A novel LncRNA-based prognostic score reveals TP53-dependent subtype of lung adenocarcinoma with poor survival

The prognostic signatures play an essential role in the era of personalised therapy for cancer patients including lung adenocarcinoma (LUAD). Long noncoding RNA (LncRNA), a relatively novel class of RNA, has shown to play a crucial role in all the areas of cancer biology. Here, we developed and validated a robust LncRNA-based prognostic signature for LUAD patients using three different cohorts. In the discovery cohort, four LncRNAs were identified with 10% false discovery rate and a hazard ratio of >10 using univariate Cox regression analysis. A risk score, generated from the four LncRNAs’ expression, was found to be a significant predictor of survival in the discovery and validation cohort (p = 9.97 × 10 ⁻⁸ and 1.41 × 10 ⁻³, respectively). Further optimisation of four LncRNAs signature in the validation cohort, generated a three LncRNAs prognostic score (LPS), which was found to be an independent predictor of survival in both the cohorts ( p = 1.00 × 10 ⁻⁶ and 7.27 × 10 ⁻⁴, respectively). The LPS also significantly divided survival in clinically important subsets, including Stage I ( p = 9.00 × 10 ⁻⁴ and 4.40 × 10 ⁻², respectively), KRAS wild-type (WT), KRAS mutant ( p = 4.00 × 10 ⁻³ and 4.30 × 10 ⁻², respectively) and EGFR WT ( p = 2.00 × 10 ⁻⁴). In multivariate analysis LPS outperformed, eight previous prognosticators. Further, individual members of LPS showed a significant correlation with survival in microarray data sets. Mutation analysis showed that high-LPS patients have a higher mutation rate and inactivation of the TP53 pathway. In summary, we identified and validated a novel LncRNA signature LPS for LUAD.     

Foraminifers of the Viséan–Serpukhovian boundary interval in Western Palaeotethys: a review

A detailed revision of foraminiferal zonal schemes in sections throughout Europe and North Africa for the Viséan–Serpukhovian boundary interval suggests that several foraminiferal taxa might have the potential to form reliable markers throughout the Palaeotethys. This would support the currently investigated boundary definition based on the First Appearance Datum of the conodont Lochriea ziegleri. However, correlation of these foraminiferal markers in the Western Palaeotethys region has encountered several problems, partly arising from taxonomic issues, but mainly because of apparent discrepancies between the First Occurrence Data (FOD). Analysis of the available foraminiferal data has revealed that some taxa show marked delays in their FODs, due to the timing of westward dispersal within the Palaeotethys, emanating from a probable source in eastern Russia. As a result of this investigation, two dispersal routes have been identified, a northern branch and a southern branch. In general, the displacements within the southern branch occurred more rapidly than in the northern branch. In addition to different dispersal routes, separation of the main foraminiferal markers in stratigraphical sections from different regions can result from isolation of shallow‐water facies of the inner platform from those of relatively deeper‐water settings in the outer platform, the latter showing more consistent foraminiferal FODs. The differences in palaeobathymetry and associated energy levels have enabled two foraminiferal zonal schemes to be distinguished for the Viséan–Serpukhovian boundary interval in the Western Palaeotethys, one for the inner platform and a second one for the outer platform.     

Glutamine regulates mitochondrial uncoupling protein 2 to promote glutaminolysis in neuroblastoma cells

Mitochondrial uncoupling protein 2 (UCP2) is highly abundant in rapidly proliferating cells that utilize aerobic glycolysis, such as stem cells, cancer cells, and cells of the immune system. However, the function of UCP2 has been a longstanding conundrum. Considering the strict regulation and unusually short life time of the protein, we propose that UCP2 acts as a “signaling protein” under nutrient shortage in cancer cells. We reveal that glutamine shortage induces the rapid and reversible downregulation of UCP2, decrease of the metabolic activity and proliferation of neuroblastoma cells, that are regulated by glutamine per se but not by glutamine metabolism. Our findings indicate a very rapid (within 1?h) metabolic adaptation that allows the cell to survive by either shifting its metabolism to the use of the alternative fuel glutamine or going into a reversible, more quiescent state. The results imply that UCP2 facilitates glutamine utilization as an energetic fuel source, thereby providing metabolic flexibility during glucose shortage. The targeting UCP2 by drugs to intervene with cancer cell metabolism may represent a new strategy for treatment of cancers resistant to other therapies.     

Circular RNA circMTO1 suppresses bladder cancer metastasis by sponging miR-221 and inhibiting epithelial-to-mesenchymal transition

Bladder cancer remains a leading cause of cancer-related death because of its distant metastasis and high recurrence rates. Deregulation of circular RNAs (circRNAs) can act either as tumor suppressors or oncogenes to control cell proliferation, migration, and metastasis. The role of circMTO1 in bladder cancer remain unknown. In this study, we investigated whether circMTO1 could use as a biomarker and therapeutic target for bladder cancer treatment. We first demonstrated that circMTO1 was an important circRNA frequently downregulated in bladder cancer tissue, and lower circMTO1 levels were positively correlated with bladder cancer patients' metastasis and poorer survival. Ectopic expression of circMTO1 in bladder cancer cells inhibited cell's epithelial-to-mesenchymal transition (EMT) and metastasis. In addition, we also revealed that circMTO1 was able to sponge miR-221 and overexpression of circMTO1 negatively regulated the E-cadherin/N-cadherin pathway to inhibit bladder cancer cells' EMT by competing for miR-221. In conclusion, our findings provide comprehensive evidences that circMTO1 is a prognostic biomarker in bladder cancer and suggest that circMTO1 may function as a novel therapeutic target in human bladder cancer.     

Small interfering RNA–mediated gene suppression as a therapeutic intervention in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the lethal and difficult-to-cure cancers worldwide. Owing to the late diagnosis and drug resistance of malignant hepatocytes, treatment of this cancer by conventional chemotherapy agents is challenging, and researchers are seeking new alternative treatment options to overcome therapy resistance in this neoplasm. RNA interference (RNAi) is a potent and specific approach in targeting gene expression and has emerged as a novel therapeutic tool for many diseases, including cancers. Small interfering RNA (siRNA) is a type of RNAi that is produced intracellularly from exogenous synthetic oligonucleotides and can selectively knock down target gene expression in a sequence-specific manner. Various factors play roles in the initiation and progression of HCC and provide multiple candidate targets for siRNA intervention. In addition, due to the liver's unique architecture and availability of some hepatic siRNA delivery methods, this organ has received much more attention as a target tissue for such oligonucleotide action. Recent advances in designing nanoparticle systems for the in vivo delivery of siRNAs have markedly enhanced the potency of siRNA-mediated gene silencing under clinical development for HCC therapy. The utility of siRNAs as anti-HCC agents is the subject of the current review. siRNA-based gene therapies could be one of the main feasible approaches for HCC therapy in the future.     

Circular RNA circRNA_15698 aggravates the extracellular matrix of diabetic nephropathy mesangial cells via miR-185/TGF-β1

Circular RNAs (circRNAs) are a novel type of noncoding RNAs that modulate the pathogenesis of multiple diseases. Nevertheless, the role of circRNAs in diabetic nephropathy (DN) pathogenesis is still ambiguous. In the current study, our team aims to investigate the expression profiles of circRNAs in DN and identify the function of circRNA on mesangial cells. CircRNAs microarray analysis revealed dysregulated circRNA in db/db DN mice, and circRNA_15698 was validated to be upregulated in both db/db mice and mouse mesangial cells (SV40-MES13) that were exposed to high glucose (25 mM) using real-time polymerase chain reaction. Loss-of-functional experiments showed that circRNA_15698 knockdown significantly inhibited the expression levels of collagen type I (Col. I), collagen type IV (Col. IV), and fibronectin. Moreover, the cellular localization of circRNA_15698 was mainly in the cytoplasm. Bioinformatics tools and luciferase reporter assay confirmed that circRNA_15698 acted as a ‘sponge’ of miR-185, and then positively regulated the transforming growth factor-β1 (TGF-β1) protein expression, suggesting a circRNA_15698/miR-185/TGF-β1 pathway. Further validation experiments validated that circRNA_15698/miR-185/TGF-β1 promoted extracellular matrix (ECM)-related protein synthesis. In summary, our study preliminarily investigates the role of circRNAs in mesangial cells and ECM accumulation, providing a novel insight for DN pathogenesis.     

DNA barcode and minibarcode identification of freshwater fishes from Cerrado headwater streams in Central Brazil

The extraordinary species diversity of the Neotropical freshwater fish fauna is world renown. Yet, despite rich species diversity, taxonomic and genetic resources for its Cerrado ichthyofauna remain poorly developed. We provide a reference library of 149 DNA barcodes for 39 species/lineages of Cerrado headwater stream fishes from the Brazilian Distrito Federal and nearby areas and test the utility of distance-based criteria, tree-based criteria and minibarcodes for specimen identification. Mean Kimura 2-parameter genetic distances within species to orders ranged 1·8–12·1%. However, mean intraspecific v. congeneric-interspecific distances (0·9–1·3%) overlapped extensively and distance-based barcoding failed to achieve correct identifications due to c. 4–12·1% error rates and 19·5% ambiguous identifications related to the presence of singletons. Overlap was reduced and best-match success rates improved drastically to 83·5% when Characidium barcodes representing potential misidentifications or undescribed species were removed. Tree-based monophyly criteria generally performed similarly to distance methods, correctly differentiating up to c. 85% of species/lineages despite neighbour-joining and Bayesian tree errors (random lineage-branching events, long-branch attraction). Five clusters (Ancistrus aguaboensis, Characidium spp., Eigenmannia trilineata, Hasemania hanseni and Hypostomus sp. 2) exhibited deep intraspecific divergences or para−/polyphyly and multiple Barcode Index Number assignments indicative of putative candidate species needing taxonomic re-examination. Sliding-window analyses also indicated that a 200 bp minibarcode region performed just as well at specimen identification as the entire barcode gene. Future DNA barcoding studies of Distrito Federal–Cerrado freshwater fishes will benefit from increased sampling coverage, as well as consideration of minibarcode targets for degraded samples and next-generation sequencing.