Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell–cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.

The activity of human enhancers is modulated by the splicing of their associated lncRNAs

Pervasive enhancer transcription is at the origin of more than half of all long noncoding RNAs in humans. Transcription of enhancer-associated long noncoding RNAs (elncRNA) contribute to their cognate enhancer activity and gene expression regulation in cis. Recently, splicing of elncRNAs was shown to be associated with elevated enhancer activity. However, whether splicing of elncRNA transcripts is a mere consequence of accessibility at highly active enhancers or if elncRNA splicing directly impacts enhancer function, remains unanswered. We analysed genetically driven changes in elncRNA splicing, in humans, to address this outstanding question. We showed that splicing related motifs within multi-exonic elncRNAs evolved under selective constraints during human evolution, suggesting the processing of these transcripts is unlikely to have resulted from transcription across spurious splice sites. Using a genome-wide and unbiased approach, we used nucleotide variants as independent genetic factors to directly assess the causal relationship that underpin elncRNA splicing and their cognate enhancer activity. We found that the splicing of most elncRNAs is associated with changes in chromatin signatures at cognate enhancers and target mRNA expression. We provide evidence that efficient and conserved processing of enhancer-associated elncRNAs contributes to enhancer activity.

Circulating Long Noncoding RNAs Positively Correlate with the Increased Risk, Elevated Severity and Unfavorable Prognosis in the Sepsis Patients

Objective This study aimed to evaluate the correlation of circulating long noncoding RNAs (lncRNAs) expression with disease risk, severity, inflammatory cytokines levels and prognosis in patients with sepsis. Methods Differential expression profiles of lncRNA in the serum of sepsis rats were screened by high-throughput transcriptome sequencing. Homologous lncRNAs in the upregulation group were identified by homology analysis in rats and humans. The expression differences of these homologous lncRNAs in the serum of 176 sepsis patients and 176 healthy controls (HCs) were detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). And inflammatory cytokines levels were detected by enzyme-linked immunosorbent assay (ELISA). A receiver operating characteristic (ROC) curve was used to verify the diagnostic and prognosis values. Spearman correlation coefficient was used to analyze the correlation between the variables. Follow-up was performed to observe the 28-day mortality. Results Among the screened differentially up-regulated lncRNAs, only two lncRNAs were homologous in rats and humans, which in human named PKN2-antisense RNA 1 (PKN2-AS1) and AC068888.1, respectively. Those two lncRNAs were significantly increased in patients with sepsis compared with those in HCs (P < 0.001), in patients with septic shock compared with those no septic shock (P < 0.001), and in non-survivors compared with survivors (P < 0.001). And those two lncRNAs were positively correlated with sepsis-related organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHE) II score, lactate (Lac), c-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in sepsis patients. Likelihood ratio forward stepwise multivariate logistic regression analysis revealed that high lncRNA AC068888.1 expression was an independent risk factor for septic shock (P < 0.001) and unfavorable prognosis (P = 0.006), but high lncRNA PKN2-AS1 expression was only for unfavorable prognosis (P = 0.019). The ROC curve exhibited a significant predictive value for sepsis risk with area under the curve (AUC) values of 0.879 and 0.842, respectively. For predicting septic shock risk, combining lncRNA AC068888.1 with SOFA score and Lac level, the ROC curve analysis significantly improved the predictability (AUC = 0.882). For predicting 28-day death risk, combining those two lncRNAs with SOFA and APACHE II scores, the ROC curve analysis also significantly improved the predictability (AUC = 0.860). The Kaplan–Meier curves indicated that the survival probability was much worse with those two lncRNAs high expression compared to low expression in patients with sepsis (P < 0.001). Conclusion The circulating absolute expression levels of lncRNA PKN2-AS1 and AC068888.1 in the serum may be used for the early diagnosis, clinical severity evaluation and prognosis of sepsis.