Circ_0039908/miR-let-7c/RRM2 Axis Was Identified Played an Important Role in Lung Adenocarcinoma by Integrated Analysis

Background Circular RNAs (circRNAs) are shown to play a significant role in cancer initiation and progression by interacting on microRNAs (miRNAs) which act as one kind of competing endogenous RNAs (ceRNAs) for the regulation effect on target gene expressions. This study was performed to explore the prognosis-related circRNAs in LUAD patients by integrated analysis and find the mechanism it worked. Methods The miRNAs and mRNAs, accompanied with circRNAs expressions were obtained through The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, The cytoHubba app of Cytoscape was used to identify hubgenes. q-RT PCR was performed to identify the expression of circRNA, miRNA and mRNA, Cell Counting Kit-8 (CCK-8) and clone formation assays were used to evaluate the proliferation ability of different kinds of cells in vitro. Transwell assays were utilized to assess the motility of tumor cells. Results Finally, circRNA_0039908/let7c-5p/RRM2 axis were identified in our research, it can play an important role in the LUAD pathogenesis progression and we found that the ability of proliferation and metastasis of LUAD cells can be suppressed after knockdown of circRNA_0039908. This work indicates that circRNA_0039908/let7c-5p/RRM2 axis may be a promising target in the prognosis and treatment of LUAD patients. Conclusion Circ_0039908/miR-let-7c/RRM2 axis can promote the ability of proliferation, migration and invasion of LUAD cells.

Genetic Basis of Follicle Development in Dazu Black Goat by Whole-Transcriptome Sequencing

The follicle development (FD) is an important factor determining litter size in animals. Recent studies have found that noncoding RNAs (ncRNAs) play an important role in FD. In particular, the role of the regulatory mechanism of competing endogenous RNAs (ceRNAs) that drive FD has attracted increasing attention. Therefore, this study explored the genetic basis of goat FD by obtaining the complete follicular transcriptome of Dazu black goats at different developmental stages. Results revealed that 128 messenger RNAs (mRNAs), 4 long noncoding RNAs (lncRNAs), 49 microRNAs (miRNAs), and 290 circular RNAs (circRNAs) were significantly differentially expressed (DE) between large and small follicles. Moreover, DEmRNAs were enriched in many signaling pathways related to FD, as well as GO terms related to molecular binding and enzyme activity. Based on the analysis of the ceRNA network (CRN), 34 nodes (1 DElncRNAs, 10 DEcircRNAs, 14 DEmiRNAs, and 9 DEmRNAs) and 35 interactions (17 DEcircRNAs–DEmRNAs, 2 DElncRNAs–DEmiRNAs, and 16 DEmRNA–DEmiRNAs) implied that the CRN could be involved in the FD of goats. In conclusion, we described gene regulation by DERNAs and lncRNA/circRNA–miRNA–mRNA CRNs in the FD of goats. This study provided insights into the genetic basis of FD in precise transcriptional regulation.

An RNA–RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity

Hepatocellular carcinoma (HCC) is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy. A new modality of epigenetic regulation has emerged involving RNA–RNA crosstalk networks where two or more competing endogenous RNAs (ceRNAs) bind to the same microRNAs. However, the contribution of such mechanisms in HCC has not been well studied. Herein, potential HMGB1-driven RNA–RNA crosstalk networks were evaluated at different HCC stages, identifying the mTORC2 component RICTOR as a potential HMGB1 ceRNA in HBV+ early stage HCC. Indeed, elevated HMGB1 mRNA was found to promote the expression of RICTOR mRNA through competitively binding with the miR-200 family, especially miR-429. Functional assays employing overexpression or interference strategies demonstrated that the HMGB1 and RICTOR 3′untranslated regions (UTR) epigenetically promoted the malignant proliferation, self-renewal, and tumorigenesis in HCC cells. Intriguingly, interference against HMGB1 and RICTOR in HCC cells promoted a stronger anti-PD-L1 immunotherapy response, which appeared to associate with the production of PD-L1+ exosomes. Mechanistically, the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms, activating a positive feedback loop involving mTORC2-AKT-C-MYC to upregulate glutamine synthetase (GS) expression, and inducing mTORC1 signaling to derepress SIRT4 on glutamate dehydrogenase (GDH). Meanwhile, this crosstalk network could impede the efficacy of immunotherapy through mTORC1-P70S6K dependent PD-L1 production and PD-L1+ exosomes activity. In conclusion, our study highlights the non-coding regulatory role of HMGB1 with implications for RNA-based therapeutic targeting together with a prediction of anti-PD-L1 immunotherapy in HCC.

Depletion of the miR-34a “sponge” MALAT1 in aging skeletal muscle: Implications for age-related muscle loss

We have recently shown that increased levels of reactive oxygen species (ROS) in aging skeletal muscle are associated with increased expression of the senescence-associated microRNA miR-34a-5p (miR-34a). The histone deacetylase Sirt1 is a validated target of miR-34a, and miR-34a expression is induced by the tumor suppressor p53 which is itself stimulated by ROS. Long noncoding RNAs (lncRNAs) are known to function as “sponges” for microRNAs, but the role of such competing endogenous RNAs (ceRNA) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4-6 mos) and aged (22-24) male and female mice the expression of several lncRNAs that are predicted to bind miR-34a-5p in silico and whose predicted binding has been validated experimentally. Results indicate a significant decrease in lncRNA MALAT1 expression with aging. MALAT1 is known to be highly expressed during the later stages of myoblast differentiation and myotube maturation. We therefore treated C2C12 cells at 48 hrs with hydrogen peroxide (10 uM) and examined changes in MALAT1 expression. MALAT1 was significantly decreased with H2O2 treatment, whereas miR-34a is increased in C2C12 cells after hydrogen peroxide exposure. Age-related muscle atrophy mediated by ROS may therefore result in part from related mechanisms involving miR-34a activity: an increase in miR-34a targeting Sirt1 resulting from p53 activation and an increase in miR-34a bioavailability resulting from a decline in miR-34a “sponging” due to ceRNA MALAT1 depletion. These findings suggest that therapeutic interventions increasing MALAT1 expression in muscle may potentially enhance the preservation of muscle mass with aging.

The Roles and Mechanisms of lncRNAs in Liver Fibrosis

Long non-coding RNAs (lncRNAs) can potentially regulate all aspects of cellular activity including differentiation and development, metabolism, proliferation, apoptosis, and activation, and benefited from advances in transcriptomic and genomic research techniques and database management technologies, its functions and mechanisms in physiological and pathological states have been widely reported. Liver fibrosis is typically characterized by a reversible wound healing response, often accompanied by an excessive accumulation of extracellular matrix. In recent years, a range of lncRNAs have been investigated and found to be involved in several cellular-level regulatory processes as competing endogenous RNAs (ceRNAs) that play an important role in the development of liver fibrosis. A variety of lncRNAs have also been shown to contribute to the altered cell cycle, proliferation profile associated with the accelerated development of liver fibrosis. This review aims to discuss the functions and mechanisms of lncRNAs in the development and regression of liver fibrosis, to explore the major lncRNAs involved in the signaling pathways regulating liver fibrosis, to elucidate the mechanisms mediated by lncRNA dysregulation and to provide new diagnostic and therapeutic strategies for liver fibrosis.

Mining sponge phenomena in RNA expression data

In the last few years, the interactions among competing endogenous RNAs (ceRNAs) have been recognized as a key post-transcriptional regulatory mechanism in cell differentiation, tissue development, and disease. Notably, such sponge phenomena substracting active microRNAs from their silencing targets have been recognized as having a potential oncosuppressive, or oncogenic, role in several cancer types. Hence, the ability to predict sponges from the analysis of large expression data sets (e.g. from international cancer projects) has become an important data mining task in bioinformatics. We present a technique designed to mine sponge phenomena whose presence or absence may discriminate between healthy and unhealthy populations of samples in tumoral or normal expression data sets, thus providing lists of candidates potentially relevant in the pathology. With this aim, we search for pairs of elements acting as ceRNA for a given miRNA, namely, we aim at discovering miRNA-RNA pairs involved in phenomena which are clearly present in one population and almost absent in the other one. The results on tumoral expression data, concerning five different cancer types, confirmed the effectiveness of the approach in mining interesting knowledge. Indeed, 32 out of 33 miRNAs and 22 out of 25 protein-coding genes identified as top scoring in our analysis are corroborated by having been similarly associated with cancer processes in independent studies. In fact, the subset of miRNAs selected by the sponge analysis results in a significant enrichment of annotation for the KEGG32 pathway “microRNAs in cancer” when tested with the commonly used bioinformatic resource DAVID. Moreover, often the cancer datasets where our sponge analysis identified a miRNA as top scoring match the one reported already in the pertaining literature.

Characterization of Host lncRNAs in Response to Vibrio splendidus Infection and Function as Efficient miRNA Sponges in Sea Cucumber

Long non-coding RNAs (lncRNAs) have been reported to play critical roles during pathogen infection and innate immune response in mammals. Such observation inspired us to explore the expression profiles and functions of lncRNAs in invertebrates upon bacterial infection. Here, the lncRNAs of sea cucumber (Apostichopus japonicus) involved in Vibrio splendidus infection were characterized. RNA-seq obtained 2897 differentially expressed lncRNAs from Vibrio splendidus infected coelomocytes of sea cucumbers. The potential functions of the significant differentially expressed lncRNAs were related to immunity and metabolic process based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Moreover, we identify a lncRNA (XLOC_028509), which is downregulated with Vibrio splendidus challenged, further study indicated that XLOC_028509 adsorb miR-2008 and miR-31 as competing endogenous RNAs (ceRNAs) through base complementarity, which in turn decreased the amount of miRNAs (microRNAs) bound to the 3’UTRs (untranslated regions) of mRNAs to reduce their inhibition of target gene translation. These data demonstrated that the lncRNAs of invertebrates might be important regulators in pathogen-host interactions by sponging miRNAs.

Identification of a lncRNA-Related Competing Endogenous RNA Network in Recurrent Implantation Failure

Background Impaired endometrial receptivity is supposed to be a major element leading to recurrent implantation failure (RIF). Numerous studies have identified that the lncRNAs-miRNAs-mRNAs regulation network functions in the generation of receptive uterus. Long non-coding RNAs could act as competing endogenous RNAs in the pathogenesis of RIF. However, our understanding of the underlying mechanism is still limited. Results Based on the RNA-Seq results, 617 DEmRNAs, 69 DElncRNAs and 107 DEmiRNAs were identified in the RIF group compared with the control group. To investigate the role of lncRNAs in RIF, we constructed a lncRNA related ceRNA network. A total of 3 lncRNAs, 8 miRNAs and 69 genes were identified. Above all, our study obtained 120 lncRNAs-miRNAs-mRNAs relationships in the ceRNA network. Among three hub lncRNAs, PART1 and PWRN1 were upregulated whereas PGM5P3-AS1 was downregulated in RIF endometrium. Meanwhile, three down-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-134-5p, hsa-miR-1225-5p) and five up-regulated miRNAs (hsa-miR-30c-5p, hsa-miR-30b-5p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-196b-5p) were shown. Conclusions We constructed a lncRNA-related ceRNA network and identified three hub lncRNAs in recurrent implantation failure. The results may provide further understanding in the pathogenesis of RIF as well as potential diagnostic and therapeutic targets.

Identification of a lncRNA-related Competing Endogenous RNA Network in Recurrent Implantation Failure

Background: Impaired endometrial receptivity is supposed to be a major element leading to recurrent implantation failure (RIF). Numerous studies have identified that the lncRNAs-miRNAs-mRNAs regulation network functions in the generation of receptive uterus. Long non-coding RNAs could act as competing endogenous RNAs in the pathogenesis of RIF. However, our understanding of the underlying mechanism is still limited. Results: Based on the RNA-Seq results, 617 DEmRNAs, 69 DElncRNAs and 107 DEmiRNAs were identified in the RIF group compared with the control group. To investigate the role of lncRNAs in RIF, we constructed a lncRNA related ceRNA network. A total of 3 lncRNAs, 8 miRNAs and 69 genes were identified. Above all, our study obtained 120 lncRNAs-miRNAs-mRNAs relationships in the ceRNA network. Among three hub lncRNAs, PART1 and PWRN1 were upregulated whereas PGM5P3-AS1 was downregulated in RIF endometrium. Meanwhile, three down-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-134-5p, hsa-miR-1225-5p) and five up-regulated miRNAs (hsa-miR-30c-5p, hsa-miR-30b-5p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-196b-5p) were shown. Conclusions: We constructed a lncRNA-related ceRNA network and identified three hub lncRNAs in recurrent implantation failure. The results may provide further understanding in the pathogenesis of RIF as well as potential diagnostic and therapeutic targets.