Search

A majority of the human genome is transcribed into noncoding RNAs, of which long noncoding RNAs (lncRNAs) form a large and heterogeneous fraction. While lncRNAs are mostly noncoding, recent evidence suggests that cryptic translation within some lncRNAs may produce proteins with important regulatory functions. In this issue of the JCI, Zheng, Wei, and colleagues used an integrative functional genomic strategy to systematically identify cryptic lncRNA-encoded ORFs that play a role in estrogen receptor-positive ([ER.sup.+]) breast cancer (BC). They identified 758 cryptic lncRNA-encoded ORFs undergoing active translation, of which 28 had potential functional and clinical relevance in [ER.sup.+] BC. The LINC00992- encoded polypeptide GT3-INCP was upregulated in [ER.sup.+] BC and drove tumor growth. GT3-INCP was regulated by estrogen and the ER and acted via the transcription factor GATA3 to regulate BC susceptibility and risk genes. These findings discern a largely unexplored class of molecules and have implications for many pathologies, including cancer., Functionally and clinically relevant cryptic lncRNA-encoded proteins While most of the genome is transcribed into RNA, only about 2% of these RNAs are translated into functional proteins and peptides. The [...]

Background Each year, over 16,000 patients die from malignant brain cancer in the US. Long noncoding RNAs (lncRNAs) have recently been shown to play critical roles in regulating neurogenesis and brain tumor progression. To better understand the role of lncRNAs in brain cancer, we performed a global analysis to identify and characterize all annotated and novel lncRNAs in both grade II and III gliomas as well as grade IV glioblastomas (glioblastoma multiforme [GBM]). Methods and Findings We determined the expression of all lncRNAs in over 650 brain cancer and 70 normal brain tissue RNA sequencing datasets from The Cancer Genome Atlas (TCGA) and other publicly available datasets. We identified 611 induced and 677 repressed lncRNAs in glial tumors relative to normal brains. Hundreds of lncRNAs were specifically expressed in each of the three lower grade glioma (LGG) subtypes (IDH1/2 wt, IDH1/2 mut, and IDH1/2 mut 1p19q codeletion) and the four subtypes of GBMs (classical, mesenchymal, neural, and proneural). Overlap between the subtype-specific lncRNAs in GBMs and LGGs demonstrated similarities between mesenchymal GBMs and IDH1/2 wt LGGs, with 2-fold higher overlap than would be expected by random chance. Using a multivariate Cox regression survival model, we identified 584 and 282 lncRNAs that were associated with a poor and good prognosis, respectively, in GBM patients. We developed a survival algorithm for LGGs based on the expression of 64 lncRNAs that was associated with patient prognosis in a test set (hazard ratio [HR] = 2.168, 95% CI = 1.765-2.807, p < 0.001) and validation set (HR = 1.921, 95% CI = 1.333-2.767, p < 0.001) of patients from TCGA. The main limitations of this study are that further work is needed to investigate the clinical relevance of our findings, and that validation in an independent dataset is needed to determine the robustness of our survival algorithm. Conclusions This work identifies a panel of lncRNAs that appear to be prognostic in gliomas and provides a critical resource for future studies examining the role of lncRNAs in brain cancers., Author(s): Brian J. Reon 1,2, Jordan Anaya 2, Ying Zhang 3, James Mandell 1, Benjamin Purow 3, Roger Abounader 3, Anindya Dutta 2,* Introduction Malignant gliomas are the most common [...]

DMT1 (divalent metal transporter 1) is a hydrogen-coupled divalent metal transporter with a substrate preference for iron, although the protein when expressed in frog oocytes transports a broad range of metals, including the toxic metals cadmium and lead. Wild-type Caco-2 cells displayed saturable transport of lead and iron that was stimulated by acid. Cadmium and manganese inhibited transport of iron, but zinc and lead did not. The involvement of DMT1 in the transport of toxic metals was examined by establishing clonal DMT1 knockdown and control Caco-2 cell lines. Knockdown cell lines displayed much lower levels of DMT1 mRNA and a smaller [V.sub.max] for iron uptake compared with control cell lines. One clone was further characterized and found to display an ~50% reduction in uptake of iron across a pH range from 5.5 to 7.4. Uptake for cadmium also decreased 50% across the same pH range, but uptake for lead did not. These results show that DMT1 is important in iron and cadmium transport in Caco-2 cells but that lead enters these cells through an independent hydrogen-driven mechanism. divalent metal transporter 1; transport; intestine

Blood flow is not distributed evenly in the brain at all times, so that capillaries are not all filled at the same time. The patterns of perfusion in brain capilalries were studied in rat brains whose blood flow was reduced to see if these patterns change as blood supply is changed. Evans blue dye was introduced intravenously, then the rats were decapitated and the heads were frozen and examined for variations in dye concentration in the capillaries. When the dye was introduced to blood vessels under conditions of hypocapnia, they showed a more homogenous distribution of dye compared to patterns observed in normocapnia and hypercapnia.