MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation.

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

Carotenoid Lutein Selectively Inhibits Breast Cancer Cell Growth and Potentiates the Effect of Chemotherapeutic Agents through ROS-Mediated Mechanisms.

Increasing evidence suggests that dietary carotenoids may reduce the risk of breast cancer. However, anti-breast cancer effects of carotenoids have been controversial, albeit understudied. Here, we investigated the effects of specific carotenoids on a wide range of breast cancer cell lines, and found that among several carotenoids (including ß-carotene, lutein, and astaxanthin), lutein significantly inhibits breast cancer cell growth by inducing cell-cycle arrest and caspase-independent cell death, but it has little effect on the growth of primary mammary epithelial cells (PmECs). Moreover, lutein-mediated growth inhibition of breast cancer cells is quantitatively similar to that induced by chemotherapeutic taxanes, paclitaxel and docetaxel, and exposure to lutein plus taxanes additively inhibits breast cancer cell growth. Analysis of mechanisms showed that lutein treatment significantly increases the intracellular reactive oxygen species (ROS) production in triple-negative breast cancer (TNBC) cells, but not in normal PmECs. Lutein-induced growth inhibition is also attenuated by the radical oxygen scavenger N-acetyl cysteine, suggesting a role for ROS generation in the growth inhibitory effect of lutein on TNBC cells. Additionally, we found that the p53 signaling pathway is activated and HSP60 levels are increased by lutein treatment, which may contribute partly to the induction of growth inhibition in TNBC cells. Our findings show that lutein promotes growth inhibition of breast cancer cells through increased cell type-specific ROS generation and alternation of several signaling pathways. Dietary lutein supplementation may be a promising alternative and/or adjunct therapeutic candidate against breast cancer.

Maternal and pediatric health and disease: integrating biopsychosocial models and epigenetics.

The concepts of allostasis (stability through adaptation) and accumulated life stress (McEwen's allostatic load) aim to understand childhood and adult outcomes. Chronic malnutrition, changes in social condition, and adverse early-life experiences may program phenotypes and contribute to long-lasting disease risk. However, integration of life course approaches, social and economic contexts, and comparison among different biopsychosocial models has not generally been explored. This review critically examines the literature and evaluates recent insights into how environmental stress can alter lifelong hypothalamic-pituitary-adrenal axis and immune system responsiveness and induce metabolic and neurodevelopmental maladaptation. Models of biopsychosocial stress overlap but may consider different conditions. Concepts include allostasis, which incorporates hormonal responses to predictable environmental changes, and Geronimus's "weathering," which aims to explain how socially structured, repeated stress can accumulate and increase disease vulnerability. Weathering emphasizes roles of internalized/interpersonal racism in outcomes disparities. For Mexican immigrants and Mexican Americans, the "acculturation" framework has proven especially useful to explore disparities, including preterm birth and neuropsychiatric risks in childhood. Complexities of stress assessments and recent research into epigenetic mechanisms mediating effects of physical, nutritional, psychological, and social stress are reviewed.

Sustaining careers of physician-scientists in neonatology and pediatric critical care medicine: formulating supportive departmental policies.

Understanding mechanisms of childhood disease and development of rational therapeutics are fundamental to progress in pediatric intensive care specialties. However, Division Chiefs and Department Chairs face unique challenges when building effective laboratory-based research programs in Neonatal and Pediatric Intensive Care, owing to high clinical demands necessary to maintain competence as well as financial pressures arising from fund flow models and the current extramural funding climate. Given these factors, the role of institutional support that could facilitate successful transition of promising junior faculty to independent research careers is ever more important. Would standardized guidelines of such support provide greater consistency among institutions? We addressed preliminary questions during a national focus group, a workshop and a survey of junior and senior academicians to solicit recommendations for optimal levels of protected time and resources when starting an independent laboratory. The consensus was that junior faculty should be assigned no more than 8 wk clinical service and should obtain start-up funds of $500K-1M exclusive of a 5-y committed salary support. Senior respondents placed a higher premium on protected time than junior faculty.

Role of macular xanthophylls in prevention of common neovascular retinopathies: retinopathy of prematurity and diabetic retinopathy.

Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are important causes of blindness among children and working-age adults, respectively. The development of both diseases involves retinal microvascular degeneration, vessel loss and consequent hypoxic and inflammatory pathologic retinal neovascularization. Mechanistic studies have shown that oxidative stress and subsequent derangement of cell signaling are important factors in disease progression. In eye and vision research, role of the dietary xanthophyll carotenoids, lutein and zeaxanthin, has been more extensively studied in adult onset macular degeneration than these other retinopathies. These carotenoids also may decrease severity of ROP in preterm infants and of DR in working-age adults. A randomized controlled clinical trial of carotenoid supplementation in preterm infants indicated that lutein has functional effects in the neonatal eye and is anti-inflammatory. Three multicenter clinical trials all showed a trend of decreased ROP severity in the lutein supplemented group. Prospective studies on patients with non-proliferative DR indicate serum levels of lutein and zeaxanthin are significantly lower in these patients compared to normal subjects. The present review describes recent advances in lutein and zeaxanthin modulation of oxidative stress and inflammation related to ROP and DR and discusses potential roles of lutein/zeaxanthin in preventing or lessening the risks of disease initiation or progression.

ß-carotene regulates expression of ß-carotene 15,15'-monoxygenase in human alveolar epithelial cells.

ß-Carotene 15,15'-monooxygenase (CMO1, BCMO1) converts ß-carotene to retinaldehyde (retinal) and is a key enzyme in vitamin A metabolism. CMO1 activity is robust in the intestine and liver, where cmo1 gene transcription may be subject to negative feedback by accumulation of its metabolic products. Evidence from CMO1 null animals also indicates that non-gastrointestinal CMO1 may be required for tissue-specific conversion of ß-carotene into vitamin A. The aim of this study was to investigate the effects of the enzymatic substrate, ß-carotene, on regulation of CMO1 in a cell model of human alveolar pneumocytes. We demonstrate that CMO1 is expressed in human alveolar epithelial (A549) cells and converts ß-carotene into retinal and biologically active retinoic acids (RA). Exposure to ß-carotene suppresses CMO1 expression at both mRNA and protein levels. ß-Carotene, but not all-trans RA, decreases CMO1 promoter activity in a time- and dosage-dependent manner. This ß-carotene-mediated inhibition of CMO1 expression results from decreased binding of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα) in the CMO1 promoter. ß-Carotene treatment also antagonizes PPARγ activity in HEK293 cells that stably express CMO1 wild-type, but not in cells that express the CMO1 mutant or vector alone. These findings have implications for local vitamin A synthesis in the lung, especially during systemic vitamin A insufficiency and may also help to explain, in part, the mechanism underlying the increased lung cancer risk upon ß-carotene supplementation in smokers.

Obesity, assisted reproductive technology, and early preterm birth--Florida, 2004-2006.

Florida resident birth certificates for 2004-2006 were linked to the Centers for Disease Control and Prevention's National ART Surveillance System and were used to investigate 1) whether the association of assisted reproductive technology (ART) with preterm birth varies by prepregnancy body mass index and 2) whether the association varies by plurality. Preterm birth was defined as early preterm birth (gestation <34 weeks) and late preterm birth (gestation 34-36 weeks). Descriptive statistics and multinomial logistic regression were used to explore maternal and infant differences by ART status and plurality. Of 581,403 women included in the study, 24.0% were overweight, 18.6% were obese, 7.3% had late preterm birth, 2.6% had early preterm birth, and 0.67% conceived through ART. Among singleton births, ART was associated with increased early preterm birth risk among underweight (odds ratio (OR) = 2.94, 95% confidence interval (CI): 1.27, 6.81), overweight (OR = 1.75, 95% CI: 1.12, 2.72), and obese (OR = 2.37, 95% CI: 1.51, 3.71) women. Among twins, ART was significantly associated with increased risk among overweight (OR = 1.61, 95% CI: 1.12, 2.32) and obese (OR = 1.85, 95% CI: 1.18, 2.90) women. Differences in the associations between ART and early preterm birth by body mass index and plurality warrant further investigation.

Recommendations for the Use of the Veggie Meter® for Spectroscopy-Based Skin Carotenoid Measurements in the Research Setting.

Carotenoids are a class of phytochemical compounds found in a variety of fruits and vegetables (F/V) and, therefore, are commonly used as a biomarker for F/V intake. The Veggie Meter® is a noninvasive research-grade instrument that detects and quantifies carotenoids in the skin. To determine current practices and examine variability among users, a survey was administered to researchers using the device (n = 19, response rate = 35.8%) and variation in anatomical site preparation, calibration, number of measurements, measurement site, and documentation was observed. A protocol was developed in partnership with Veggie Meter® users to outline the preparation, calibration, and data collection procedures for using this device for research purposes. Although many protocol conditions will benefit from additional validation, this standardized protocol supports the development of a universal data repository to establish usual observed ranges, with the ultimate goal of examining associations between skin carotenoid scores and diet-related health outcomes.

Hepatic stellate cells are an important cellular site for ß-carotene conversion to retinoid.

Hepatic stellate cells (HSCs) are responsible for storing 90-95% of the retinoid present in the liver. These cells have been reported in the literature also to accumulate dietary ß-carotene, but the ability of HSCs to metabolize ß-carotene in situ has not been explored. To gain understanding of this, we investigated whether ß-carotene-15,15'-monooxygenase (Bcmo1) and ß-carotene-9',10'-monooxygenase (Bcmo2) are expressed in HSCs. Using primary HSCs and hepatocytes purified from wild type and Bcmo1-deficient mice, we establish that Bcmo1 is highly expressed in HSCs; whereas Bcmo2 is expressed primarily in hepatocytes. We also confirmed that HSCs are an important cellular site within the liver for accumulation of dietary ß-carotene. Bcmo2 expression was found to be significantly elevated for livers and hepatocytes isolated from Bcmo1-deficient compared to wild type mice. This elevation in Bcmo2 expression was accompanied by a statistically significant increase in hepatic apo-12'-carotenal levels of Bcmo1-deficient mice. Although apo-10'-carotenal, like apo-12'-carotenal, was readily detectable in livers and serum from both wild type and Bcmo1-deficient mice, we were unable to detect either apo-8'- or apo-14'-carotenals in livers or serum from the two strains. We further observed that hepatic triglyceride levels were significantly elevated in livers of Bcmo1-deficient mice fed a ß-carotene-containing diet compared to mice receiving no ß-carotene. Collectively, our data establish that HSCs are an important cellular site for ß-carotene accumulation and metabolism within the liver.

ß-Carotene exerts anti-colon cancer effects by regulating M2 macrophages and activated fibroblasts.

The tumor microenvironment (TME), consisting of stromal fibroblasts, immune cells, cancer cells and other cell types, plays a crucial role in cancer progression and metastasis. M2 macrophages and activated fibroblasts (AFs) modulate behavior of cancer cells in the TME. Since nutritional effects on cancer progression, including colorectal cancer (CRC), may be mediated by alterations in the TME, we determined the ability of ß-carotene (BC) to mediate anti-cancer effects through regulation of macrophage polarization and fibroblast activation in CRC. The M2 macrophage phenotype was induced by treating U937 cells with phorbol-12-myristate-13-acetate and interleukin (IL)-4. Treatment of these M2 macrophages with BC led to suppression of M2-type macrophage-associated markers and of the IL-6/STAT3 signaling pathway. In separate experiments, AFs were induced by treating CCD-18Co cells with transforming growth factor-ß1. BC treatment suppressed expression of fibroblast activation markers. In addition, conditioned media from BC-treated M2 macrophages and AF inhibited cancer stem cell markers, colon cancer cell invasiveness and migration, and the epithelial-mesenchymal transition (EMT). In vivo, BC supplementation inhibited tumor formation and the expression of M2 macrophage markers in an azoxymethane/dextran sodium sulfate-induced colitis-associated CRC mouse model. To our knowledge, the present findings provide the first evidence suggesting that the potential therapeutic effects of BC on CRC are mediated by the inhibition of M2 macrophage polarization and fibroblast activation.

ß-Carotene 15,15'-oxygenase inhibits cancer cell stemness and metastasis by regulating differentiation-related miRNAs in human neuroblastoma.

Neuroblastoma (NB) is the most common pediatric malignancy and is considered to possess cancer stem cells (CSCs) properties which can drive tumor initiation and metastasis. ß-carotene 15,15'-oxygenase (BCO1) is the main enzyme that catalyzes the first step in vitamin A biosynthesis from pro-vitamin A carotenoids. Retinoids (vitamin A) play a critical role in NB differentiation. However, the biological functions of BCO1 in NB remained to be elucidated. Here, we investigated the effects of BCO1 on NB CSCs with stably expressing BCO1 in NB cells. We show that BCO1 significantly suppressed self-renewal and markers of NB CSCs. Moreover, BCO1 inhibited the metastatic potential of NB cells and suppressed the enzymatic activity and expression of MMPs, as well as expression of HIF-1α and its downstream targets. In vivo, BCO1 reduced the metastatic incidence and volumes of metastatic tumors and downregulated the expression of CSCs markers, MMPs, and HIF-1α in tumor tissues of a mouse xenograft model. A possible mechanism underlying the anti-cancer activities of BCO1 is proposed based on miRNAs sequencing array data which suggests a role for BCO1 in regulating miRNAs associated with neuronal differentiation, cell-cell adhesion, and the Wnt signaling pathway. Thus, our results demonstrate new chemotherapeutic roles for BCO1 in malignant NB that mediate suppression of cancer stemness and metastasis.

Role of aspartyl-(asparaginyl) beta-hydroxylase in placental implantation: Relevance to early pregnancy loss.

Aspartyl-(asparaginyl) beta-hydroxylase (AAH) is a type 2 transmembrane protein with catalytic activity that hydroxylates epidermal growth factor-like domains of proteins that have a functional role in cell motility and invasion. Extravillous cytotrophoblasts (CTB) are motile and invasive unpolarized epithelial cells that mediate early implantation through interaction with the endometrium. This study characterizes the potential role of AAH in CTB implantation using human placentas from (1) terminated pregnancies (n = 11), (2) normal term deliveries (n = 21), (3) spontaneous abortuses (n = 21), and (4) small-for-gestational-age (SGA) term deliveries (n = 21). The SGA cases all had established clinical histories of intrauterine growth restriction or preeclampsia. Formalin-fixed, paraffin-embedded sections of placenta were immunostained using the 15C7 monoclonal antibody generated to recombinant AAH. In addition, snap-frozen or RNAlater-preserved specimens (Ambion, Austin, TX) were used for RNA analysis of AAH expression by real-time quantitative reverse transcriptase-polymerase chain reaction and protein analysis by Western blotting. The immunohistochemical staining studies demonstrated AAH expression in amniocytes, villous CTB, syncytiotrophoblast, extravillous CTB, decidua, and endometrial glands at all gestational ages and in all 4 groups. Higher levels of AAH immunoreactivity were observed in extravillous CTB compared with villous CTB. Immunohistochemical staining and RNA analysis demonstrated abundant AAH expression in placental trophoblastic cells as well as in decidua and endometrial glands, with reduced expression in spontaneous abortion and SGA, suggesting that AAH may serve as a biomarker of impaired implantation. The high levels of AAH in decidua and endometrial glands suggest a role for this molecule in "receptivity" of endometrium.

Inhibition of pulmonary ß-carotene 15, 15'-oxygenase expression by glucocorticoid involves PPARα.

ß-carotene 15,15'-oxygenase (BCO1) catalyzes the first step in the conversion of dietary provitamin A carotenoids to vitamin A. This enzyme is expressed in a variety of developing and adult tissues, suggesting that its activity may regulate local retinoid synthesis. Vitamin A and related compounds (retinoids) are critical regulators of lung epithelial development, integrity, and injury repair. A balance between the actions of retinoids and glucocorticoids (GCs) promotes normal lung development and, in particular, alveolarization. Alterations in this balance, including vitamin A deficiency and GC excess, contribute to the development of chronic lung disorders. Consequently, we investigated if GCs counteract retinoid effects in alveolar epithelial cells by mechanisms involving BCO1-dependent local vitamin A metabolism. We demonstrate that BCO1 is expressed in human fetal lung tissue and human alveolar epithelial-like A549 cells. Our results indicate A549 cells metabolize ß-carotene to retinal and retinoic acid (RA). GCs exposure using dexamethasone (DEX) decreases BCO1 mRNA and protein levels in A549 cells and reduces BCO1 promoter activity via inhibiting peroxisome proliferator-activated receptor γ (PPARγ) DNA binding. DEX also induces expression of PPARα, which in turn most likely causes a decrease in PPARγ/RXRα heterodimer binding to the bco1 gene promoter and consequent inhibition of bco1 gene expression. PPARα knockdown with siRNA abolishes DEX-induced suppression of BCO1 expression, confirming the requirement for PPARα in this DEX-mediated BCO1 mechanism. Taken together, these findings provide the first evidence that GCs regulate vitamin A (retinoid) signaling via inhibition of bco1 gene expression in a PPARα-dependent manner. These results explicate novel aspects of local GC:retinoid interactions that may contribute to alveolar tissue remodeling in chronic lung diseases that affect children and, possibly, adults.

Metabolic Effects of Inflammation on Vitamin A and Carotenoids in Humans and Animal Models.

The association between inflammation and vitamin A (VA) metabolism and status assessment has been documented in multiple studies with animals and humans. The relation between inflammation and carotenoid status is less clear. Nonetheless, it is well known that carotenoids are associated with certain health benefits. Understanding these relations is key to improving health outcomes and mortality risk in infants and young children. Hyporetinolemia, i.e., low serum retinol concentrations, occurs during inflammation, and this can lead to the misdiagnosis of VA deficiency. On the other hand, inflammation causes impaired VA absorption and urinary losses that can precipitate VA deficiency in at-risk groups of children. Many epidemiologic studies have suggested that high dietary carotenoid intake and elevated plasma concentrations are correlated with a decreased risk of several chronic diseases; however, large-scale carotenoid supplementation trials have been unable to confirm the health benefits and in some cases resulted in controversial results. However, it has been documented that dietary carotenoids and retinoids play important roles in innate and acquired immunity and in the body's response to inflammation. Although animal models have been useful in investigating retinoid effects on developmental immunity, it is more challenging to tease out the effects of carotenoids because of differences in the absorption, kinetics, and metabolism between humans and animal models. The current understanding of the relations between inflammation and retinoid and carotenoid metabolism and status are the topics of this review.

Effects of the Macular Carotenoid Lutein in Human Retinal Pigment Epithelial Cells.

Retinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Oxidative stress-induced damage to the RPE occurs as part of the pathogenesis of age-related macular degeneration and neovascular retinopathies (e.g., retinopathy of prematurity, diabetic retinopathy). The xanthophyll carotenoids, lutein and zeaxanthin, are selectively taken up by the RPE, preferentially accumulated in the human macula, and transferred to photoreceptors. These macular xanthophylls protect the macula (and the broader retina) via their antioxidant and photo-protective activities. This study was designed to investigate effects of various carotenoids (ß-carotene, lycopene, and lutein) on RPE cells subjected to either hypoxia or oxidative stress, in order to determine if there is effect specificity for macular pigment carotenoids. Using human RPE-derived ARPE-19 cells as an in vitro model, we exposed RPE cells to various concentrations of the specific carotenoids, followed by either graded hypoxia or oxidative stress using tert-butyl hydroperoxide (tBHP). The results indicate that lutein and lycopene, but not ß-carotene, inhibit cell growth in undifferentiated ARPE-19 cells. Moreover, cell viability was decreased under hypoxic conditions. Pre-incubation of ARPE-19 cells with lutein or lycopene protected against tBHP-induced cell loss and cell co-exposure of lutein or lycopene with tBHP essentially neutralized tBHP-dependent cell death at tBHP concentrations up to 500 µM. Our findings indicate that lutein and lycopene inhibit the growth of human RPE cells and protect the RPE against oxidative stress-induced cell loss. These findings contribute to the understanding of the protective mechanisms attributable to retinal xanthophylls in eye health and retinopathies.

Cooperation between MEF2 and PPARgamma in human intestinal beta,beta-carotene 15,15'-monooxygenase gene expression.

BACKGROUND: Vitamin A and its derivatives, the retinoids, are essential for normal embryonic development and maintenance of cell differentiation. beta, beta-carotene 15,15'-monooxygenase 1 (BCMO1) catalyzes the central cleavage of beta-carotene to all-trans retinal and is the key enzyme in the intestinal metabolism of carotenes to vitamin A. However, human and various rodent species show markedly different efficiencies in intestinal BCMO1-mediated carotene to retinoid conversion. The aim of this study is to identify potentially human-specific regulatory control mechanisms of BCMO1 gene expression. RESULTS: We identified and functionally characterized the human BCMO1 promoter sequence and determined the transcriptional regulation of the BCMO1 gene in a BCMO1 expressing human intestinal cell line, TC-7. Several functional transcription factor-binding sites were identified in the human promoter that are absent in the mouse BCMO1 promoter. We demonstrate that the proximal promoter sequence, nt -190 to +35, confers basal transcriptional activity of the human BCMO1 gene. Site-directed mutagenesis of the myocyte enhancer factor 2 (MEF2) and peroxisome proliferator-activated receptor (PPAR) binding elements resulted in decreased basal promoter activity. Mutation of both promoter elements abrogated the expression of intestinal cell BCMO1. Electrophoretic mobility shift and supershift assays and transcription factor co-expression in TC-7 cells showed MEF2C and PPARgamma bind to their respective DNA elements and synergistically transactivate BCMO1 expression. CONCLUSION: We demonstrate that human intestinal cell BCMO1 expression is dependent on the functional cooperation between PPARgamma and MEF2 isoforms. The findings suggest that the interaction between MEF2 and PPAR factors may provide a molecular basis for interspecies differences in the transcriptional regulation of the BCMO1 gene.

Mitochondrial ß-Carotene 9',10' Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function.

Despite numerous inquiries into protective roles of lycopene in prostate cancer prevention or therapy, little is known about mechanisms by which lycopene or its metabolites inhibit prostate cancer. The enzyme ß-carotene 9',10'-oxygenase (BCO2), which catalyzes asymmetric cleavage of several carotenoids, is the principal regulator of lycopene metabolism, but the range of BCO2 biological functions is incompletely understood. This study investigated expression and functional roles of BCO2 in human prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor cell growth in androgen-resistant cells. Notably, restoring bco2 expression in prostate cancer cells inhibited cell proliferation and colony formation, irrespective of lycopene exposure. Exogenous expression of either wild-type BCO2 or a mutant (enzymatically inactive) BCO2 in prostate cancer cells reduced NF-κB activity and decreased NF-κB nuclear translocation and DNA binding. Together, these results indicate epigenetic loss of BCO2 expression is associated with prostate cancer progression. Moreover, these findings describe previously unanticipated functions of BCO2 that are independent of its enzymatic role in lycopene metabolism. IMPLICATIONS: This study identifies BCO2 as a tumor suppressor in prostate cancer. BCO2-mediated inhibition of NF-κB signaling implies BCO2 status is important in prostate cancer progression. Mol Cancer Res; 14(10); 966-75. ©2016 AACR.

Novel Somatic Copy Number Alteration Identified for Cervical Cancer in the Mexican American Population.

Cervical cancer affects millions of Americans, but the rate for cervical cancer in the Mexican American is approximately twice that for non-Mexican Americans. The etiologies of cervical cancer are still not fully understood. A number of somatic mutations, including several copy number alterations (CNAs), have been identified in the pathogenesis of cervical carcinomas in non-Mexican Americans. Thus, the purpose of this study was to investigate CNAs in association with cervical cancer in the Mexican American population. We conducted a pilot study of genome-wide CNA analysis using 2.5 million markers in four diagnostic groups: reference (n = 125), low grade dysplasia (cervical intraepithelial neoplasia (CIN)-I, n = 4), high grade dysplasia (CIN-II and -III, n = 5) and invasive carcinoma (squamous cell carcinoma (SCC), n = 5) followed by data analyses using Partek. We observed a statistically-significant difference of CNA burden between case and reference groups of different sizes (>100 kb, 10-100 kb and 1-10 kb) of CNAs that included deletions and amplifications, e.g., a statistically-significant difference of >100 kb deletions was observed between the reference (6.6%) and pre-cancer and cancer (91.3%) groups. Recurrent aberrations of 98 CNA regions were also identified in cases only. However, none of the CNAs have an impact on cancer progression. A total of 32 CNA regions identified contained tumor suppressor genes and oncogenes. Moreover, the pathway analysis revealed endometrial cancer and estrogen signaling pathways associated with this cancer (p < 0.05) using Kyoto Encyclopedia of Genes and Genomes (KEGG). This is the first report of CNAs identified for cervical cancer in the U.S. Latino population using high density markers. We are aware of the small sample size in the study. Thus, additional studies with a larger sample are needed to confirm the current findings.

Genome-wide methylome analyses reveal novel epigenetic regulation patterns in schizophrenia and bipolar disorder.

Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3'-UTRs and 5'-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3'-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.