RNA Editing in Pathogenesis of Cancer

Several adenosine or cytidine deaminase enzymes deaminate transcript sequences in a cell type or environment-dependent manner by a programmed process called RNA editing. RNA editing enzymes catalyze A>I or C>U transcript alterations and have the potential to change protein coding sequences. In this brief review, we highlight some recent work that shows aberrant patterns of RNA editing in cancer. Transcriptome sequencing studies reveal increased or decreased global RNA editing levels depending on the tumor type. Altered RNA editing in cancer cells may provide a selective advantage for tumor growth and resistance to apoptosis. RNA editing may promote cancer by dynamically recoding oncogenic genes, regulating oncogenic gene expression by noncoding RNA and miRNA editing, or by transcriptome scale changes in RNA editing levels that may affect innate immune signaling. Although RNA editing markedly increases complexity of the cancer cell transcriptomes, cancer-specific recoding RNA editing events have yet to be discovered. Epitranscriptomic changes by RNA editing in cancer represent a novel mechanism contributing to sequence diversity independently of DNA mutations. Therefore, RNA editing studies should complement genome sequence data to understand the full impact of nucleic acid sequence alterations in cancer

A Recurrent Stop-Codon Mutation in Succinate Dehydrogenase Subunit B Gene in Normal Peripheral Blood and Childhood T-Cell Acute Leukemia

BACKGROUND: Somatic cytidine mutations in normal mammalian nuclear genes occur during antibody diversification in B lymphocytes and generate an isoform of apolipoprotein B in intestinal cells by RNA editing. Here, I describe that succinate dehydrogenase (SDH; mitochondrial complex II) subunit B gene (SDHB) is somatically mutated at a cytidine residue in normal peripheral blood mononuclear cells (PBMCs) and T-cell acute leukemia. Germ line mutations in the SDHB, SDHC or SDHD genes cause hereditary paraganglioma (PGL) tumors which show constitutive activation of homeostatic mechanisms induced by oxygen deprivation (hypoxia). PRINCIPAL FINDINGS: To determine the prevalence of a mutation identified in the SDHB mRNA, 180 samples are tested. An SDHB stop-codon mutation c.136C>T (R46X) is present in a significant fraction (average = 5.8%, range = less than 1 to 30%, n = 52) of the mRNAs obtained from PBMCs. In contrast, the R46X mutation is present in the genomic DNA of PBMCs at very low levels. Examination of the PBMC cell-type subsets identifies monocytes and natural killer (NK) cells as primary sources of the mutant transcript, although lesser contributions also come from B and T lymphocytes. Transcript sequence analyses in leukemic cell lines derived from monocyte, NK, T and B cells indicate that the mutational mechanism targeting SDHB is operational in T-cell acute leukemia. Accordingly, substantial levels (more than 3%) of the mutant SDHB transcripts are detected in five of 20 primary childhood T-cell acute lymphoblastic leukemia (T-ALL) bone marrow samples, but in none of 20 B-ALL samples. In addition, distinct heterozygous SDHB missense DNA mutations are identified in Jurkat and TALL-104 cell lines which are derived from T-ALLs. CONCLUSIONS: The identification of a recurrent, inactivating stop-codon mutation in the SDHB gene in normal blood cells suggests that SDHB is targeted by a cytidine deaminase enzyme. The SDHB mutations in normal PBMCs and leukemic T cells might play a role in cellular pre-adaptation to hypoxia

Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer (OvCa) most often derives from ovarian surface epithelial (OSE) cells. Several lines of evidence strongly suggest that increased exposure to progesterone (P4) protects women against developing OvCa. However, the underlying mechanisms of this protection are incompletely understood.</p> <p>Methods</p> <p>To determine downstream gene targets of P4, we established short term <it>in vitro </it>cultures of non-neoplastic OSE cells from six subjects, exposed the cells to P4 (10^-6M) for five days and performed transcriptional profiling with oligonucleotide microarrays containing over 22,000 transcripts.</p> <p>Results</p> <p>We identified concordant but modest gene expression changes in cholesterol/lipid homeostasis genes in three of six samples (responders), whereas the other three samples (non-responders) showed no expressional response to P4. The most up-regulated gene was <it>TMEM97 </it>which encodes a transmembrane protein of unknown function (MAC30). Analyses of outlier transcripts, whose expression levels changed most significantly upon P4 exposure, uncovered coordinate up-regulation of 14 cholesterol biosynthesis enzymes, insulin-induced gene 1, low density lipoprotein receptor, <it>ABCG1</it>, endothelial lipase, stearoyl- CoA and fatty acid desaturases, long-chain fatty-acyl elongase, and down-regulation of steroidogenic acute regulatory protein and <it>ABCC6</it>. Highly correlated tissue-specific expression patterns of <it>TMEM97 </it>and the cholesterol biosynthesis genes were confirmed by analysis of the GNF Atlas 2 universal gene expression database. Real-time quantitative RT-PCR analyses revealed 2.4-fold suppression of the <it>TMEM97 </it>gene expression in short-term cultures of OvCa relative to the normal OSE cells.</p> <p>Conclusion</p> <p>These findings suggest that a co-regulated transcript network of cholesterol/lipid homeostasis genes and <it>TMEM97 </it>are downstream targets of P4 in normal OSE cells and that <it>TMEM97 </it>plays a role in cholesterol and lipid metabolism. The P4-induced alterations in cholesterol and lipid metabolism in OSE cells might play a role in conferring protection against OvCa.</p

Humidification Solution as a Source for Spreading Burkholderia cepaciain a Neonatal Intensive Care Unit

Burkholderia cepaciais an important opportunistic organism in hospitalized and immunocompromised patients especially in newborns. The natural ecology of these bacteria associated with plants is also a cause of infectious potential. The disease-causing potential of bacteria as a nosocomial pathogen may be due to its ability to survive in antiseptic solutions, contamination equipment. The patient was hospitalized for prematurity and respiratory distress syndrome. He was treated with surfactant intratracheally for the respiratory distress syndrome. Umbilical catheter was inserted. Ampicillin and gentamicin treatments were initiated. The patient who received respiratory support for a long time was given a steroid protocol because of bronchopulmonary dysplasia. Burkholderia cepacia was detected in the blood and tracheal aspirate cultures of the patient, whose infection markers increased and a new area of infection was detected on the chest radiograph. Colistin and ciprofloxacin treatments were given according to the culture antibiogram. Screening tests revealed B. cepaciacolonization in incubator moistening solutions. All incubator humidification solutions in the hospital were changed. Burkholderia cepaciais a rare cause of nosocomial infection in intensive care units but resistant to many treatments. With its capability to colonize water and grow on microbicides, the presence of B. cepaciain a patient's blood warrants further investigation in institutions providing care

Son dönem kalp yetersizliği olgularında sol ventrikül destek cihazı implantasyonu sonrası gelişen sağ ventrikül yetmezliği risk faktörlerinin retrospektif olarak belirlenmesi

Giriş: Bu çalışmanın amacı LVAD implantasyonu sonrası RV yetmezliği gelişimini öngörecek parametreler saptamaktır. LVAD implantasyonu sonrası morbidite ve mortalitenin önemli bir nedeni olan RV yetmezliğini öngörmede, klinik değerlendirme tek başına yetersiz kalmaktadır. Materyal-metod: Kliniğimizde LVAD implantasyonu yapılan 100 hastanın klinik, hemodinamik ve ekokardiyografik verileri retrospektif olarak değerlendirildi. RV yetmezliği 14 günden uzun süren inotrop ihtiyacı veya ECMO ya da RVAD implantasyon ihtiyacı olarak tanımlandı. Bulgular: RV yetmezliği 100 hastanın 29'sinde gelişmiştir (29%). INTERMACS sınıfı, hipoalbuminemi, hiponatremi, yüksek ürik asit, INR ve kreatinin değerleri, %35'in altında RVEF, düşük TAPSE, 3. derece ve daha fazla triküspid kapak yetmezliği, uzamış kardiyopulmoner baypas süresi (2 saatin üstü), preoperatif intraaortik balon pompası(IABP) ihtiyacı, postoperatif kanama (24 saatte 1000cc ve üzeri) parametreleri LVAD implantasyonu sonrası RV yetmezliği için risk faktörü olarak saptanmıştır. Çoklu lojistik regresyon testi uygulandığında IABP (OR: 46,370), kreatinin (OR: 11,951), TAPSE (OR: 8,104), asit varlığı (OR: 51,036), postoperatif kanama (OR: 19,665), triküspit kapak yetmezliği (OR: 9,052) RV yetmezliği için en anlamlı bağımsız risk faktörleri olarak bulunmuştur. Preoperatif entübasyon ihtiyacı, IABP, INTERMACS sınıfı, hipoalbumeni, hiponatremi, yüksek kreatinin düzeyleri ve postoperatif kanama 30 günlük mortalite ile ilişkili bulunmuştur. Çoklu lojistik regresyon analizinde IABP (OR: 5,015), hiponatremi (OR: 4,953), yüksek kreatinin (OR: 6,397) ve postoperatif kanama (OR: 8,848) en anlamlı bağımsız değişkenlerdir. Sonuçlar RV yetmezliği LVAD implantasyonu sonrası en ölümcül komplikasyondur. RV yetmezliği gelişmeden harekete geçmek hayati önem taşır. Bu çalışmanın bulgularının daha iyi hasta seçimi ve zamanlama için önemli olduğunu düşünmekteyiz

Stem-loop structure preference for site-specific RNA editing by APOBEC3A and APOBEC3G

APOBEC3A and APOBEC3G cytidine deaminases inhibit viruses and endogenous retrotransposons. We recently demonstrated the novel cellular C-to-U RNA editing function of APOBEC3A and APOBEC3G. Both enzymes deaminate single-stranded DNAs at multiple TC or CC nucleotide sequences, but edit only a select set of RNAs, often at a single TC or CC nucleotide sequence. To examine the specific site preference for APOBEC3A and -3G-mediated RNA editing, we performed mutagenesis studies of the endogenous cellular RNA substrates of both proteins. We demonstrate that both enzymes prefer RNA substrates that have a predicted stem-loop with the reactive C at the 3′-end of the loop. The size of the loop, the nucleotides immediately 5′ to the target cytosine and stability of the stem have a major impact on the level of RNA editing. Our findings show that both sequence and secondary structure are preferred for RNA editing by APOBEC3A and -3G, and suggest an explanation for substrate and site-specificity of RNA editing by APOBEC3A and -3G enzymes