Implications in Cancer of Nuclear Micro RNAs, Long Non-Coding RNAs, and Circular RNAs Bound by PRC2 and FUS.

The eukaryotic genome is mainly transcribed into non-coding RNAs (ncRNAs), including different RNA biotypes, such as micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), among others. Although miRNAs are assumed to act primarily in the cytosol, mature miRNAs have been reported and functionally characterized in the nuclei of different cells. Further, lncRNAs are important regulators of different biological processes in the cell nucleus as part of different ribonucleoprotein complexes. CircRNAs constitute a relatively less-characterized RNA biotype that has a circular structure as result of a back-splicing process. However, circRNAs have recently attracted attention in different scientific fields due to their involvement in various biological processes and pathologies. In this review, we will summarize recent studies that link to cancer miRNAs that have been functionally characterized in the cell nucleus, as well as lncRNAs and circRNAs that are bound by core components of the polycomb repressive complex 2 (PRC2) or the protein fused in sarcoma (FUS), highlighting mechanistic aspects and their diagnostic and therapeutic potential.

Association of the EPAS1 rs7557402 Polymorphism with Hemodynamically Significant Patent Ductus Arteriosus Closure Failure in Premature Newborns under Pharmacological Treatment with Ibuprofen.

Patent ductus arteriosus (PDA) is frequent in preterm newborns, and its incidence is inversely associated with the degree of prematurity. The first choice of pharmacological treatment is ibuprofen. Several genes, including EPAS1, have been proposed as probable markers associated with a genetic predisposition for the development of PDA in preterm infants. EPAS 1 NG_016000.1:g.84131C>G or rs7557402 has been reported to be probably benign and associated with familial erythrocytosis by the Illumina Clinical Services Laboratory. Other variants of EPAS1 have been previously reported to be benign for familial erythrocytosis because they decrease gene function and are positive for familial erythrocytosis because the overexpression of EPAS1 is a key factor in uncontrolled erythrocyte proliferation. However, this could be inconvenient for ductal closure, since for this process to occur, cell proliferation, migration, and differentiation should take place, and a decrease in EPAS1 gene activity would negatively affect these processes. Single-nucleotide polymorphisms (SNPs) in EPAS1 and TFAP2B genes were searched with high-resolution melting and Sanger sequencing in blood samples of preterm infants with hemodynamically significant PDA treated with ibuprofen at the National Institute of Perinatology. The variant rs7557402, present in the EPAS1 gene eighth intron, was associated with a decreased response to treatment (p = 0.007, OR = 3.53). The SNP rs7557402 was associated with an increased risk of pharmacological treatment failure. A probable mechanism involved could be the decreased activity of the product of the EPAS1 gene.

Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer.

Background: Small cell lung cancer (SCLC) is an extremely aggressive cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC remains elusive. Methods: We analyzed human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines by classical methods of molecular biology and biochemistry. In addition, we performed RNA-sequencing-based transcriptomic analysis in human lung cancer cells and human lung tissue samples, as well as high-resolution mass spectrometric analysis of the protein cargo from extracellular vesicles (EVs) that were isolated from human lung cancer cells. Results: Our results demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which may be used for stratification of SCLC patients and prognosis prediction of LC patients. We also found a cell-cell communication mechanism based on EVs containing ITGB2, which were secreted by SCLC cells and induced in control human lung tissue RAS/MAPK/ERK signaling and SCLC markers. Conclusions: We uncovered a mechanism of ITGB2-mediated EGFR activation in SCLC that explains EGFR-inhibitor resistance independently of EGFR mutations, suggesting the development of therapies targeting ITGB2 for patients with this extremely aggressive lung cancer type.

Nutriepigenomics in Environmental-Associated Oxidative Stress.

Complex molecular mechanisms define our responses to environmental stimuli. Beyond the DNA sequence itself, epigenetic machinery orchestrates changes in gene expression induced by diet, physical activity, stress and pollution, among others. Importantly, nutrition has a strong impact on epigenetic players and, consequently, sustains a promising role in the regulation of cellular responses such as oxidative stress. As oxidative stress is a natural physiological process where the presence of reactive oxygen-derived species and nitrogen-derived species overcomes the uptake strategy of antioxidant defenses, it plays an essential role in epigenetic changes induced by environmental pollutants and culminates in signaling the disruption of redox control. In this review, we present an update on epigenetic mechanisms induced by environmental factors that lead to oxidative stress and potentially to pathogenesis and disease progression in humans. In addition, we introduce the microenvironment factors (physical contacts, nutrients, extracellular vesicle-mediated communication) that influence the epigenetic regulation of cellular responses. Understanding the mechanisms by which nutrients influence the epigenome, and thus global transcription, is crucial for future early diagnostic and therapeutic efforts in the field of environmental medicine.