The acetyl-coenzyme-A carboxylase (ACC) gene contains two promoters: promoter I (PI) and promoter II (PII). Depending upon which promoter is active, two classes of ACC mRNA are formed. The physiological significance of the presence of two promoters in the gene is not clear at this time. However, this question can be indirectly approached by examination of their expression patterns under different physiological conditions. We have examined the activities of these two promoters under different physiological conditions by means of primer extension analysis. Under normal conditions, the Wistar rat, fed standard chow ad libitum, expresses only basal levels of PI in white adipose tissue and PII in the liver. Starvation leads to the virtual disappearance of transcriptional products from these promoters. When fatty acid synthesis is stimulated by refeeding a fat-free diet to starved rats, both PI and PII are activated in the liver; however, in white adipose tissue, only PI, not PII, is responsive to this nutritional induction. On the other hand, in streptozotocin-diabetic rats, in which the activity of both promoters in both tissues is depressed, the administration of insulin quickly induces PI in adipose tissues, but has no significant effect on either of the promoters in the liver. During the weaning transition, the increase in hepatic lipogenesis is accompanied by activation of PI and PII when the pups are weaned onto a fat-free diet. Weaning onto a standard chow causes only a slight increase in PII. During the lactation period, profound alterations occur in the metabolism of the lipogenic tissues. In the lactating rat mammary gland only PII is active, and its activity is increased throughout lactation, reaching a plateau by day 7. Concomitantly, all ACC gene activity is completely shut off in the adipose tissue, while in the liver, PII, the only promoter active, is affected only minimally. The fat accumulation of the genetically obese Zucker rats is largely due to an abnormally high hepatic lipogenesis. In the obese Zucker rat (fa/fa), the level of expression of PII is similar to that in its lean siblings; however, PI is constitutively expressed at high levels, comparable to those in the Wistar rat that has been subjected to the starvation/refeeding induction. These studies demonstrate that the in vivo transcriptional control of the dual promoter rat ACC gene is a highly regulated and tissue-specific process.

Background Incidence of unilateral retinoblastoma varies globally suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is inversely associated with risk of retinoblastoma in offspring. Methods Using a case-control study design, we examined the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes, methylenetetrahydrofolate reductase (MTHFR677C>T, rs1801133) and dihydrofolate reductase (DHFR 19base pair deletion of intron 1a [DHFR19bpdel], rs70991108). In central Mexico, we enrolled 103 mothers of children with newly diagnosed unilateral retinoblastoma and 97 control mothers who had healthy children in an IRB approved study. Mothers were interviewed regarding perinatal characteristics including use of prenatal vitamin supplements and gave peripheral blood samples used for PCR-based genotyping of rs1801133 and rs70991108. Results The risk of having a child with unilateral retinoblastoma were associated with maternal homozygosity for DHFR19bpdel (OR=3.78, 95%CI:1.89,7.55; p=0.0002), even after controlling for child’s DHFR19bpdel genotype (OR=2.81, 95%CI:1.32,5.99; p=0.0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel-associated risk was significantly elevated only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to risk of having a child with retinoblastoma. Conclusion Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biological folate is associated with increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population.

BackgroundmiRNAs exert their effect through a negative regulatory mechanism silencing expression upon hybridizing to their target mRNA, and have a prominent position in the control of many cellular processes including carcinogenesis. Previous miRNA studies on retinoblastoma (Rb) have been limited to specific miRNAs reported in other tumors or to medium density arrays. Here we report expression analysis of the whole miRNome on 12 retinoblastoma tumor samples using a high throughput microarray platform including 2578 mature miRNAs.MethodsTwelve retinoblastoma tumor samples were analyzed using an Affymetrix platform including 2578 mature miRNAs. We applied RMA analysis to normalize raw data, obtained categorical data from detection call values, and also used signal intensity derived expression data. We used Diana-Tools-microT-CDS to find miRNA targets and ChromDraw to map miRNAs in chromosomes.ResultsWe discovered a core-cluster of 30 miRNAs that were highly expressed in all the cases and a cluster of 993 miRNAs that were uniformly absent in all cases. Another 1022 miRNA were variably present in the samples reflecting heterogeneity between tumors. We explored mRNA targets, pathways and biological processes affected by some of these miRNAs. We propose that the core-cluster of 30 miRs represent miRNA machinery common to all Rb, and affecting most pathways considered hallmarks of cancer. In this core, we identified miR-3613 as a potential and critical down regulatory hub, because it is highly expressed in all the samples and its potential mRNA targets include at least 36 tumor suppressor genes, including RB1. In the variably expressed miRNA, 36 were differentially expressed between males and females. Some of the potential pathways targeted by these 36 miRNAs were associated with hormonal production.ConclusionThese findings indicate that Rb tumor samples share a common miRNA expression profile regardless of tumor heterogeneity, and shed light on potential novel therapeutic targets such as mir-3613 This is the first work to delineate the miRNA landscape in retinoblastoma tumor samples using an unbiased approach.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3421-3) contains supplementary material, which is available to authorized users.

Background More invasive retinoblastoma (Rb), characterized by increased morbidity and mortality, with lower rates of eye salvage and higher rates of extraocular dissemination, appears more prevalent in resource-poor countries. The relationship of diagnostic delay (lag time) and socio-demographic factors on the extent of disease at diagnosis has not been examined separately for unilateral and bilateral Rb. Methods At diagnosis, consenting parents of 179 Mexican children with Rb were interviewed about initial symptoms and household demographic characteristics. Clinical presentation was classified using St. Jude’s, International Staging System (ISS), and International Intraocular Retinoblastoma Classification (IIRC) criteria. Lag time (delay between noting symptoms and diagnosis), and socio-demographic factors were examined as predictors for higher stage at diagnosis and overall survival (OS). Results In bilateral disease, lag time predicts stage at diagnosis using St. Jude’s, and ISS criteria (p<0.005 in multivariate regression), and OS (p<.05,CoxHazards), but not extent of intraocular disease (by IIRC). In unilateral disease, lag time predicts neither extent of disease (using ISS, St Jude’s and IIRC), nor OS. Indicators of prenatal poverty, including lower maternal education and the presence of dirt flooring in the home, predict more advanced disease by IIRC for bilateral Rb, and for unilateral by ISS, and St Jude’s (p<0.001) as well as OS (p<0.05). Conclusion These results suggest unilateral and bilateral retinoblastoma differ in factors governing progression and extra-retinal extension, possibly reflecting underlying biological heterogeneity. Impact This demonstrates differing effect of social factors on extent of intra- and extraocular disease depending on laterality with implications for screening strategies.