The increase of long noncoding RNA Fendrr in hepatocytes contributes to liver fibrosis by promoting IL-6 production.

Liver fibrosis/cirrhosis is a pathological state caused by excessive extracellular matrix deposition. Sustained activation of hepatic stellate cells (HSC) is the predominant cause of liver fibrosis, but the detailed mechanism is far from clear. In this study, we found that long noncoding RNA Fendrr is exclusively increased in hepatocytes in the murine model of CCl4- and bile duct ligation-induced liver fibrosis, as well as in the biopsies of liver cirrhosis patients. In vivo, ectopic expression of Fendrr aggravated the severity of CCl4-induced liver fibrosis in mice. In contrast, inhibiting Fendrr blockaded the activation of HSC and ameliorated CCl4-induced liver fibrosis. Our mechanistic study showed that Fendrr binds to STAT2 and enhances its enrichment in the nucleus, which then promote the expression of interleukin 6 (IL-6), and, ultimately, activates HSC in a paracrine manner. Accordingly, disrupting the interaction between Fendrr and STAT2 by ectopic expression of a STAT2 mutant attenuated the profibrotic response inspired by Fendrr in the CCl4-induced liver fibrosis. Notably, the increase of Fendrr in patient fibrotic liver is positively correlated with the severity of fibrosis and the expression of IL-6. Meanwhile, hepatic IL-6 positively correlates with the extent of liver fibrosis and HSC activation as well, thus suggesting a causative role of Fendrr in HSC activation and liver fibrosis. In conclusion, these observations identify an important regulatory cross talk between hepatocyte Fendrr and HSC activation in the progression of liver fibrosis, which might represent a potential strategy for therapeutic intervention.

LncRNA FENDRR with m6A RNA methylation regulates hypoxia-induced pulmonary artery endothelial cell pyroptosis by mediating DRP1 DNA methylation.

BACKGROUND: Pyroptosis is a form of programmed cell death involved in the pathophysiological progression of hypoxic pulmonary hypertension (HPH). Emerging evidence suggests that N6-methyladenosine (m6A)-modified transcripts of long noncoding RNAs (lncRNAs) are important regulators that participate in many diseases. However, whether m6A modified transcripts of lncRNAs can regulate pyroptosis in HPH progression remains unexplored. METHODS: The expression levels of FENDRR in hypoxic pulmonary artery endothelial cells (HPAECs) were detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). Western blot, Lactate dehydrogenase (LDH) release assay, Annexin V-FITC/PI double staining, Hoechst 33342/PI fluorescence staining and Caspase-1 activity assay were used to detect the role of FENDRR in HPAEC pyroptosis. The relationship between FENDRR and dynamin-related protein 1 (DRP1) was explored using bioinformatics analysis, Chromatin Isolation by RNA Purification (CHIRP), Electrophoretic mobility shift assay (EMSA) and Methylation-Specific PCR (MSP) assays. RNA immunoprecipitation (RIP) and m6A dot blot were used to detect the m6A modification levels of FENDRR. A hypoxia-induced mouse model of pulmonary hypertension (PH) was used to test preventive effect of conserved fragment TFO2 of FENDRR. RESULTS: We found that FENDRR was significantly downregulated in the nucleus of hypoxic HPAECs. FENDRR overexpression inhibited hypoxia-induced HPAEC pyroptosis. Additionally, DRP1 is a downstream target gene of FENDRR, and FENDRR formed an RNA-DNA triplex with the promoter of DRP1, which led to an increase in DRP1 promoter methylation that decreased the transcriptional level of DRP1. Notably, we illustrated that the m6A reader YTHDC1 plays an important role in m6A-modified FENDRR degradation. Additionally, conserved fragment TFO2 of FENDEE overexpression prevented HPH in vivo. CONCLUSION: In summary, our results demonstrated that m6A-induced decay of FENDRR promotes HPAEC pyroptosis by regulating DRP1 promoter methylation and thereby provides a novel potential target for HPH therapy.

An integrated analysis of the competing endogenous RNA network associated of prognosis of stage I lung adenocarcinoma.

BACKGROUND: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are involving in the tumorigenesis and metastasis of lung cancer. The aim of the study is to systematically characterize the lncRNA-associated competing endogenous RNA (ceRNA) network and identify key lncRNAs in the development of stage I lung adenocarcinoma (LUAD). METHODS: Totally, 1,955 DEmRNAs, 165 DEmiRNAs and 1,107 DElncRNAs were obtained in 10 paired normal and LUAD tissues. And a total of 8,912 paired lncRNA-miRNA-mRNA network was constructed. Using the Cancer Genome Atlas (TCGA) dataset, the module of ME turquoise was revealed to be most relevant to the progression of LUAD though Weighted Gene Co-expression Network Analysis (WGCNA). RESULTS: Of the lncRNAs identified, LINC00639, RP4-676L2.1 and FENDRR were in ceRNA network established by our RNA-sequencing dataset. Using univariate Cox regression analysis, FENDRR was a risk factor of progression free survival (PFS) of stage I LUAD patients (HRs = 1.69, 95%CI 1.07-2.68, P < .050). Subsequently, diffe rential expression of FENDRR in paired normal and LUAD tissues was detected significant by real-time quantitative (qRT-PCR) (P < 0.001). CONCLUSIONS: This study, for the first time, deciphered the regulatory role of FENDRR/miR-6815-5p axis in the progression of early-stage LUAD, which is needed to be established in vitro and in vivo.

Predictive urinary RNA biomarkers of kidney injury after extracorporeal shock wave lithotripsy.

BACKGROUND: Extracorporeal shock wave lithotripsy (ESWL) is considered one of the best choices for the treatment of various kinds of urinary tract calculi, although it might cause acute kidney injury. OBJECTIVE: To measure the urinary long non-coding RNA-messenger RNA (LncRNA-mRNA) panel before and after ESWL to evaluate post-ESWL renal injury in a reliable and non-invasive method. PATIENTS AND METHODS: The study included 60 patients with renal stones treated with ESWL and 30 healthy volunteers. Voided urine samples were obtained before, 2 h, and 1 day after ESWL. We measured the urinary level of LncRNA (SBF2-AS1, FENDRR-19) and mRNA (GBP1, NLRP3) by real-time qPCR and compared the results with serum creatinine and eGFR. RESULTS: LncRNA (SBF2-AS1, FENDRR-19) and mRNA (GBP1, NLRP3) levels were higher in patients with renal stones when compared with healthy volunteers. They showed a statistically significant increase in the level of LncRNA-mRNA panel in baseline and after ESWL treatment. CONCLUSION: LncRNA (SBF2-AS1, FENDRR-19) and mRNA (GBP1, NLRP3) levels were significantly elevated following ESWL treatment, highlighting the usefulness of urinary biomarkers in identifying patients at higher risk of developing renal injury after ESWL treatment.

LncRNA-Fendrr protects against the ubiquitination and degradation of NLRC4 protein through HERC2 to regulate the pyroptosis of microglia.

OBJECTIVES: Targeted inhibition of inflammatory response can reduce diabetic cerebral ischemia-reperfusion (I/R) injure. Pyroptosis is characterized by caspase-1 dependence and the release of a large number of pro-inflammatory factors. LncRNA-Fendrr is associated with a variety of diseases, but Fendrr has not been studied in diabetic cerebral I/R. NLR-family CARD-containing protein 4 (NLRC4) regulate the pyroptosis of microglia cells. This study was designed to investigate whether Fendrr is involved in the effects of diabetic cerebral I/R injury. METHODS: The diabetic brain I/R model in mice was constructed. Mouse microglia cell line BV-2 cells were exposed to high glucose followed by hypoxia/reoxygenation (H/R). Fendrr and some pyroptosis-associated proteins were detected by qRT-PCR, western blot or ELISA. HE staining was used to detect pathological changes. Microglia pyroptosis was detected by TUNEL staining. RNA pull-down and RNA Immunoprecipitation were used to detect binding of Fendrr to HERC2 (E3 ubiquitin ligase), and CO-IP detected binding of HERC2 to NLRC4. The ubiquitination of NLRC4 was detected by ubiquitination experiments. RESULTS: Fendrr was significantly increased in the diabetic cerebral I/R model, and NLRC4 inflammatory complex and pyroptosis mediated inflammatory factors were increased. NLRC4 and inflammatory cytokines associated with pyroptosis were decreased in the high glucose-treated hypoxia/reoxygenation (H/R)-induced microglia after Fendrr knockdown. Fendrr bound to HERC2 protein, and HERC2 bound to NLRC4. Meanwhile, Fendrr could inhibit the ubiquitination of NLRC4, HERC2 promoted the ubiquitination of NLRC4 protein. Moreover, the effect of Fendrr overexpression in the diabetic cerebral I/R model of microglia can be reversed by HERC2 overexpression. CONCLUSION: Fendrr can protect against the ubiquitination and degradation of NLRC4 protein through E3 ubiquitin ligase HERC2, thereby accelerating the pyroptosis of microglia.

LncRNA FENDRR promotes apoptosis of Leydig cells in late-onset hypogonadism by facilitating the degradation of Nrf2.

This study aimed to investigate the role of lncRNA FENDRR in apoptosis of Leydig cells and the further mechanism. The apoptosis of Leydig cells (TM3 cell line) was induced by H2O2-treatment and detected by flow cytometry. The function of FENDRR was determined by in vitro and in vivo silencing experiments. The mechanism of FENDRR in regulating the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was assessed by RNA immunoprecipitation, RNA pull-down, and ubiquitination assays. FENDRR expression was up-regulated in H2O2-treated TM3 cells. Knockdown of FENDRR augmented Nrf2 and HO-1 protein levels and testosterone production in H2O2-treated TM3 cells, whereas the apoptosis rate and caspase 3 activity were decreased. Mechanically, FENDRR bound to Nrf2 and promoted its ubiquitination and degradation. Nrf2 overexpression reversed the effects FENDRR overexpression on apoptosis, caspase 3 activity, and testosterone concentration in H2O2-treated TM3 cells. The in vivo experiments showed that FENDRR silence increased serum testosterone level and improved testosterone-related anti-depression behaviors of late-onset hypogonadism (LOH) mice. Our findings suggested that FENDRR could promote apoptosis of Leydig cells in LOH partly through facilitating Nrf2 degradation.

Long Noncoding RNA FENDRR Inhibits Lung Fibroblast Proliferation via a Reduction of ß-Catenin.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and usually lethal lung disease and it has been widely accepted that fibroblast proliferation is one of the key characteristics of IPF. Long noncoding RNAs (lncRNAs) play vital roles in the pathogenesis of many diseases. In this study, we investigated the role of lncRNA FENDRR on fibroblast proliferation. Human lung fibroblasts stably overexpressing FENDRR showed a reduced cell proliferation compared to those expressing the control vector. On the other hand, FENDRR silencing increased fibroblast proliferation. FENDRR bound serine-arginine rich splicing factor 9 (SRSF9) and inhibited the phosphorylation of p70 ribosomal S6 kinase 1 (PS6K), a downstream protein of the mammalian target of rapamycin (mTOR) signaling. Silencing SRSF9 reduced fibroblast proliferation. FENDRR reduced ß-catenin protein, but not mRNA levels. The reduction of ß-catenin protein levels in lung fibroblasts by gene silencing or chemical inhibitor decreased fibroblast proliferation. Adenovirus-mediated FENDRR transfer to the lungs of mice reduced asbestos-induced fibrotic lesions and collagen deposition. RNA sequencing of lung tissues identified 7 cell proliferation-related genes that were up-regulated by asbestos but reversed by FENDRR. In conclusion, FENDRR inhibits fibroblast proliferation and functions as an anti-fibrotic lncRNA.

Fendrr involves in the pathogenesis of cardiac fibrosis via regulating miR-106b/SMAD3 axis.

Cardiovascular diseases (CVDs) is the first cause of death worldwide, generally exhibiting a high morbidity, high disability rate and high mortality especially in the elderly persons (>50 years old). Previously, extensive studies have demonstrated that cardiac fibrosis plays cardinal roles in the pathogenesis of CVDs. However, due to the unclear underlying mechanisms of cardiac fibrosis, its clinical intervention remains very lacking. Long non-coding RNAs (lncRNAs), a class of non-coding RNA but differing from microRNAs, are generally considered as transcripts with a length ranging 200 to 100 nucleotides. Recently, accumulating evidence showed that lncRNAs involve in the pathogenesis of cardiac fibrosis. Fendrr (FOXF1 adjacent non-coding developmental regulatory RNA), is a spliced long non-coding RNA transcribed bi-directionally with FOXF1 on the opposite strand. Fendrr has been demonstrated to be essential for normal development of the heart and body wall in mouse, and shows a good anti-fibrotic activity in pulmonary fibrosis. In this study, we aimed to explore the effects of Fendrr on cardiac fibrosis. Intriguingly, we first observed that lncRNA Fendrr was up-regulated in the heart tissues of transverse aortic constriction (TAC) induced cardiac fibrosis mouse models, determined by RT-QPCR. Loss-function of Fendrr significantly alleviated the cardiac fibrosis phenotypes induced by TAC, indicating that Fendrr is required for the pathogenesis of cardiac fibrosis. In mechanism, we demonstrated experimentally that Fendrr directly targeting miR-106b, by which the lncRNA promotes cardiac fibrosis (indicated by the elevation of Col1a1, Col3a1, CTGF and ACTA2 expression) in a miR-106b mediated manner. Collectively, our findings highlight the axis of Fendrr/miR-106b/Samd3 in the pathogenesis of cardiac fibrosis, which may be a promising target for clinical intervention target of cardiac fibrosis.

FENDRR suppresses cervical cancer proliferation and invasion by targeting miR-15a/b-5p and regulating TUBA1A expression.

BACKGROUND: Previous literature has revealed long non-coding RNAs (lncRNAs) are crucial regulators for cell functions and gene expression. LncRNA fetal-lethal non-coding developmental regulatory RNA (FENDRR) was reported as a biological suppressor in several types of human cancers, yet relevant mechanisms and biological effects of FENDRR with regards to cervical cancer (CC) are not explored until now. METHODS: In this study, quantitative real-time polymerase chain reaction (qRT-PCR) analysis detected gene expression in tissues and cells. Gain- or loss-of-function experiments revealed the biological effects of FENDRR and miR-15a/b-5p on CC cell functions. Bioinformatics tools were used to predict the relevant genes. Mechanism experiments including RNA immunoprecipitation (RIP) assay, pull down assay and luciferase reporter assay depicted the binding situation and coexistence of indicated genes. RESULTS: FENDRR was downregulated in CC tissues and cells, which suppressed CC progression. MiR-15a-5p and miR-15b-5p shared binding sites with FENDRR and had interaction with FENDRR. Tubulin alpha1A (TUBA1A) was downregulated in CC tissues and positively modulated by FENDRR. TUBA1A was the target of miR-15a/b-5p. TUBA1A silencing rescued the effect of FENDRR overexpression on CC cell growth and migration. CONCLUSION: FENDRR inhibits CC progression through upregulating TUBA1A in a miR-15a/b-5p-dependent manner.

Good or not good: Role of miR-18a in cancer biology.

miR-18a is a member of primary transcript called miR-17-92a (C13orf25 or MIR17HG) which also contains five other miRNAs: miR-17, miR-19a, miR-20a, miR-19b and miR-92a. This cluster as a whole shows specific characteristics, where miR-18a seems to be unique. In contrast to the other members, the expression of miR-18a is additionally controlled and probably functions as its own internal controller of the cluster. miR-18a regulates many genes involved in proliferation, cell cycle, apoptosis, response to different kinds of stress, autophagy and differentiation. The disturbances of miR-18a expression are observed in cancer as well as in different diseases or pathological states. The miR-17-92a cluster is commonly described as oncogenic and it is known as 'oncomiR-1', but this statement is a simplification because miR-18a can act both as an oncogene and a suppressor. In this review we summarize the current knowledge about miR-18a focusing on its regulation, role in cancer biology and utility as a potential biomarker.

The interaction between ANXA2 and lncRNA Fendrr promotes cell apoptosis in caerulein-induced acute pancreatitis.

BACKGROUND: Annexin A2 (ANXA2) plays a crucial role in acute pancreatitis (AP). However, its potential mechanism remains unclear. METHODS: In the present study, we used caerulein-treated AR42J rat pancreatic acinar cells as cell model of AP to investigate the potential functions of ANXA2 and its predicted long noncoding RNA (lncRNA) FOXF1 adjacent noncoding developmental regulatory RNA (lncRNA Fendrr). Cell apoptosis was evaluated by flow cytometry using annexinV-fluorescein isothiocyanate/propidium iodide staining. The expressions of ANAX2 and lncRNA Fendrr were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, Western blot analysis was performed to determine the protein levels of ANXA2, Bcl-2, and Bax. The association between lncRNA Fendrr and ANXA2 was disclosed by RNA pull-down, RNA immunoprecipitation, and electrophoretic mobility shift assays. RESULTS: ANXA2 was elevated in caerulein-induced AP model and promoted apoptosis of AR42J cells. LncRNA Fendrr was also upregulated in AP cell model and directly bound ANXA2 protein. Further studies indicated that the interaction between ANXA2 and lncRNA Fendrr contributed to the apoptosis of AR42J cells in AP cell model. CONCLUSION: Our study demonstrated that ANXA2 promoted AP progression via interacting with lncRNA Fendrr in vitro, which will provide a novel insight into the therapeutic target for AP.

Long non-coding RNA FENDRR inhibits proliferation and invasion of hepatocellular carcinoma by down-regulating glypican-3 expression.

Long non-coding RNA FENDRR is implicated in progression of several cancers, but its exact role and mechanism in hepatocellular carcinoma (HCC) are largely unknown. In this study, we investigated the expression and biological roles of FENDRR in HCC tissues and cell lines. We found that the expression levels of FENDRR were significantly down-regulated in HCC tissues and cells. FENDRR overexpression could inhibit the growth of HCC cells in vitro and in vivo. Moreover, up-regulation of FENDRR suppressed the migration and invasion of HCC cells. Mechanistically, we demonstrated that FENDRR interacted directly with Glypican-3 (GPC3) promoter and methylated GPC3 promoter, which led to down-regulation of GPC3 expression. Ectopic expression of GPC3 ablated the inhibitory effects of FENDRR on HCC cell proliferation, migration and invasion. Taken together, we provided the first evidence for the inhibitory activity of FENDRR in HCC, which is causally linked to targeting GPC3 at the epigenetic level. Restoration of FENDRR may be a potential approach to prevent HCC progression and metastasis.

LncRNA FENDRR promotes high-glucose-induced proliferation and angiogenesis of human retinal endothelial cells.

The study aimed to investigate the role of lncRNA FENDRR in proliferation and angiogenesis of human retinal endothelial cells (HRECs). HRECs were cultured in high-glucose medium to mimic diabetic retinopathy (DR) model. We overexpressed or knocked down FENDRR in HRECs to evaluate the effect of FENDRR expression on cell proliferation, migration, and capillary morphogenesis of HRECs under either normal glucose or high glucose condition. Results showed that VEGF and FENDRR expression were increased in blood from DR patients compared with the control subjects. Furthermore, high glucose treatment upregulated expression of VEGF and FENDRR secreted from HRECs, in a dose- and time-dependent manner. Importantly, FENDRR overexpression significantly promoted the high-glucose-induced proliferation, migration, capillary morphogenesis, and VEGF expression in HRECs. In contrast, FENDRR knockdown exerted the opposite effects. In conclusion, lncRNA FENDRR promotes the high-glucose-induced proliferation and angiogenesis of HRECs and may serve as a potential target for anti-angiogenic therapy for DR.

LncRNA-FENDRR mediates VEGFA to promote the apoptosis of brain microvascular endothelial cells via regulating miR-126 in mice with hypertensive intracerebral hemorrhage.

BACKGROUND: LncRNA-FENDRR is a kind of endothelial genes critical for vascular development. Moreover, miR-126 and vascular endothelial growth factor A (VEGFA) are also involved in the physiological process of vascular endothelial cells. This study aimed to the underlying mechanism of FENDRR involving miR-126 and VEGFA in hypertensive intracerebral hemorrhage (HICH). METHODS: C57BL/6 mice were chosen to establish HICH model. The expression of FENDRR, miR-126, and VEGFA at mRNA level was determined by qRT-PCR. The protein expression of VEGFA was assessed using Western blot. RIP assay and RNA pull-down assay were used to the relationship between FENDRR and miR-126. Flow cytometry was used to analyze cell apoptosis. RESULTS: The levels of FENDRR and VEGFA were increased, and miR-126 expression was decreased in vascular endothelial cells (VECs) from the right brain of model mice and human brain microvascular endothelial cells (HBMECs) treated by thrombin. Overexpression of FENDRR promoted the apoptosis of HBMECs. FENDRR regulating VEGFA participated in HBMECs apoptosis through targeting miR-126. Downregulation of FENDRR was indicated to relieve the HICH in mice. CONCLUSIONS: FENDRR could promote the apoptosis of HBMECs via miR-126 regulating VEGFA in HICH.

Long non-coding RNA FENDRR reduces prostate cancer malignancy by competitively binding miR-18a-5p with RUNX1.

CONTEXT: Prostate cancer (PCa) is one of the most commonly diagnosed malignancy in men in the western world. OBJECTIVE: We aim to investigate the biological role of long non-coding RNA FENDRR and its mechanism in PCa. MATERIALS AND METHODS: We determined the expression of FENDRR and miR-18a-5p in PCa tissues and examined the regulatory mechanism in PCa cell lines. RESULTS: FENDRR transcripts in human PCa tissues were significantly decreased compared with the normal controls. Reduced expression of FENDRR was correlated with the increase of pathological degree and poor prognosis in PCa patients. Upregulation of FENDRR inhibited cell proliferation, increased apoptosis and decreased invasion and migration ability, which was inhibited by miR-18a-5p mimic. Knockdown of FENDRR resulted in a significant increase of PCa cell proliferation and decrease of apoptosis and this effect was inhibited miR-18a-5p inhibitor. FENDRR and RUNX1 contain potential target sites for miR-18a-5p. miR-18a-5p mimic inhibited RUNX1 expression and luciferase activity. FENDRR could increase RUNX1 expression, which was inhibited by miR-18a-5p. The effect of FENDRR on cell proliferation, apoptosis and invasion and migration ability was suppressed by silence of RUNX1. DISCUSSION AND CONCLUSION: These results position FENDRR/miR-18a-5p/RUNX1 as a potential therapeutic target and biomarker for PCa.

The long non-coding RNAs MHRT, FENDRR and CARMEN, their expression levels in peripheral blood mononuclear cells in patients with essential hypertension and their relation to heart hypertrophy.

Long non-coding RNAs (lncRNAs) participate in the modulation of cardiac hypertrophy, and they represent potential therapeutic targets in cardiovascular disease. We investigated the expression profiles of selected lncRNAs in peripheral blood mononuclear cells of patients with essential hypertension in relation to left ventricular hypertrophy. We assessed the expression levels of the lncRNAs MHRT, FENDRR and CARMEN using real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly higher MHRT, FENDRR and CARMEN expression levels compared with healthy controls. In addition, we observed significant negative correlations of MHRT (r = -0.323, P = 0.003) and FENDRR (r = -0.380, P = 0.001) and a positive correlation of CARMEN (r = 0.458, P < 0.001) expression levels with left ventricular mass index. Our data reveal that the lncRNAs MHRT, FENDRR and CARMEN show distinct expression profiles in hypertensive patients and they possibly represent candidate therapeutic targets in hypertensive heart disease.

Aberrantly downregulated FENDRR by arecoline elevates ROS and myofibroblast activation via mitigating the miR-214/MFN2 axis.

Long non-coding RNA FENDRR possesses both anti-fibrotic and anti-cancer properties, but its significance in the development of premalignant oral submucous fibrosis (OSF) remains unclear. Here, we showed that FENDRR was downregulated in OSF specimens and fibrotic buccal mucosal fibroblasts (fBMFs), and overexpression of FENDRR mitigated various myofibroblasts hallmarks, and vice versa. In the course of investigating the mechanism underlying the implication of FENDRR in myofibroblast transdifferentiation, we found that FENDRR can directly bind to miR-214 and exhibit its suppressive effect on myofibroblast activation via titrating miR-214. Moreover, we showed that mitofusin 2 (MFN2), a protein that is crucial to the fusion of mitochondria, was a direct target of miR-214. Our data suggested that FENDRR was positively correlated with MFN2 and MFN2 was required for the inhibitory property of FENDRR pertaining to myofibroblast phenotypes. Additionally, our results showed that the FENDRR/miR-214 axis participated in the arecoline-induced reactive oxygen species (ROS) accumulation and myofibroblast transdifferentiation. Building on these results, we concluded that the aberrant downregulation of FENDRR in OSF may be associated with chronic exposure to arecoline, leading to upregulation of ROS and myofibroblast activation via the miR-214-mediated suppression of MFN2.

The long non-coding RNA Fendrr links epigenetic control mechanisms to gene regulatory networks in mammalian embryogenesis.

Epigenetic control mechanisms determine active and silenced regions of the genome. It is known that the Polycomb Repressive Complex 2 (PRC2) and the Trithorax group/Mixed lineage leukemia (TrxG/Mll) complex are able to set repressive and active histone marks, respectively. Long non-coding RNAs (lncRNAs) can interact with either of these complexes and guide them to regulatory elements, thereby modifying the expression levels of target genes. The lncRNA Fendrr is transiently expressed in lateral mesoderm of mid-gestational mouse embryos and was shown to interact with both PRC2 and TrxG/Mll complexes in vivo. Gene targeting revealed that loss of Fendrr results in impaired differentiation of tissues derived from lateral mesoderm, the heart and the body wall, ultimately leading to embryonic death. Molecular data suggests that Fendrr acts via dsDNA/RNA triplex formation at target regulatory elements, and directly increases PRC2 occupancy at these sites. This, in turn, modifies the ratio of repressive to active marks, adjusting the expression levels of Fendrr target genes in lateral mesoderm. We propose that Fendrr also mediates long-term epigenetic marks to define expression levels of its target genes within the descendants of lateral mesoderm cells. Here we discuss approaches for lncRNA gene knockouts in the mouse, and suggest a model how Fendrr and possibly other lncRNAs act during embryogenesis.

Long non-coding RNA FENDRR suppresses cancer-associated fibroblasts and serves as a prognostic indicator in colorectal cancer.

Genetically abnormal fibroblasts are notably more prevalent in colorectal cancer (CRC) than in adjacent normal tissue, emphasizing their significance in driving the heterogeneity of the tumor microenvironment. Functioning as a significant regulatory gene in the context of fibrosis, FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) has exhibited abnormal expression in colorectal cancer and interstitial localization in our experiments. However, current research on the role of FENDRR in cancer has focused solely on its impact on cancer cells. Its crucial role in the tumor stroma is yet to be explored. The goal of this study was to understand the relationship between atypical FENDRR expression, its distinct localization, and genetically abnormal fibroblasts in CRC. We aimed to establish the function of FENDRR within the stromal compartment of patients through bioinformatics. Our study confirmed that FENDRR suppresses cancer-associated fibroblasts by inhibiting their activation and collagen generation in CRC. Furthermore, our findings suggest that low FENDRR expression indicates a poor prognosis. Therefore, we propose that FENDRR is a promising therapeutic target for future studies in CRC.

LncRNA FENDRR Suppresses Melanoma Growth via Influencing c-Myc mRNA Level.

Background: Long non-coding RNAs (lncRNAs) play an important role in the occurrence of melanoma. However, the specific molecular mechanisms that regulate its biological function are still poorly understood. Therefore, the main purpose of this study is to elucidate the internal mechanism of lncRNA-FENDRR as a biological marker for the occurrence of SKCM and its influence on its proliferation. Results: FENDRR is low expressed in skin cutaneous melanoma (SKCM) tissues and appears to be at an even lower level as the tumor progresses. However, the high expression of FENDRR can affect the proliferation of SKCM cell line A375. The results of flow cytometry showed that after overexpression of FENDRR, the cell cycle was arrested in the G1/G0 phase. Bioinformatics analysis and RIP results showed that FENDRR could be combined with YTHDF1. Together, these complexes regulate c-Myc mRNA level and determine cell proliferation. Conclusion: We found that overexpression of FENDRR can effectively inhibit SKCM, which provides a new theoretical basis for new therapeutic approaches and targeted RNA drugs.