up-regulation of microRNA-378 via the ESR1 pathway to result in the down-regulation of a tumour suppressor called Disabled-2 (Dab2). Estrogen suppression of Dab2 was reproducible in vivo and across many cell types including mouse oviductal epithelium and primary cultures of human ovarian cancer cells. Suppression of Dab2 resulted in increased proliferation, loss of contact inhibition, morphological dysplasia, and resistance to oncogene-induced senescence - all factors that can sensitize OSE to transformation. Given that DAB2 is highly expressed in healthy human OSE and is absent in the majority of ovarian tumours, this study has taken the first steps to provide a mechanistic explanation for how estrogen therapy may play a role in the initiation of ovarian cancer.
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http://dx.doi.org/10.1038/s41598-017-16219-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711839PMC
December 2017

Raman micro-spectroscopy applied to treatment resistant and sensitive human ovarian cancer cells.

J Biophotonics 2017 Oct 23;10(10):1327-1334. Epub 2016 Dec 23.

Department of Physics, Carleton University, K1S 5B6, Ottawa, Canada.

Despite the many advances intended to enhance the response to treatment, the survival rate of patients with ovarian cancer has only marginally improved in the past few decades. One major cause for this, is the lack of diagnostics for platinum-resistant disease. The goal of this study was to determine whether Raman micro-spectroscopy in conjunction with multivariate statistical analysis could discriminate between chemically fixed cisplatin-resistant (A2780cp) and cisplatin-sensitive (A2780s) human ovarian carcinoma cells. Raman spectra collected from individual cells were pre-processed and subsequently analyzed with Principal Component Analysis - Linear Discriminant Analysis (PCA-LDA). Statistically significant differences (P <  0.0001) were observed between the Raman spectra of A2780s and A2780cp cells. A diagnostic accuracy of 82% was obtained using the PCA-LDA classifier model for the discrimination between the A2780s and A2780cp cells. The loading plot analysis suggests that relative increases in proteins and glutathione in the cisplatin-resistant cells compared to the cisplatin-sensitive cells are most likely the major source of discrimination between the two types of cells. These results support the potential application of Raman spectroscopy in the identification of chemo-resistant tumors prior to treatment.
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http://dx.doi.org/10.1002/jbio.201600211DOI Listing
October 2017
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