Importance Of Long Non-coding RNAs Research Articles

A Study on Associations of Long Noncoding RNA HOTAIR Polymorphisms With Genetic Susceptibility to Chronic Kidney Disease.

The importance of long noncoding RNAs (lncRNAs) in various biological processes has been increasingly recognized in recent years. This study investigated how gene polymorphism in HOX transcript antisense RNA (HOTAIR) lncRNA affects the predisposition to chronic kidney disease (CKD). This study comprised 150 patients with CKD and 150 healthy controls. A PCR-RFLP and ARMS-PCR techniques were used for genotyping the five target polymorphisms. According to our findings, rs4759314 confers strong protection against CKD in allelic, dominant, and codominant heterozygote genetic patterns. Furthermore, rs3816153 decreased CKD risk by 78% when TT versus GG, 55% when GG+GT versus TT, and 74% when GT versus TT+GG. In contrast, the CC+CT genotype [odds ratio (OR) = 1.66, 95% confidence intervals (CIs) = 1.05-2.63] and the T allele (OR = 1.50, 95% CI = 1.06-2.11) of rs12826786, as well as the TT genotype (OR = 2.52, 95% CI = 1.06-5.98) of rs3816153 markedly increased the risk of CKD in the Iranian population. Although no linkage disequilibrium was found between the studied variants, the Crs12826786Trs920778Grs1899663Grs4759314Grs3816153 haplotype was associated with a decreased risk of CKD by 86% (OR = 0.14, 95% CI = 0.03-0.66). The rs920778 was not correlated with CKD risk, whereas the HOTAIR rs4759314, rs12826786, rs1899663, and rs3816153 polymorphisms affected the risk of CKD in our population. It seems essential to conduct repeated studies across various ethnic groups to explore the link between HOTAIR variants and their impact on the disease outcome.

Fatty acid metabolism-related lncRNAs are potential biomarkers for survival prediction in clear cell renal cell carcinoma.

Metabolic reprogramming of energy is a newly recognized characteristic of cancer. In our current investigation, we examined the possible predictive importance of long noncoding RNAs (lncRNAs) associated to fatty acid metabolism in clear cell renal cell carcinoma (ccRCC). We conducted an analysis of the gene expression data obtained from patients diagnosed with ccRCC using the Cancer Genome Atlas (TCGA) database and the ArrayExpress database. We performed a screening to identify lncRNAs that are differentially expressed in fatty acid metabolism. Based on these findings, we developed a prognostic risk score model using these fatty acid metabolism-related lncRNAs. We then validated this model using Cox regression analysis, Kaplan-Meier survival analysis, and principal-component analysis (PCA). Furthermore, the prognostic risk score model was successfully validated using both the TCGA cohort and the E-MTAB-1980 cohort. We utilized gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to determine the correlation between fatty acid metabolism and the PPAR signaling pathway in patients with ccRCC at various clinical stages and prognoses. We have discovered compelling evidence of the interaction between immune cells in the tumor microenvironment and tumor cells, which leads to immune evasion and resistance to drugs. This was achieved by the utilization of advanced techniques such as the CIBERSORT method, ESTIMATE R package, ssGSEA algorithm, and TIMER database exploration. Ultimately, we have established a network of competing endogenous RNA (ceRNA) that is related to fatty acid metabolism. The findings of our study suggest that medicines focused on fatty acid metabolism could be clinically significant for individuals with ccRCC. The utilization of this risk model, which is centered around the lncRNAs associated with fatty acid metabolism, could potentially provide valuable prognostic information and hold immunotherapeutic implications for patients with ccRCC.

Long noncoding RNA lnc-SNAPC5-3:4 inhibits malignancy by directly upregulating miR-224-3p in non-small cell lung cancer

The mounting body of evidence demonstrates the growing importance of long noncoding RNAs in the advancement of tumors. This study aimed to investigate the molecular mechanism of lnc-SNAPC5-3:4 in non-small cell lung cancer (NSCLC). We investigated the expression of miR-224-3p and lnc-SNAPC5-3:4 in clinical NSCLC samples and NSCLC cell lines using reverse transcription polymerase chain reaction (RT-PCR). In vitro studies, A549 cell growth was estimated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EDU), and flow cytometry assays. In vivo studies, NSCLC tumorigenesis was determined using xenograft tumor mouse models, tumor growth was evaluated using antigen Kiel 67 (Ki67) staining, and tumor apoptosis was detected through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The relationship between lnc-SNAPC5-3:4 and miR-224-3p was determined by luciferase reporter gene assay. Results indicated that the expression of lnc-SNAPC5-3:4 was observed to be downregulated in NSCLC tissues and cell lines. After overexpression of lnc-SNAPC5-3:4 in cultured A549 cells, proliferation decreased and apoptosis increased. Furthermore, the expression of miR-224-3p was targeted and negatively regulated by lnc-SNAPC5-3:4. The lnc-SNAPC5-3:4 upregulation inhibited cell proliferation and promoted apoptosis, which was partially blocked by miR-224-3p overexpression in A549 cells. In addition, we constructed a subcutaneous inoculation model using BALB/c nude mice, and the results indicated that lnc-SNAPC5-3:4 overexpression restrained the growth of subcutaneous tumors, decreased Ki67 expression levels, and increased apoptosis, as indicated by TUNEL staining in nude mice. However, miR-224-3p transfection resulted in the reversal of the inhibitory effect of lnc-SNAPC5-3:4 on tumor growth. In conclusion, our study revealed that lnc-SNAPC5-3:4 inhibits tumor progression in NSCLC by targeting miR-224-3p. This study provides a potential therapeutic target for inhibiting NSCLC progression.

Importance of long non-coding RNAs in the pathogenesis, diagnosis, and treatment of prostate cancer.

Long non-coding RNAs (lncRNAs) are regulatory transcripts with essential roles in the pathogenesis of almost all types of cancers, including prostate cancer. They can act as either oncogenic lncRNAs or tumor suppressor ones in prostate cancer. Small nucleolar RNA host genes are among the mostly assessed oncogenic lncRNAs in this cancer. PCA3 is an example of oncogenic lncRNAs that has been approved as a diagnostic marker in prostate cancer. A number of well-known oncogenic lncRNAs in other cancers such as DANCR, MALAT1, CCAT1, PVT1, TUG1 and NEAT1 have also been shown to act as oncogenes in prostate cancer. On the other hand, LINC00893, LINC01679, MIR22HG, RP1-59D14.5, MAGI2-AS3, NXTAR, FGF14-AS2 and ADAMTS9-AS1 are among lncRNAs that act as tumor suppressors in prostate cancer. LncRNAs can contribute to the pathogenesis of prostate cancer via modulation of androgen receptor (AR) signaling, ubiquitin-proteasome degradation process of AR or other important signaling pathways. The current review summarizes the role of lncRNAs in the evolution of prostate cancer with an especial focus on their importance in design of novel biomarker panels and therapeutic targets.

Systematic Identification of Long Non-Coding RNAs under Allelopathic Interference of Para-Hydroxybenzoic Acid in S. lycopersicum

The importance of long noncoding RNAs (lncRNAs) in plant development has been established, but a systematic analysis of the lncRNAs expressed during plant allelopathy has not been carried out. We performed RNA-seq experiments on S. lycopersicum subjected to different levels of para-hydroxybenzoic acid (PHBA) stress during plant allelopathy and identified 61,729 putative lncRNAs. Of these, 7765 lncRNAs cis-regulated 5314 protein-coding genes (PGs). Among these genes, 1116 lncRNAs and 2239 PGs were involved in a complex web of transcriptome regulation, and we divided these genes into 12 modules. Within these modules, 458 lncRNAs and 975 target genes were found to be highly correlated. Additionally, 989 lncRNAs trans-regulated 1765 PGs, and we classified them into 11 modules, within which 335 lncRNAs were highly correlated with their 633 corresponding target genes. Only 98 lncRNAs in S. lycopersicum had homologs in the lncRNA database of Arabidopsis thaliana, all of which were affected by the PHBA treatments. MiRNAs that interacted with both mRNAs and lncRNAs were selected on the basis of weighted correlation network analysis (WGCNA) results to make lncRNA-miRNA-mRNA triplets. Our study presents a systematic identification of lncRNAs involved in plant allelopathy in S. lycopersicum and provides research references for future studies.

Long noncoding RNA TNFRSF10A-AS1 promotes colorectal cancer through upregulation of HuR.

BACKGROUNDRecent studies have emphasized the emerging importance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC). However, the functions and regulatory mechanisms of numerous lncRNAs in CRC have not been fully elucidated.AIMTo explore the functional role and underlying molecular mechanisms of lncRNA TNFRSF10A-AS1 in CRC.METHODSTNFRSF10A-AS1 expression was measured by quantitative real-time polymerase chain reaction in CRC, and the relationship between TNFRSF10A-AS1 levels and the clinicopathological features of CRC patients was analyzed. The effect of TNFRSF10A-AS1 expression on CRC proliferation and metastasis was examined in vitro and in vivo. Mechanistically, we investigated how TNFRSF10A-AS1 is involved in CRC as a competitive endogenous RNA.RESULTSTNFRSF10A-AS1 was expressed at a high level in CRC and the upregulation of TNFRSF10A-AS1 was associated with advanced T grade and tumor size in CRC patients. A functional investigation revealed that TNFRSF10A-AS1 enhanced the proliferation, migration ability and invasion ability of colon cancer cells in vitro and in vivo. A mechanistic analysis demonstrated that TNFRSF10A-AS1 acted as a miR-3121-3p molecular sponge to regulate HuR expression, ultimately promoting colorectal tumorigenesis and progression.CONCLUSIONTNFRSF10A-AS1 exerts a tumor-promoting function through the miR-3121-3p/HuR axis in CRC, indicating that it may be a novel target for CRC therapy.

LINC01857 promotes the proliferation, migration, and invasion of gastric cancer cells via regulating miR-4731-5p/HOXC6.

The great importance of long non-coding RNAs (lncRNAs) in tumorigenesis has been acknowledged gradually. LINC01857 is previously reported to be highly expressed in gastric cancer (GC), while the regulatory mechanism of LINC01857 in GC is largely unknown. In this study, we detected high expression of LINC01857 from the GC microarray GSE109476. Additionally, LINC01857 expression is remarkably upregulated in GC cell lines (AGS, MKN-45, HGC-27, and SGC-7901) compared with the normal gastric mucosal cell line GES-1. Functionally, LINC01857 knockdown suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT) of GC cells, while LINC01857 overexpression promoted the proliferation, migration, invasion, and EMT of GC cells. Furthermore, our data demonstrate that LINC01857 targeted miR-4731-5p and subsequently increased the expression of HOXC6 in GC. Rescue experiments showed that miR-4731-5p inhibition and HOXC6 overexpression could reverse the biological behavior of GC cells induced by LINC01857 knockdown. In conclusion, we demonstrated that LINC01857 sponged miR-4731-5p to promote the expression of HOXC6 and eventually acts as an oncogene in GC.

Overexpression of FOXD2-AS1 enhances proliferation and impairs differentiation of glioma stem cells by activating the NOTCH pathway via TAF-1.

Emerging data have highlighted the importance of long noncoding RNAs (lncRNAs) in exerting critical biological functions and roles in different forms of brain cancer, including gliomas. In this study, we sought to investigate the role of lncRNA FOXD2 adjacent opposite strand RNA 1 (FOXD2‐AS1) in glioma cells. First, we used sphere formation assay and flow cytometry to select U251 glioma stem cells (GSCs). Then, we quantified the expression of lncRNA FOXD2‐AS1, TATA‐box binding protein associated factor 1 (TAF‐1) and NOTCH1 in glioma tissues and GSCs, as well as the expression of GSC stem markers, OCT4, SOX2, Nanog, Nestin and CD133 in GSCs. Colony formation assay, sphere formation assay, and flow cytometry were used to evaluate GSC stemness. Next, the correlations among lncRNA FOXD2‐AS1, TAF‐1 and NOTCH1 were investigated. LncRNA FOXD2‐AS1, TAF‐1 and NOTCH1 were found to be elevated in glioma tissues and GSCs, and silencing lncRNA FOXD2‐AS1 inhibited stemness and proliferation, while promoting apoptosis and differentiation of GSCs. LncRNA FOXD2‐AS1 overexpression also led to increased NOTCH1 by recruiting TAF‐1 to the NOTCH1 promoter region, thereby promoting stemness and proliferation, while impairing cell apoptosis and differentiation. Mechanistically, lncRNA FOXD2‐AS1 elevation promoted glioma in vivo by activating the NOTCH signalling pathway via TAF‐1 upregulation. Taken together, the key findings of our investigation support the proposition that downregulation of lncRNA FOXD2‐AS1 presents a viable and novel molecular candidate for improving glioma treatment.

Tumor promoting long non‐coding RNA CASC15 affects HMGB2 expression by sponging miR‐582‐5p in colorectal cancer

The importance of long non-coding RNAs (lncRNAs) in the regulation of tumorigenesis has been gradually recognized. The roles of lncRNA cancer susceptibility candidate 15 (CASC15) in cancers have been validated by several independent groups; however, its role in colorectal cancer (CRC) remains to be explored. Levels of CASC15 in CRC cells and normal cells were measured using a quantitative real-time polymerase chain reaction method. In vitro functional assays were performed to detect the effects of CASC15 on cell proliferation, invasion and apoptosis. Bioinformatic analyses and luciferase activity assays were conducted to investigate the targets for CASC15. Animal experiments were conducted to analyze the effect of CASC15 on tumor growth in vivo. The CASC15 level is revealed to be significantly elevated in CRC cells compared to that in normal cells. In vitro assays revealed that CASC15 overexpression stimulates cell growth and invasion, whereas its down-expression has opposite effects. Furthermore, CASC15 can bind with microRNA-582-5p (miR-582-5p) to modulate high mobility group box 2 (HMGB2) expression. We also showed that silencing of CASC15 inhibits tumor growth. In summary, CASC15 overexpression could promote CRC carcinogenesis, indicating that knockdown of CASC15 might be a possible therapeutic measure to hinder carcinogenesis. The results of the present study could help us to understand the mechanisms behind CRC progression.

Transcriptome analysis of colorectal cancer liver metastasis: The importance of long non-coding RNAs and fusion transcripts in the disease pathogenesis

BackgroundDespite several attempts to define the many genomic aspects of colorectal cancer liver metastasis (CRC-LM), there is still a lack of a complete and accurate picture of the cancer transcriptome and its function in the generation of metastasis. MethodsCancer Genome Atlas Sequence Read Archive (SRA) was used to get RNA sequencing data for CRC-LM and primary CRC. The CDseqR deconvolution method followed by the edgeR statistical approach was employed to accurately find differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was used to determine the long non-coding RNA (lncRNA) and mRNA pairs in CRC-LM etiology. Three alternative methods were used to explore fusion transcripts to anticipate the potential driver chimeras. ResultsMultiple cancer-related pathways were enriched in the up-regulated genes, including cell cycle, DNA replication, and RNA transport. SPP1 was the most up-regulated gene important in the cellular proliferation and migration and CCDC152 was the most down-regulated gene known in the metastatic spread of CRC. There were seven distinct lncRNAs discovered, two of which were novel (LOC107984834 and LOC107985040) and associated with metastatic related pathways such as the extracellular matrix-receptor interaction. Overall survival analysis demonstrated that SPP1 and LOC107985040 were significantly associated with poor prognosis outcomes. Seven new fusion transcripts were found in seven CRC-LM patients (22.5%) anticipated to have potential driver functions in cancer. ConclusionThe newly discovered dysregulated genes and other transcriptome abnormalities could contribute to a better understanding of the CRC-LM underlying mechanism, leading to the development of new diagnostic, prognostic, and therapeutic molecular options for personalized medicine.

Computational detection of a genome instability-derived lncRNA signature for predicting the clinical outcome of lung adenocarcinoma.

Evidence has been emerging of the importance of long non‐coding RNAs (lncRNAs) in genome instability. However, no study has established how to classify such lncRNAs linked to genomic instability, and whether that connection poses a therapeutic significance. Here, we established a computational frame derived from mutator hypothesis by combining profiles of lncRNA expression and those of somatic mutations in a tumor genome, and identified 185 candidate lncRNAs associated with genomic instability in lung adenocarcinoma (LUAD). Through further studies, we established a six lncRNA‐based signature, which assigned patients to the high‐ and low‐risk groups with different prognosis. Further validation of this signature was performed in a number of separate cohorts of LUAD patients. In addition, the signature was found closely linked to genomic mutation rates in patients, indicating it could be a useful way to quantify genomic instability. In summary, this research offered a novel method by through which more studies may explore the function of lncRNAs and presented a possible new way for detecting biomarkers associated with genomic instability in cancers.

New Insights into the Importance of Long Non-Coding RNAs in Lung Cancer: Future Clinical Approaches.

In mammals, a large part of the gene expression products come from the non-coding ribonucleotide sequences of the protein. These short and long sequences are within the range of tens to hundreds of nucleotides, encompassing more than 200 RNA molecules, and their function is known as the molecular structure of long non-coding RNA (lncRNA). LncRNA molecules are unique nucleotides that have a substantial role in epigenetic regulation, transcription, and post-transcriptional modifications in different ways. According to the results of recent studies, lncRNAs have been shown to assume various roles, including tumor suppression or oncogenic functions in common types of cancer such as lung and breast cancer. These non-coding RNAs (ncRNAs) play a pivotal role in activating transcription factors, managing the ribonucleoproteins, the framework for collecting co-proteins, intermittent processing regulations, chromatin status alterations, and maintaining the control within the cell. Cutting-edge technologies have been introduced to disclose several types of lncRNAs within the nucleus and the cytoplasm, which have accomplished important achievements that are applicable in medicine. Due to these efforts, various data centers have been created to facilitate and modify scientific information related to these molecules, including detection, classification, biological evolution, gene status, spatial structure, status, and location of these small molecules. In the present study, we attempt to present the impacts of these ncRNAs on lung cancer with an emphasis on their mechanisms and functions.

Metastasis associated long noncoding RNAs in glioblastoma: Biomarkers and therapeutic targets.

Glioblastoma (GBM) is the most aggressive, malignant, and therapeutically challenging Grade IV tumor of the brain. Although the possibilityof distant metastasis is extremely rare, GBM is known to cause intracranial metastasis forming aggressive secondary lesions resulting in a dismal prognosis. Metastasis also plays an important role in tumor dissemination and recurrence making GBM largely incurable. Recent studies have indicated the importance of long noncoding RNAs (lncRNAs) in GBM metastasis. lncRNAs are a class of regulatory noncoding RNAs (>200 nt) that interact with DNA, RNA, and proteins to regulate various biological processes. This is the first comprehensive review summarizing the lncRNAs associated with GBM metastasis and the underlying molecular mechanism involved in migration/invasion. We also highlight the complex network of lncRNA/miRNA/protein that collaborate/compete to regulate metastasis-associated genes. Many of these lncRNAs also show attractive potential as diagnostic/prognostic biomarkers. Finally, we discuss various therapeutic strategies and potential applications of lncRNAs as therapeutic targets for the treatment of GBM.

Silencing of lncRNA MEG8 Represses the Viability, Migration, and Invasion of Wilms’ Tumor Cells through Mediating miR-23a-3p/CRK Axis

Purpose: Compelling evidence has unveiled the importance of long noncoding RNAs (lncRNAs) in malignant behavior of Wilms’ tumor (WT). Hereon, we intend to assess the function and associated molecular mechanism of lncRNA maternally expressed gene 8 (MEG8) in WT cells. Methods: Expression levels of MEG8, miR-23a-3p, and CT10 regulator of kinase (CRK) were determined by quantitative real-time polymerase chain reaction. Cell viability was assessed by MTT assay. Besides, wound healing assay and transwell assay were applied to examine abilities of cell migration and invasion, respectively. Dual-luciferase reporter assay was employed to test the interplay among MEG8, miR-23a-3p, and CRK. Western blot was used to detect relative protein expression of CRK. Results: MEG8 and CRK expression was elevated, while miR-23a-3p expression was decreased in WT tissues and cells. The histologic type, lymphatic metastasis, and National Wilms Tumor Study (NWTS) stage were associated with the expression of MEG8, miR-23a-3p, and CRK in WT patients. MEG8 knockdown or miR-23a-3p overexpression restrained WT cells in cell viability, migration, and invasiveness in vitro. As to mechanism exploration, MEG8 could directly bind to miR-23a-3p and then miR-23a-3p targeted CRK. MEG8 was inversely correlated with miR-23a-3p and positively correlated with CRK in WT tissues. Meantime, miR-23a-3p was inversely correlated with CRK in WT tissues. Additionally, MEG8 knockdown-mediated suppressive impacts on cell viability, migration, and invasiveness were reversed by overexpression of CRK or repression of miR-23a-3p in WT cells. Conclusions: The cell viability, migration, and invasiveness of WT cells were repressed by MEG8 knockdown via targeting the miR-23a-3p/CRK axis.

Long non‑coding RNA ZSCAN16‑AS1 promotes the malignant properties of hepatocellular carcinoma by decoying microRNA‑451a and consequently increasing ATF2 expression.

The importance of long noncoding RNAs (lncRNAs) in the oncogenicity of hepatocellular carcinoma (HCC) has been widely studied. However, the detailed functions of ZSCAN16 antisense RNA 1 (ZSCAN16-AS1) have seldom been explored in HCC until the present study. In the present study, experiments were performed to clarify whether ZSCAN16-AS1 is implicated in the oncogenesis and progression of HCC and to explore the possible underlying mechanisms. ZSCAN16-AS1 expression was analyzed using reverse transcription-quantitative PCR. The effects of ZSCAN16-AS1 on the biological behavior of HCC cells were demonstrated by functional experiments. The direct binding capacity of ZSCAN16-AS1 with microRNA-451a (miR-451a) was indicated by the luciferase reporter assay and RNA immunoprecipitation. The high expression of ZSCAN16-AS1 was confirmed in HCC by The Cancer Genome Atlas database and the cohort of the present study. Survival data revealed that patients with a high ZSCAN16-AS1 level had worse prognosis compared with those with a low ZSCAN16-AS1 level. Following ZSCAN16-AS1 knockdown, HCC cell proliferation, migration and invasion were curbed, whereas cell apoptosis was promoted in vitro. The absence of ZSCAN16-AS1 restricted tumor growth of HCC cells in vivo. Mechanistically, ZSCAN16-AS1 acted as a competing endogenous RNA by decoying miR-451a in HCC cells. Furthermore, activating transcription factor 2 (ATF2), a direct target of miR-451a, was under the regulation of ZSCAN16-AS1, which was exerted by sequestering miR-451a. In addition, miR-451a knockdown or ATF2 resumption reversed the proliferation suppression, apoptosis promotion and migration and invasion inhibition triggered by ZSCAN16-AS1 silencing. In conclusion, ZSCAN16-AS1, a pro-oncogenic lncRNA, aggravated the malignancy of HCC by controlling the miR-451a/ATF2 axis. An understanding of the competing endogenous RNA network of ZSCAN16-AS1/miR-451a/ATF2 in HCC might be instrumental in the development of attractive targets for molecular therapy.

The evolving complexity of DNA damage foci: RNA, condensates and chromatin in DNA double-strand break repair

Formation of biomolecular condensates is increasingly recognized as a mechanism employed by cells to deal with stress and to optimize enzymatic reactions. Recent studies have characterized several DNA repair foci as phase-separated condensates, behaving like liquid droplets. Concomitantly, the apparent importance of long non-coding RNAs and RNA-binding proteins for the repair of double-strand breaks has raised many questions about their exact contribution to the repair process. Here we discuss how RNA molecules can participate in condensate formation and how RNA-binding proteins can act as molecular scaffolds. We furthermore summarize our current knowledge about how properties of condensates can influence the choice of repair pathway (homologous recombination or non-homologous end joining) and identify the open questions in this field of emerging importance.

LINC00470 Stimulates Methylation of PTEN to Facilitate the Progression of Endometrial Cancer by Recruiting DNMT3a Through MYC.

ObjectivesIncreasing researches emphasize the importance of long non-coding RNAs (lncRNAs) in the development of endometrial cancer (EC). There is wide recognition that LINC00470 is a critical participant in the tumorigenesis of cancers such as gastric cancer and glioblastoma, but its possible effects on EC progression remain to be explored.MethodsWe collected EC tissues and cells, where the expression of LINC00470 was determined, and followed by the Kaplan-Meier analysis of EC patient survival. We next examined the effect of LINC00470 and phosphatase and tensin homolog (PTEN) on EC cell migration, invasion, tube formation in vitro, and angiogenesis in mice xenografted with tumor after gain- or loss-of-function treatments. RNA pull-down, Co-IP, and ChIP experiments were performed to analyze the targeting relationships among LINC00470, MYC and DNMT3a.ResultsLINC00470 was aberrantly upregulated in EC and its high expression correlated to prognosis of EC patients. LINC00470 promoted invasiveness, migration, and angiogenesis of EC cells, and facilitated tumorigenesis and metastasis in vivo, but those effects were reversed by up-regulating PTEN. Functionally, LINC00470 bound to MYC in EC and that LINC00470 stimulated the binding of MYC to DNMT3a, and thus recruited DNMT3a through MYC to promote PTEN methylation.ConclusionsOur findings revealed that LINC00470 stimulated PTEN methylation to inhibit its expression by MYC-induced recruitment of DNMT3a, thus aggravating EC.

The Role of Long Non-Coding RNAs in Trophoblast Regulation in Preeclampsia and Intrauterine Growth Restriction.

Preeclampsia (PE) and Intrauterine Growth Restriction (IUGR) are two pregnancy-specific placental disorders with high maternal, fetal, and neonatal morbidity and mortality rates worldwide. The identification biomarkers involved in the dysregulation of PE and IUGR are fundamental for developing new strategies for early detection and management of these pregnancy pathologies. Several studies have demonstrated the importance of long non-coding RNAs (lncRNAs) as essential regulators of many biological processes in cells and tissues, and the placenta is not an exception. In this review, we summarize the importance of lncRNAs in the regulation of trophoblasts during the development of PE and IUGR, and other placental disorders.

The long non-coding RNA PFI protects against pulmonary fibrosis by interacting with splicing regulator SRSF1.

Pulmonary fibrosis (PF) is a type of interstitial pneumonia with complex etiology and high mortality, characterized by progressive scarring of the alveolar interstitium and myofibroblastic lesions. Recently, there has been growing appreciation of the importance of long non-coding RNAs (lncRNAs) in organ fibrosis. The aim of this study was to investigate the role of lncRNAs in lung fibrosis. We used a qRT-PCR assay to identify dysregulated lncRNAs in the lungs of mice with experimental, bleomycin (BLM)-induced pulmonary fibrosis, and a series of molecular assays to assess the role of the novel lncRNA NONMMUT060091, designated as pulmonary fibrosis inhibitor (PFI), which was significantly downregulated in lung fibrosis. Functionally, knockdown of endogenous PFI by smart silencer promoted proliferation, differentiation, and extracellular matrix (ECM) deposition in primary mouse lung fibroblasts (MLFs). In contrast, overexpression of PFI partially abrogated TGF-β1-induced fibrogenesis both in MLFs and in the human fetal lung fibroblast MRC-5 cells. Similarly, PFI overexpression attenuated BLM-induced pulmonary fibrosis compared with wild type (WT) mice. Mechanistically, using chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) and an RNA pull-down assay, PFI was found to directly bind Serine/arginine-rich splicing factor 1 (SRSF1), and to repress its expression and pro-fibrotic activity. Furthermore, silencing of SRSF1 inhibited TGF-β1-induced proliferation, differentiation, and ECM deposition in MRC-5 cells by limiting the formation of the EDA+Fn1 splicing isoform; whereas forced expression of SRSF1 by intratracheal injection of adeno-associated virus 5 (AAV5) ablated the anti-fibrotic effect of PFI in BLM-treated mice. Overall, these data reveal that PFI mitigated pulmonary fibrosis through negative regulation of the expression and activity of SRSF1 to decrease the formation of the EDA+Fn1 splicing isoform, and suggest that PFI and SRSF1 may serve as potential targets for the treatment of lung fibrosis.

152 LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C

Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determine a comprehensive map of lineage-specific lncRNAs in human dermal lymphatic and blood vascular endothelial cells (LECs and BECs), combining RNA-Seq and CAGE-Seq. Subsequent antisense oligonucleotide-knockdown transcriptomic profiling of two LEC- and two BEC-specific lncRNAs identifies LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein interaction studies, and phenotype rescue analyses reveal that LETR1 is a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides several lines of evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.