Identification and functional analysis of circulating small extracellular vesicle lncRNA signatures in children with fulminant myocarditis.

Fulminant myocarditis (FM) is the most serious type of myocarditis. However, the molecular mechanism underlying the pathogenesis of FM has not been fully elucidated. Small extracellular vesicles (sEVs) play important roles in many diseases, but any potential role in paediatric FM has not been reported. Here, the differential signatures of lncRNAs in plasma sEVs were studied in FM children and healthy children using transcriptome sequencing followed by functional analysis. Then immune-related lncRNAs were screened to study their role in immune mechanisms, the levels and clinical relevance of core immune-related lncRNAs were verified by qRT-PCR in a large sample size. Sixty-eight lncRNAs had increased levels of plasma sEVs in children with FM and 11 had decreased levels. Functional analysis showed that the sEVs-lncRNAs with different levels were mainly related to immunity, apoptosis and protein efflux. Seventeen core immune-related sEVs-lncRNAs were screened, functional enrichment analysis showed that these lncRNAs were closely related to immune activation, immune cell migration and cytokine pathway signal transduction. The results of the study show that sEVs-lncRNAs may play an important role in the pathogenesis of fulminant myocarditis in children, especially in the mechanism of immune regulation.

Interaction of BANCR in the relationship between Hashimoto's thyroiditis and papillary thyroid carcinoma expression patterns and possible molecular mechanisms.

BACKGROUND: Previous studies have established a connection between Hashimoto's thyroiditis (HT) and an increased risk of papillary thyroid carcinoma (PTC). However, the molecular mechanisms driving this association are not well understood. The long non-coding RNA (lncRNA) BRAF-activated non-coding RNA (BANCR) has been implicated in various cancers, suggesting a potential role in the HT-PTC linkage. METHODS: This study investigated the expression levels of BANCR in PTC and HT samples, compared to control tissues. We also examined the association between BANCR expression and clinicopathological features, including lymph node metastasis. Furthermore, we explored the molecular mechanisms of BANCR in PTC pathogenesis and its potential as a therapeutic target. RESULTS: BANCR expression was significantly lower in PTC samples than in controls, while it was moderately increased in HT samples. In PTC cases with concurrent HT, BANCR expression was markedly reduced compared to normal tissues. Our analysis revealed BANCR's role as an oncogene in PTC, influencing various cancer-related signaling pathways. Interestingly, no significant correlation was found between BANCR expression and lymph node metastasis. CONCLUSION: Our findings underscore the involvement of BANCR in the connection between HT and PTC. The distinct expression patterns of BANCR in PTC and HT, especially in PTC with concurrent HT, provide new insights into the molecular interplay between these conditions. This study opens avenues for the development of innovative diagnostic and therapeutic strategies targeting BANCR in PTC and HT.

Role of long noncoding RNAs in diabetes-associated peripheral arterial disease.

Diabetes mellitus (DM) is a metabolic disease that heightens the risks of many vascular complications, including peripheral arterial disease (PAD). Various types of cells, including but not limited to endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages (MΦs), play crucial roles in the pathogenesis of DM-PAD. Long non-coding RNAs (lncRNAs) are epigenetic regulators that play important roles in cellular function, and their dysregulation in DM can contribute to PAD. This review focuses on the developing field of lncRNAs and their emerging roles in linking DM and PAD. We review the studies investigating the role of lncRNAs in crucial cellular processes contributing to DM-PAD, including those in ECs, VSMCs, and MΦ. By examining the intricate molecular landscape governed by lncRNAs in these relevant cell types, we hope to shed light on the roles of lncRNAs in EC dysfunction, inflammatory responses, and vascular remodeling contributing to DM-PAD. Additionally, we provide an overview of the research approach and methodologies, from identifying disease-relevant lncRNAs to characterizing their molecular and cellular functions in the context of DM-PAD. We also discuss the potential of leveraging lncRNAs in the diagnosis and therapeutics for DM-PAD. Collectively, this review provides a summary of lncRNA-regulated cell functions contributing to DM-PAD and highlights the translational potential of leveraging lncRNA biology to tackle this increasingly prevalent and complex disease.

Icariin Regulates EMT and Stem Cell-Like Character in Breast Cancer through Modulating lncRNA NEAT1/TGFß/SMAD2 Signaling Pathway.

Metastases and drug resistance are the major risk factors associated with breast cancer (BC), which is the most common type of tumor affecting females. Icariin (ICA) is a traditional Chinese medicine compound that possesses significant anticancer properties. Long non-coding RNAs (lncRNAs) are involved in a wide variety of biological and pathological processes and have been shown to modulate the effectiveness of certain drugs in cancer. The purpose of this study was to examine the potential effect of ICA on epithelial mesenchymal transition (EMT) and stemness articulation in BC cells, as well as the possible relationship between its inhibitory action on EMT and stemness with the NEAT1/transforming growth factor ß (TGFß)/SMAD2 pathway. The effect of ICA on the proliferation (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony assays), EMT (Western blotting, immunofluorescence, and wound healing), and stemness (mammosphere formation assays, Western blotting) of BC cells were examined. According to the findings, ICA suppressed the proliferation, EMT, and stem cell-like in MDA-MB-231 cells, and exerted its inhibitory impact by downregulating the TGFß/SMAD2 signaling pathway. ICA could significantly downregulate the expression of lncRNA NEAT1, and silencing NEAT1 enhanced the effect of ICA in suppressing EMT and expression of different stem cell markers. In addition, silencing NEAT1 was found to attenuate the TGFß/SMAD2 signaling pathway, thereby improving the inhibitory impact of ICA on stemness and EMT in BC cells. In conclusion, ICA can potentially inhibit the metastasis of BC via affecting the NEAT1/TGFß/SMAD2 pathway, which provides a theoretical foundation for understanding the mechanisms involved in potential application of ICA for BC therapy.

Non-Coding Ribonucleic Acids as Diagnostic and Therapeutic Targets in Cardiac Fibrosis.

PURPOSE OF REVIEW: Cardiac fibrosis is a crucial juncture following cardiac injury and a precursor for many clinical heart disease manifestations. Epigenetic modulators, particularly non-coding RNAs (ncRNAs), are gaining prominence as diagnostic and therapeutic tools. RECENT FINDINGS: miRNAs are short linear RNA molecules involved in post-transcriptional regulation; lncRNAs and circRNAs are RNA sequences greater than 200 nucleotides that also play roles in regulating gene expression through a variety of mechanisms including miRNA sponging, direct interaction with mRNA, providing protein scaffolding, and encoding their own products. NcRNAs have the capacity to regulate one another and form sophisticated regulatory networks. The individual roles and disease relevance of miRNAs, lncRNAs, and circRNAs to cardiac fibrosis have been increasingly well described, though the complexity of their interrelationships, regulatory dynamics, and context-specific roles needs further elucidation. This review provides an overview of select ncRNAs relevant in cardiac fibrosis as a surrogate for many cardiac disease states with a focus on crosstalk and regulatory networks, variable actions among different disease states, and the clinical implications thereof. Further, the clinical feasibility of diagnostic and therapeutic applications as well as the strategies underway to advance ncRNA theranostics is explored.

SNAI1-activated long non-coding RNA LINC01711 promotes hepatic fibrosis cell proliferation and migration by regulating XYLT1.

Liver fibrosis is the result of the accumulation of extracellular matrix (ECM) that cannot be cleared. Bioinformatic analysis showed that LINC01711 was significantly overexpressed in hepatic fibrosis. The regulatory mechanism of LINC01711 was clarified and confirmed the transcription factors associated with LINC01711. Functionally, LINC01711 promoted LX-2 cell proliferation and migration, indicating that it exerts effects promoting the progression of hepatic fibrosis. Mechanistically, LINC01711 increased the expression of xylosyltransferase 1 (XYLT1), which is an important protein for constructing the ECM. We also confirmed that SNAI1 activated LINC01711 transcription. Taking these findings together, LINC01711 was induced by SNAI1 and promoted the proliferation and migration of LX-2 cells via XYLT1. This study will help to understand the function of LINC01711 and its regulatory mechanism in hepatic fibrosis.

MEG3-Mediated Oral Squamous-Cell-Carcinoma-Derived Exosomal miR-421 Activates Angiogenesis by Targeting HS2ST1 in Vascular Endothelial Cells.

Exosomal microRNAs (miRNAs) from cancer cells play a key role in mediating the oral squamous cell carcinoma (OSCC) microenvironment. The objective of this study was to investigate how the long non-coding RNA (lncRNA) MEG3 affects OSCC angiogenesis through exosomal miR-421. Global miRNA microarray analysis and quantitative real-time PCR (qRT-PCR) were performed to determine the level of miRNAs in OSCC cell-derived exosomes. Cell migration, invasion, tube formation, immunohistochemistry, and hemoglobin concentrations were used to study the effects of exosomal miR-421 in angiogenesis. Western blotting was used to determine the expression level of HS2ST1 and VEGFR2-related downstream proteins. MiRNA array and qRT-PCR identified the upregulation of miR-421 in OSCC cell-derived exosomes. Furthermore, exosomal miR-421 can be taken up by human umbilical vein endothelial cells (HUVECs) and then target HS2ST1 through VEGF-mediated ERK and AKT phosphorylation, thereby promoting HUVEC migration, invasion, and tube formation. Additionally, forced expression of the lncRNA MEG3 in OSCC cells reduced exosomal miR-421 levels and then increased HS2ST1 expression, thereby reducing the VEGF/VEGFR2 pathway in HUVECs. Our results demonstrate a novel mechanism by which lncRNA MEG3 can act as a tumor suppressor and regulate endothelial angiogenesis through the exosomal miR-421/HS2ST1 axis, which provides a potential therapeutic strategy for OSCC angiogenesis.

Novel LncRNA AK023507 inhibits cell metastasis and proliferation in Papillary Thyroid Cancer through ß-catenin/Wnt Signaling Pathway.

INTRODUCTION: Papillary Thyroid Cancer (PTC) represents a commonly encountered type of thyroid malignancy whose occurrence and development is influenced by long non-coding RNA (LncRNA). A novel lncRNA (LncRNA AK023507), known to have tumor suppressive functions, was shown to prevent breast cancer cells from proliferating and metastasizing, but its mechanism in PTC is unclear. METHODS: Using PTC tissues and cell lines, the expression of LncRNA AK023507 was investigated by quantitative Real-time Polymerase Chain Reaction (qRT-PCR). The effects of knockdown or overexpression of LncRNA AK023507 on cell growth and movement were investigated through various cell experiments in vitro. The presence of important functional proteins was determined by Western blotting, with the recovery experiment used for verification. RESULTS: LncRNA AK023507 was found to have low expression in both the PTC cell lines and tissue samples. Knockdown of LncRNA AK023507 in PTC cells significantly promoted cell proliferation, migration, and invasion, while overexpression of LncRNA AK023507 resulted in the opposite effects. Furthermore, LncRNA AK023507 could regulate the expression of ß-catenin/Wnt signaling pathway as confirmed by recovery experiment. CONCLUSION: By acting through the ß-catenin/Wnt signaling pathway, LncRNA AK023507 prevented PTC cells from proliferating and metastasizing. These novel findings indicate that LncRNA AK023507 could be of prognostic and diagnostic value as a potential biomarker of PTC.

The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases.

Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating brain gene networks. LncRNA abnormalities are thought to underlie the complex etiology of numerous neuropsychiatric disorders. One example is the human lncRNA gene GOMAFU, which is found dysregulated in schizophrenia (SCZ) postmortem brains and harbors genetic variants that contribute to the risk of SCZ. However, transcriptome-wide biological pathways regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel suppressor of human neuronal interferon (IFN) response pathways that are hyperactive in the postmortem SCZ brains. We analyzed recently released transcriptomic profiling datasets in clinically relevant brain areas derived from multiple SCZ cohorts and found brain region-specific dysregulation of GOMAFU. Using CRISPR-Cas9 to delete the GOMAFU promoter in a human neural progenitor cell model, we identified transcriptomic alterations caused by GOMAFU deficiency in pathways commonly affected in postmortem brains of SCZ and autism spectrum disorder (ASD), with the most striking effects on upregulation of numerous genes underlying IFN signaling. In addition, expression levels of GOMAFU target genes in the IFN pathway are differentially affected in SCZ brain regions and negatively associated with GOMAFU alterations. Furthermore, acute exposure to IFN-γ causes a rapid decline of GOMAFU and activation of a subclass of GOMAFU targets in stress and immune response pathways that are affected in SCZ brains, which form a highly interactive molecular network. Together, our studies unveiled the first evidence of lncRNA-governed neuronal response pathways to IFN challenge and suggest that GOMAFU dysregulation may mediate environmental risks and contribute to etiological neuroinflammatory responses by brain neurons of neuropsychiatric diseases.

Targeting long non coding RNA by natural products: Implications for cancer therapy.

In spite of achieving substantial progress in its therapeutic strategies, cancer-associated prevalence and mortality are persistently rising globally. However, most malignant cancers either cannot be adequately diagnosed at the primary phase or resist against multiple treatments such as chemotherapy, surgery, radiotherapy as well as targeting therapy. In recent decades, overwhelming evidences have provided more convincing words on the undeniable roles of long non-coding RNAs (lncRNAs) in incidence and development of various cancer types. Recently, phytochemical and nutraceutical compounds have received a great deal of attention due to their inhibitory and stimulatory effects on oncogenic and tumor suppressor lncRNAs respectively that finally may lead to attenuate various processes of cancer cells such as growth, proliferation, metastasis and invasion. Therefore, application of phytochemicals with anticancer characteristics can be considered as an innovative approach for treating cancer and increasing the sensitivity of cancer cells to standard prevailing therapies. The purpose of this review was to investigate the effect of various phytochemicals on regulation of lncRNAs in different human cancer and evaluate their capabilities for cancer treatment and prevention.

Estrogen distinctly regulates transcription and translation of lncRNAs and pseudogenes in breast cancer cells.

Estrogen drives key transcriptional changes in breast cancer and stimulates breast cancer cells' growth with multiple mechanisms to coordinate transcription and translation. In addition to protein-coding transcripts, estrogen can regulate long non-coding RNA (lncRNA) transcripts, plus diverse non-coding RNAs including antisense, enhancer, and intergenic. LncRNA genes comprise the majority of human genes. The accidental, or regulated, translation of their short open reading frames by ribosomes remains a controversial topic. Here we report for the first time an integrated analysis of RNA abundance and ribosome occupancy level, using Ribo-seq combined with RNA-Seq, in the estrogen-responsive, estrogen receptor α positive, human breast cancer cell model MCF7, before and after hormone treatment. Translational profiling can determine, in an unbiased manner, which fraction of the genome is actually translated into proteins, as well as resolving whether transcription and translation respond concurrently, or differentially, to estrogen treatment. Our data showed specific transcripts more robustly detected in RNA-Seq than in the ribosome-profiling data, and vice versa, suggesting distinct gene-specific estrogen responses at the transcriptional and the translational level, respectively. Here, we showed that estrogen stimulation affects the expression levels of numerous lncRNAs, but not their association with ribosomes, and that most lncRNAs are not ribosome-bound. For the first time, we also demonstrated the transcriptional and translational response of expressed pseudogenes to estrogen, pointing to new perspectives for drug-target development in breast cancer in the future.

Cuproptosis-Related LncRNA-Based Prediction of the Prognosis and Immunotherapy Response in Papillary Renal Cell Carcinoma.

Cuproptosis, a new cell death pattern, is promising as an intervention target to treat tumors. Abnormal long non-coding RNA (lncRNA) expression is closely associated with the occurrence and development of papillary renal cell carcinoma (pRCC). However, cuproptosis-related lncRNAs (CRLs) remain largely unknown as prognostic markers for pRCC. We aimed to forecast the prognosis of pRCC patients by constructing models according to CRLs and to examine the correlation between the signatures and the inflammatory microenvironment. From the Cancer Genome Atlas (TCGA), RNA sequencing, genomic mutations and clinical data of TCGA-KIRP (Kidney renal papillary cell carcinoma) were analyzed. Randomly selected pRCC patients were allotted to the training and testing sets. To determine the independent prognostic impact of the training characteristic, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized, together with univariate and multivariate Cox regression models. Further validation was performed in the testing and whole cohorts. External datasets were utilized to verify the prognostic value of CRLs as well. The CRLs prognostic features in pRCC were established based on the five CRLs (AC244033.2, LINC00886, AP000866.1, MRPS9-AS1 and CKMT2-AS1). The utility of CRLs was evaluated and validated in training, testing and all sets on the basis of the Kaplan-Meier (KM) survival analysis. The risk score could be a robust prognostic factor to forecast clinical outcomes for pRCC patients by the LASSO algorithm and univariate and multivariate Cox regression. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) data demonstrated that differentially expressed genes (DEGs) are primarily important for immune responses and the PI3K-Akt pathway. Arachidonic acid metabolism was enriched in the high-risk set by Gene Set Enrichment Analysis (GSEA). In addition, Tumor Immune Dysfunction and Exclusion (TIDE) analysis suggested that there was a high risk of immune escape in the high-risk cohort. The immune functions of the low- and high-risk sets differed significantly based on immune microenvironment analysis. Finally, four drugs were screened with a higher sensitivity to the high-risk set. Taken together, a novel model according to five CRLs was set up to forecast the prognosis of pRCC patients, which provides a potential strategy to treat pRCC by a combination of cuproptosis and immunotherapy.

AGER-1 Long Non-Coding RNA Levels Correlate with the Expression of the Advanced Glycosylation End-Product Receptor, a Regulator of the Inflammatory Response in Visceral Adipose Tissue of Women with Obesity and Type 2 Diabetes Mellitus.

The advanced glycosylation end-product receptor (AGER) is involved in the development of metabolic inflammation and related complications in type 2 diabetes mellitus (T2DM). Tissue expression of the AGER gene (AGER) is regulated by epigenetic mediators, including a long non-coding RNA AGER-1 (lncAGER-1). This study aimed to investigate whether human obesity and T2DM are associated with an altered expression of AGER and lncAGER-1 in adipose tissue and, if so, whether these changes affect the local inflammatory milieu. The expression of genes encoding AGER, selected adipokines, and lncAGER-1 was assessed using real-time PCR in visceral (VAT) and subcutaneous (SAT) adipose tissue. VAT and SAT samples were obtained from 62 obese (BMI > 40 kg/m2; N = 24 diabetic) and 20 normal weight (BMI = 20-24.9 kg/m2) women, while a further 15 SAT samples were obtained from patients who were 18 to 24 months post-bariatric surgery. Tissue concentrations of adipokines were measured at the protein level using an ELISA-based method. Obesity was associated with increased AGER mRNA levels in SAT compared to normal weight status (p = 0.04) and surgical weight loss led to their significant decrease compared to pre-surgery levels (p = 0.01). Stratification by diabetic status revealed that AGER mRNA levels in VAT were higher in diabetic compared to non-diabetic women (p = 0.018). Elevated AGER mRNA levels in VAT of obese diabetic patients correlated with lncAGER-1 (p = 0.04, rs = 0.487) and with interleukin 1ß (p = 0.008, rs = 0.525) and resistin (p = 0.004, rs = 0.6) mRNA concentrations. In conclusion, obesity in women is associated with increased expression of AGER in SAT, while T2DM is associated with increased AGER mRNA levels and pro-inflammatory adipokines in VAT.

Paired guide RNA CRISPR-Cas9 screening for protein-coding genes and lncRNAs involved in transdifferentiation of human B-cells to macrophages.

CRISPR-Cas9 screening libraries have arisen as a powerful tool to identify protein-coding (pc) and non-coding genes playing a role along different processes. In particular, the usage of a nuclease active Cas9 coupled to a single gRNA has proven to efficiently impair the expression of pc-genes by generating deleterious frameshifts. Here, we first demonstrate that targeting the same gene simultaneously with two guide RNAs (paired guide RNAs, pgRNAs) synergistically enhances the capacity of the CRISPR-Cas9 system to knock out pc-genes. We next design a library to target, in parallel, pc-genes and lncRNAs known to change expression during the transdifferentiation from pre-B cells to macrophages. We show that this system is able to identify known players in this process, and also predicts 26 potential novel ones, of which we select four (two pc-genes and two lncRNAs) for deeper characterization. Our results suggest that in the case of the candidate lncRNAs, their impact in transdifferentiation may be actually mediated by enhancer regions at the targeted loci, rather than by the lncRNA transcripts themselves. The CRISPR-Cas9 coupled to a pgRNAs system is, therefore, a suitable tool to simultaneously target pc-genes and lncRNAs for genomic perturbation assays.

Analysis of differentially expressed long non-coding RNAs in LPS-induced human HMC3 microglial cells.

BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as key modulators of inflammatory gene expression, but their roles in neuroinflammation are poorly understood. Here, we identified the inflammation-related lncRNAs and correlated mRNAs of the lipopolysaccharide (LPS)-treated human microglial cell line HMC3. We explored their potential roles and interactions using bioinformatics tools such as gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG), and weighted gene co-expression network analysis (WGCNA). RESULTS: We identified 5 differentially expressed (DE) lncRNAs, 4 of which (AC083837.1, IRF1-AS1, LINC02605, and MIR3142HG) are novel for microglia. The DElncRNAs with their correlated DEmRNAs (99 total) fell into two network modules that both were enriched with inflammation-related RNAs. However, treatment with the anti-inflammatory agent JQ1, an inhibitor of the bromodomain and extra-terminal (BET) protein BRD4, neutralized the LPS effect in only one module, showing little or even enhancing effect on the other. CONCLUSIONS: These results provide insight into, and a resource for studying, the regulation of microglia-mediated neuroinflammation and its potential therapy by small-molecule BET inhibitors.

An immune-related lncRNA pairs signature to identify the prognosis and predict the immune landscape of laryngeal squamous cell carcinoma.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the most common squamous cell carcinoma. Though significant effort has been focused on molecular pathogenesis, development, and recurrence of LSCC, little is known about its relationship with the immune-related long non-coding RNA (lncRNA) pairs. METHODS: After obtaining the transcriptome profiling data sets and the corresponding clinical characteristics of LSCC patients and normal samples from The Cancer Genome Atlas (TCGA) database, a series of bioinformatic analysis was conducted to select the differently expressed immune-related lncRNAs and build a signature of immune-related lncRNA pairs. Then, the effectiveness of the signature was validated. RESULTS: A total of 111 LSCC patients and 12 normal samples' transcriptome profiling data sets were retrieved from TCGA. 301 differently expressed immune-related lncRNAs were identified and 35,225 lncRNA pairs were established. After univariate Cox analysis, LASSO regression and multivariate Cox analysis, 7 lncRNA pairs were eventually selected to construct a signature. The riskscore was computed using the following formula: Riskscore = 0.95 × (AL133330.1|AC132872.3) + (-1.23) × (LINC01094|LINC02154) + 0.65 × (LINC02575|AC122685.1) + (-1.15) × (MIR9-3HG|LINC01748) + 1.45 × (AC092687.3|SNHG12) + (-0.87) × (AC090204.1|AL158166.1) + 0.64 × (LINC01063|Z82243.1). Patients were classified into the high-risk group (> 1.366) and the low-risk group (< 1.366) according to the cutoff value (1.366), which is based on the 5-year riskscore ROC curve. The survival analysis showed that the low-risk group had a better prognosis (P < 0.001). The riskscore was better than other clinical characteristics in prognostic prediction and the area under the curves (AUCs) for the 1-, 3-, and 5-year survivals were 0.796, 0.946, and 0.895, respectively. Combining age, gender, grade, stage, and riskscore, a nomograph was developed to predict survival probability in LSCC patients. Then, the riskscore was confirmed to be related with the content of tumor-infiltration immune cells and the model could serve as a potential predictor for chemosensitivity. CONCLUSION: We successfully established a more stable signature of 7 immune-related lncRNA pairs, which has demonstrated a better prognostic ability for LSCC patients and may assist clinicians to precisely prescribe chemo drugs.

Introduction of long non-coding RNAs to regulate autophagy-associated therapy resistance in cancer.

Autophagy is a lysosomal degradation pathway that depends on various evolutionarily conserved autophagy-related genes (ATGs). Dysregulation of autophagy plays an important role in the occurrence and development of cancer. Chemotherapy, targeted therapy, radiotherapy, and immunotherapy are important treatment options for cancer, which can significantly improve the survival rate of cancer patients. However, the occurrence of therapy resistance results in therapeutic failure and poor prognosis of cancer. Accumulating studies have found that long non-coding RNAs (lncRNAs) are well known as crucial regulators to control autophagy through regulating ATGs and autophagy-associated signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, ultimately mediating chemoresistance and radioresistance. Taken together, this review systematically summarizes and elucidates the pivotal role of lncRNAs in cancer chemoresistance and radioresistance via regulating autophagy. Understanding the specific mechanism of which may provide autophagy-related therapeutic targets for cancer in the future.

LncRNA Gm16638-201 Inhibits the 14-3-3Ɛ Pathway in the Murine Prefrontal Cortex to Induce Depressive Behaviors.

The dysregulation of certain long non-coding RNAs (lncRNAs) has been considered to be involved in neuropsychiatric disorders such as depression, implying the vital role of these transcripts. We have previously identified many differentially expressed lncRNAs in chronic unpredictable mild stress (CUMS) induced mice. Among them, lncRNA Gm16638-201 was highly expressed in the hippocampus (HIP) of CUMS, but the specific role and the underlying mechanisms remain unclear. Here, we reported that lncRNA Gm16638-201 was highly expressed in the prefrontal cortex (PFC) of CUMS induced depressive mice. Bioinformatic analysis shows that Gm16638-201 is mainly located in the cytoplasm. Nine neurological-related genes (Elmo2, Satb1, Hnrnpul1, Sipa1l3, Mapt, Tada3, Sgip1, IL-16, and StarD5) were predicted to be regulated in cis or trans by Gm16638-201 and involved into the 14-3-3Ɛ neurotrophic signaling pathway. We further confirmed the down-regulation of 14-3-3Ɛ and the nine predicted target genes in the PFC of CUMS mice except for Sgip1 and IL-16. In addition, they were also down-regulated in the primary cortical cell cultures with overexpression of Gm16638-201 constructed using an adenoviral-medicated gene expression system. In conclusion, we found that overexpression of Gm16638-201 negatively regulated several target genes and inhibited the 14-3-3Ɛ pathway in the PFC of CUMS induced depressive mice. This promising result suggests that Gm16638-201 may be a potential novel therapeutic target for depression.

A novel autophagy-related long non-coding RNAs prognostic risk score for clear cell renal cell carcinoma.

BACKGROUND: As the main histological subtype of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) places a heavy burden on health worldwide. Autophagy-related long non-coding RNAs (ARlncRs) have shown tremendous potential as prognostic signatures in several studies, but the relationship between them and ccRCC still has to be demonstrated. METHODS: The RNA-sequencing and clinical characteristics of 483 ccRCC patients were downloaded download from the Cancer Genome Atlas and International Cancer Genome Consortium. ARlncRs were determined by Pearson correlation analysis. Univariate and multivariate Cox regression analyses were applied to establish a risk score model. A nomogram was constructed considering independent prognostic factors. The Harrell concordance index calibration curve and the receiver operating characteristic analysis were utilized to evaluate the nomogram. Furthermore, functional enrichment analysis was used for differentially expressed genes between the two groups of high- and low-risk scores. RESULTS: A total of 9 SARlncRs were established as a risk score model. The Kaplan-Meier survival curve, principal component analysis, and subgroup analysis showed that low overall survival of patients was associated with high-risk scores. Age, M stage, and risk score were identified as independent prognostic factors to establish a nomogram, whose concordance index in the training cohort, internal validation, and external ICGC cohort was 0.793, 0.671, and 0.668 respectively. The area under the curve for 5-year OS prediction in the training cohort, internal validation, and external ICGC cohort was 0.840, 0.706, and 0.708, respectively. GO analysis and KEGG analysis of DEGs demonstrated that immune- and inflammatory-related pathways are likely to be critically involved in the progress of ccRCC. CONCLUSIONS: We established and validated a novel ARlncRs prognostic risk model which is valuable as a potential therapeutic target and prognosis indicator for ccRCC. A nomogram including the risk model is a promising clinical tool for outcomes prediction of ccRCC patients and further formulation of individualized strategy.

Micropeptides translated from putative long non-coding RNAs.

Long non-coding RNAs (lncRNAs) transcribed in mammals and eukaryotes were thought to have no protein coding capability. However, recent studies have suggested that plenty of lncRNAs are mis-annotated and virtually contain coding sequences which are translated into functional peptides by ribosomal machinery, and these functional peptides are called micropeptides or small peptides. Here we review the rapidly advancing field of micropeptides translated from putative lncRNAs, describe the strategies for their identification, and elucidate their critical roles in many fundamental biological processes. We also discuss the prospects of research in micropeptides and the potential applications of micropeptides.