lncRNA H19 Research Articles

Expression analysis of vitamin D receptor-associated long noncoding RNAs in patients with relapsing-remittingmultiple sclerosis.

Vitamin D is a neuroactive steroid that carries out its biological functions through the vitamin D receptor (VDR). The VDR gene interacts with certain long noncoding RNAs (lncRNAs). The present study is aimed at evaluating the expression levels of the VDR gene as well as those of HOTAIR, H19, MALAT1, and P21 lncRNAs in patients with relapsing-remitting multiple sclerosis (RRMS). This research was conducted on 38 RRMS patients and 38 healthy individuals. The expression levels of VDR and selected lncRNAs in peripheral blood as well as those of vitamin D in the plasma were measured. The results revealed a significant increase in the expression of lncRNA H19 in the RRMS group compared to the control group. The analysis of the receiver operating characteristic (ROC) curve for H19 gene expression demonstrated a diagnostic value of 0.699 (95% CI: 0.575-0.823). Positive correlations were detected between VDR and lncRNA HOTAIR (r = 0.446, p = 0.008), H19 (r = 0.351, p = 0.042), MALAT1 (r = 0.464, p = 0.006), and P21 (r = 0.512, p = 0.002) in MS patients. The findings of this study suggest that lncRNA H19 could serve as a potential biomarker for MS diagnosis (Tab. 4, Fig. 1, Ref. 34).

Plasma Extracellular Vesicle LncRNA H19 as a Potential Diagnostic Biomarker for Inflammatory Bowel Diseases.

Inflammatory bowel disease (IBD) is a complex gastrointestinal disease with 2 main subtypes of Crohn's disease (CD) and ulcerative colitis (UC), whose diagnosis mainly depends on the medical history, clinical symptoms, endoscopic, histologic, radiological, and serological findings. Extracellular vesicles (EVs) are now considered an additional mechanism for intercellular communication, allowing cells to exchange biomolecules. Long noncoding RNAs (lncRNAs) that are enriched in EVs have been defined as an ideal diagnostic biomarker for diseases. In this study, we investigated the expression differences of 5 lncRNAs in tissue and plasma EVs of active IBD patients compared with patients in the remission phase and healthy controls to introduce an EV-lncRNA as a noninvasive IBD diagnostic biomarker. Twenty-two active IBD patients, 14 patients in the remission phase, 10 active rheumatoid arthritis (RA) patients, 14 irritable bowel syndrome (IBS) patients, and 22 healthy individuals were recruited in the discovery cohort. In addition, 16 patients with active IBD, 16 healthy controls, 10 inactive IBD patients, 12 active RA patients, and 14 IBS patients were also included in the validation cohort. The expression levels of 5 lncRNAs in tissue and EV-plasma were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) . Machine learning and receiver operating characteristic (ROC) curve analysis were performed to investigate the distinguishing ability of the candidate biomarkers. While the expression levels of lncRNAs CDKN2B-AS1, GAS5, and TUG1 were significantly downregulated, lncRNAs H19 and CRNDE were overexpressed in active IBD lesions. Expression of H19 was detected in plasma EVs whose isolation had been confirmed via dynamic light scattering, microscopy images, and western blotting. The classification results demonstrated the excellent ability of H19 in distinguishing IBD/active from IBD/remission, healthy control, RA, and IBS (area under the ROC curve = 0.95, 0.97,1, and 0.97 respectively). Our study suggests that circulating EV-lncRNA H19 exhibited promising potential for the diagnosis of active IBD.

The novel RNA-RNA activation of H19 on MyoD transcripts promoting myogenic differentiation of goat muscle satellite cells

The elaborate interplay of coding and noncoding factors governs muscle growth and development. Here, we reported a mutual activation between long noncoding RNA (lncRNA) H19 and MyoD (myogenic determination gene number 1) in the muscle process. We successfully cloned the two isoforms of goat H19, which were significantly enriched and positively correlated with MyoD transcripts in skeletal muscles or differentiating muscle satellite cells (MuSCs). To systematically screen genes altered by H19, we performed RNA-seq using cDNA libraries of differentiating H19-deficiency MuSCs and consequently anchored MyoD as the critical genes in mediating H19 function. Intriguingly, some transcripts of MyoD and H19 overlapped in the cytoplasm, which was dramatically damaged when the core complementary nucleotides were mutated. Meanwhile, MyoD RNA successfully pulled down H19 in MS2-RIP experiments. Furthermore, HuR could bind both H19 and MyoD transcripts, while H19 or its truncated mutants successfully stabilized MyoD mRNA, with or without HuR deficiency. In turn, novel functional MyoD protein-binding sites were identified in the promoter and exons of the H19 gene. Our results suggest that MyoD activates H19 transcriptionally, and RNA-RNA hybridization is critical for H19-promoted MyoD expression, which extends our knowledge of the hierarchy of regulatory networks in muscle growth.

The interplay between H19 and HIF-1α in mitochondrial dysfunction in myocardial infarction

Myocardial infarction(MI) causes prolonged ischemia of infarcted myocardial tissue, which triggers a wide range of hypoxia cellular responses in cardiomyocytes. Emerging evidence has indicated the critical roles of long non-coding RNAs(lncRNAs) in cardiovascular diseases, including MI. The purpose of this study was to investigate the roles of lncRNA H19 and H19/HIF-1α pathway during MI. Results showed that cell injury and mitochondrial dysfunction were induced in hypoxia-treated H9c2 cells, accompanied by an increase in the expression of H19. H19 silencing remarkably diminishes cell injury, inhibits the dysfunctional degree of mitochondria, and decreases the injury of MI rats. Bioinformatics analysis and dual-luciferase assays revealed that H19 was the hypoxia-responsive lncRNA, and HIF-1α induced H19 transcription through direct binding to the H19 promoter. Moreover, H19 participates in the HIF-1α pathway by stabilizing the HIF-1α protein. These results indicated that H19 might be a potential biomarker and therapeutic target for myocardial infarction.

The lncRNA H19/miR-29a-3p/SNIP1/c-myc regulatory axis is involved in pulmonary fibrosis induced by Nd2O3.

Some rare earth elements are occupational and environmental toxicants and can cause organ and systemic damage; therefore, they have attracted global attention. Neodymium oxide (Nd2O3) is a rare earth element that is refined and significantly utilized in China. The long noncoding RNA (lncRNA) H19 is encoded by the H19/IGF2 imprinted gene cluster located on human chromosome 11p15.5. H19 has become a research focus due to its ectopic expression leading to the promotion of fibrosis. However, the mechanisms by which it causes pulmonary fibrosis are elusive. This investigation indicates that biologically active Nd2O3 increases H19, SNIP1, and c-myc, decreases miR-29a-3p, accelerates macrophage M2 polarization, and causes pulmonary fibrosis in mice lung tissues. In macrophage-differentiated THP-1 cells, Nd2O3 (25 μg/ml) enhanced H19, SNIP1, and c-myc, reduced miR-29a-3p, accelerated macrophages M2 polarization, and stimulated fibrogenic cytokine (TGF-β1) secretion. Furthermore, the coculturing of Nd2O3-treated macrophage-differentiated THP-1 cells. And human embryonic lung fibroblast cells activated lung fibroblast, which increases the levels of collagen I, α-SMA, p-Smad2/3, and Smad4, whereas H19 knockdown or miR-29a-3p upregulation in macrophages had opposite effects. Moreover, it was revealed that H19/miR-29a-3p/SNIP1/c-myc regulatory axis is involved in pulmonary fibrosis induced by Nd2O3. Therefore, this study provides new molecular insights into the mechanism of pulmonary fibrosis by Nd2O3.

High-throughput Sequencing Reveals N6-methyladenosine-modified LncRNAs as Potential Biomarkers in Mice with Liver Fibrosis.

N6-methyladenosine (m6A) is the most frequent internal modification in eukaryotic RNA. Long noncoding RNAs (lncRNAs) are a new type of noncoding regulatory molecule with multiple cellular functions. Both are closely related to the occurrence and development of liver fibrosis (LF). However, the role of m6A-methylated lncRNAs in the progression of LF remains largely unknown. In this study, HE and Masson staining were used to observe pathological changes in the liver, m6A-modified RNA immunoprecipitation sequencing (m6A-seq) was performed to systematically evaluate the m6A modification level of lncRNAs in LF mice, meRIP-qPCR and RT-qPCR were used to detect the m6A methylation level and RNA expression level of the target lncRNAs. A total of 415 m6A peaks were detected in 313 lncRNAs in liver fibrosis tissues. There were 98 significantly different m6A peaks in LF, which were located on 84 lncRNAs, of which 45.2% of the lncRNA length was between 200-400 bp. At the same time, the first three chromosomes of these methylated lncRNAs were chromosomes 7, 5 and 1. RNA sequencing identified 154 differentially expressed lncRNAs in LF. The joint analysis of m6A-seq and RNA-seq found that there were three lncRNAs with significant changes in m6A methylation and RNA expression levels: lncRNA H19, lncRNA Gm16023 and lncRNA Gm17586. Subsequently, the verification results showed that the m6A methylation levels of lncRNA H19 and lncRNA Gm17586 were significantly increased, while that of lncRNA Gm16023 was significantly decreased, and the RNA expression of three lncRNAs was significantly decreased. Through the establishment of a lncRNA-miRNA-mRNA regulatory network, the possible regulatory relationships of lncRNA H19, lncRNA Gm16023 and lncRNA Gm17586 in LF were revealed. This study revealed the unique m6A methylation pattern of lncRNAs in LF mice, suggesting that the m6A methylation modification of lncRNAs is related to the occurrence and development of LF.

Rs217727 of lncRNA H19 is Associated with Cervical Cancer Risk in the Chinese Han Population.

Long noncoding RNAs (LncRNAs) have been revealed to involve in cervical cancer (CC) developing. The current study was designed to explore the association of SNPs (rs217727, rs2366152, rs1859168, rs10505477) located in the lncRNA H19, HOTAIR, HOTTIP and CASC8 genes with the risk of CC in a Chinese Han population. Four SNPs were selected and genotyped in 1426 participants (274 CIN patients, 448 CC patients, and 704 healthy control individuals) using MassArray. The association of these SNPs with susceptibility to CC was evaluated. Significant differences in allelic distribution of rs217727 were observed in the comparison of CC with control (P = 0.001), indicating the risk of rs217727-A allele in CC (OR = 1.33; 95% CI: 1.12-1.58). The inheritance model analysis revealed that 2AA+GA genotype represented a certain risk of CC (P = 0.001, OR = 1.35; 95% CI: 1.13-1.62). The stratified analysis revealed a risk of the rs217727-A allele for cervical squamous cell carcinoma (SCC) (P = 0.002, OR = 1.33; 95% CI: 1.11-1.60). rs217727 in lncRNA H19 exhibited a significant correlation with CC susceptibility, particularly SCC, and A/A genotype of this SNP might present as a risk in CC.

Alterations in lncRNAs H19 and TUG1 expression and their correlation with hemodynamics in myocardial infarction

Alterations in lncRNAs H19 and TUG1 expression and their correlation with hemodynamics in myocardial infarction

LncRNA H19 Inhibits Keratinocyte Cell Proliferation and Migration by Targeting miR-17-5p/RUNX1 Axis in Chronic Wounds.

The migration and proliferation of keratinocytes are critical for re-epithelization during chronic wound healing. Runt-related transcription factor 1 (RUNX1) has been indicated to repress keratinocyte proliferation. Nonetheless, the potential molecular mechanism of RUNX1 in regulating keratinocyte proliferation and migration remains unclear. Cell counting kit-8 and wound-healing assays were implemented for examining keratinocyte viability and migration, respectively. Western blotting and real-time quantitative polymerase chain reaction were utilized for quantifying protein and RNA levels. Luciferase reporter assay was employed for verifying the interaction between RUNX1, miR-17-5p, and long noncoding RNA H19. The results showed that RUNX1 depletion promoted keratinocyte proliferation and migration and repressed extracellular matrix degradation. Mechanistically, H19 upregulated RUNX1 expression by competitively absorbing miR-17-5p. Rescue experiments revealed that overexpressing RUNX1 reversed H19 silencing-mediated effects on the phenotypes of keratinocytes. In conclusion, H19 knockdown promotes keratinocyte proliferation and migration and suppresses extracellular matrix degradation via the miR-17-5p/RUNX1 axis.

Long noncoding RNA H19 promotes vascular calcification by repressing the Bax inhibitor 1/optic atrophy 1 pathway

To investigate whether long noncoding RNA H19 (lncRNA H19) induces vascular calcification by promoting calcium deposition, osteogenic differentiation and apoptosis via inhibiting the Bax inhibitor 1/optic atrophy 1 (BI-1/ OPA1) pathway. β-glycerophosphate and calcium chloride were used to induce calcification in rat vascular smooth muscle cells (VSMCs), and the effects of siH19, alone or in combination with BI-1 or OPA1 knockdown, on calcification of the cells were investigated. Osteogenic differentiation was assessed by measuring Runt-related transcription factor 2 (Runx-2) and bone morphogenetic protein 2 (BMP-2) expression with Western blotting, and cell apoptosis was evaluated by TUNEL staining and Western blotting. An ApoE-/- diabetic mouse model with high-fat feeding for 32 weeks were given an intraperitoneal injection of siH19, and the changes in calcium deposition in the aortic arch were examined using Alizarin red S staining and von Kossa staining. In rat VSMCs with calcification, the expression of lncRNA H19 was significantly increased, and the expressions of BI- 1 and OPA1 were significantly decreased. Downregulation of lncRNA H19 significantly increased the expressions of BI-1 and OPA1 proteins in the cells, and BI-1 knockdown further reduced OPA1 expression (P<0.001). The cells treated with siH19 showed total disappearance of the calcified nodules with significantly reduced expressions of Runx-2, BMP-2 and cleaved caspase-3 and a lowered cell apoptosis rate (P<0.001). Calcified nodules were again observed in the cells with lncRNA H19 knockdown combined with BI-1 or OPA1 knockdown, and the expressions of Runx-2, BMP-2, cleaved-caspase-3 and cell apoptosis rate all significantly increased (P<0.001). In the diabetic mouse model with high-fat feeding, siH19 treatment significantly reduced the calcification area and increased mRNA expressions of BI-I and OPA1 in the aortic arch. LncRNA H19 promotes vascular calcification possibly by promoting calcium deposition, osteogenic differentiation and cell apoptosis via inhibiting the BI-1/OPA1 pathway.

Serum long noncoding RNA H19/micro RNA-675-5p axis as a probable diagnostic biomarker in inflammatory bowel disease

BackgroundA significant body of research strengthens the starring role of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in the pathogenesis of inflammatory bowel disease (IBD). Here, we investigated the diagnostic utility of lncRNA H19 and miRNA-675-5p in IBD.MethodsThis study included 97 participants, thirty-five ulcerative colitis patients, thirty-two Crohn’s disease patients, and thirty IBD-free controls. History, staging, laboratory investigations, and colonoscopy were performed. Also, quantitative real-time PCR (qPCR) for revealing of lncRNA H19 and miRNA-675-5p was done.ResultsThe estimated serum levels for H19 and miRNA-675-5p in the UC and CD groups in comparison to the control group showed a high statistical difference (P = 0.0001 for each parameter). Based upon the severity of UC patients, both biomarkers showed significantly higher values between remission and moderate cases, with p-values 0.022 and 0.02, respectively. Meanwhile, in CD patients, both biomarkers revealed no statistical significance between remission and any active stage of the disease. Additionally, ROC analysis revealed that H19 could discriminate between UC and control subjects with 94.3% sensitivity and 90.0% specificity, and with 87.5% sensitivity, and 88.5% specificity in the CD group. Furthermore, miR-675-5p was able to discriminate between UC and control subjects with 85.7% sensitivity and 97.3% specificity and with 88.4% sensitivity, 95.2% specificity in the CD group. Logistic regression found a significant predictive utility of using miR-675-5p and H19 in IBD.ConclusionH19 and miRNA-675-5p can be used as diagnostic biomarkers in IBD, with superiority in UC patients with moderate activity.

Role of Lnc-RNAs in the Pathogenesis and Development of Diabetic Retinopathy.

Important advances in diabetic retinopathy (DR) research and management have occurred in the last few years. Neurodegenerative changes before the onset of microvascular alterations have been well established. So, new strategies are required for earlier and more effective treatment of DR, which still is the first cause of blindness in working age. We describe herein gene regulation through Lnc-RNAs as an interesting subject related to DR. Long non-coding RNAs (Lnc-RNAs) are non-protein-coding transcripts larger than 200 nucleotides. Lnc-RNAs regulate gene expression and protein formation at the epigenetic, transcriptional, and translational levels and can impact cell proliferation, apoptosis, immune response, and oxidative stress. These changes are known to take part in the mechanism of DR. Recent investigations pointed out that Lnc-RNAs might play a role in retinopathy development as Metastasis-Associated Lung Adenocarcinoma Transcript (Lnc-MALAT1), Maternally expressed gene 3 (Lnc-MEG3), myocardial-infarction-associated transcript (Lnc-MIAT), Lnc-RNA H19, Lnc-RNA HOTAIR, Lnc-RNA ANRIL B-Raf proto-oncogene (Lnc-RNA BANCR), small nucleolar RNA host gene 16 (Lnc-RNA SNHG16) and others. Several molecular pathways are impacted. Some of them play a role in DR pathophysiology, including the PI3K-Akt signaling axis, NAD-dependent deacetylase sirtuin-1 (Sirti1), p38 mitogen-activated protein kinase (P38/mapk), transforming growth factor beta signaling (TGF-β) and nuclear factor erythroid 2-related factor 2 (Nrf2). The way Lnc-RNAs affect diabetic retinopathy is a question of great relevance. Performing a more in-depth analysis seems to be crucial for researchers if they want to target Lnc-RNAs. New knowledge on gene regulation and biomarkers will enable investigators to develop more specialized therapies for diabetic retinopathy, particularly in the current growing context of precision medicine.

Deoxynivalenol upregulates hypoxia-inducible factor-1α to promote an "immune evasion" process by activating STAT3 signaling.

Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.

Upregulated LncRNA H19 Sponges MiR-106a-5p and Contributes to Aldosterone-Induced Vascular Calcification via Activating the Runx2-Dependent Pathway.

Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.

Structural Modifications and Novel Protein-Binding Sites in Pre-miR-675-Explaining Its Regulatory Mechanism in Carcinogenesis.

Pre-miR-675 is a microRNA expressed from the exon 1 of H19 long noncoding RNA, and the atypical expression of pre-miR-675 has been linked with several diseases and disorders including cancer. To execute its function inside the cell, pre-miR-675 is folded into a particular conformation, which aids in its interaction with several other biological molecules. However, the exact folding dynamics of pre-miR-675 and its protein-binding motifs are currently unknown. Moreover, how H19 lncRNA and pre-miR-675 crosstalk and modulate each other's activities is also unclear. The detailed structural analysis of pre-miR-675 in this study determines its earlier unknown conformation and identifies novel protein-binding sites on pre-miR-675, thus making it an excellent therapeutic target against cancer. Co-folding analysis between H19 lncRNA and pre-miR-675 determine structural transformations in pre-miR-675, thus describing the earlier unknown mechanism of interaction between these two molecules. Comprehensively, this study details the conformation of pre-miR-675 and its protein-binding sites and explains its relationship with H19 lncRNA, which can be interpreted to understand the role of pre-miR-675 in the development and progression of tumorigenesis and designing new therapeutics against cancers.

Potentilla reptans L. preconditioning regulates H19 and MIAT long noncoding RNAs in H9C2 myoblasts Ischemia/Reperfusion model

The present study aimed to evaluate the effect of the ethyl acetate fraction of P. reptans root (PEF) preconditioning on expressions of lncRNAs H19 and MIAT in H9C2 myoblasts I/R injury.H9C2 cells were treated with different concentrations ranging from (10–400 µg/ml) of PEF for 24 h, followed by simulation of I/R condition. For I/R experiments, H9C2 cells were subjected with the oxygen and glucose deprivation for 2 h.H9C2 cell viability was significantly enhanced by PEF preconditioning under I/R condition in a concentration-dependent manner up to 200 µg/ml as a EC50. The PEF significantly diminished the expression of lncRNA MIAT and rate of apoptosis against the I/R group. In addition, PEF pretreated before stimulation I/R condition increased H19 expression compared to the normal PEF group with no statistically significant differences between groups. Hence, the results suggest that PEF can protect cardiomyocytes during hypoxia-induced myocardial cell injury by targeting specific involved genes.

Six polymorphisms in the lncRNA H19 gene and the risk of cancer: a systematic review and meta-analysis

BackgroundNumerous studies have demonstrated long noncoding RNA (lncRNA) play an important role in the occurrence and progression of cancer, and single nucleotide polymorphisms (SNPs) located in lncRNA are considered to affect cancer suspensibility. Herein, a meta-analysis was carried out to better assess the relationship of H19 polymorphisms and cancer susceptibility.MethodsA literature search was conducted through using PubMed, EMBASE, and Web of Science databases to obtain relevant publications before Aug 23, 2022. The reference lists of the retrieved studies were also investigated to identify additional relevant articles. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to appraise the risk of various cancers.ResultsThere appeared to be a remarkable correlation between the rs2107425 variation and decreased cancer risk among Caucasians. Nevertheless, the rs217727 polymorphism was significantly associated with an increased risk of lung cancer, hepatocellular carcinoma and oral squamous cell carcinoma. Also, we found a significant correlation between the rs2839698 polymorphism and increased cancer risk among Asians, gastric cancer, hepatocellular carcinoma, hospital-based control and larger simple size subgroups, respectively. Similarly, the rs3741219 mutation was notably related to cancer risk in higher quality score. As for rs3024270 polymorphism, the homozygous model was markedly linked to cancer risk in overall analysis and population-based controls. There was no significant association between the rs3741216 polymorphism and cancer risk.ConclusionH19 rs2839698 and rs3024270 were closely associated with overall cancer risk. H19 rs2107425 was related to lower cancer risk among Caucasians, while the rs2839698 was related to increased cancer risk among Asians. Our results supported that H19 SNPs were significantly correlated with cancer risk.

LncRNA H19 aggravates primary graft dysfunction after lung transplantation via KLF5-mediated activation of CCL28

The present study aims to elucidate the possible involvement of H19 in primary graft dysfunction (PGD) following lung transplantation (LT) and the underlying mechanism. The transcriptome data were obtained through high-throughput sequencing analysis, and the differential long noncoding RNAs and messenger RNAs were screened for coexpression analysis. The interaction among H19, KLF5 and CCL28 was analyzed. A hypoxia-induced human pulmonary microvascular endothelial cell injury model was established, in which H19 was knocked down to elucidate its effect on the lung function, inflammatory response, and cell apoptosis. An orthotopic left LT model was constructed for in vivo mechanistic validation. High-throughput transcriptome sequencing analysis revealed the involvement of the H19/KLF5/CCL28 signaling axis in PGD. Silencing of H19 reduced inflammatory response and thus improved PGD. CCL28 secreted by human pulmonary microvascular endothelial cells after LT recruited neutrophils and macrophages. Mechanistic investigations indicated that H19 augmented the expression of CCL28 by binding to the transcription factor KLF5. Abundant expression of CCL28 reversed the alleviating effect of H19 silencing on PGD. In conclusion, the results point out that H19 exerts a promoting effect on PGD through increasing KLF5 expression and the subsequent CCL28 expression. Our study provides a novel insight into the mechanism of action of H19.

E7 Peptide Enables BMSC Adhesion and Promotes Chondrogenic Differentiation of BMSCs Via the LncRNA H19/miR675 Axis.

Therapeutic strategies based on utilizing endogenous BMSCs have been developed for the regeneration of bone, cartilage, and ligaments. We previously found that E7 peptide (EPLQLKM) could enhance BMSC homing in bio-scaffolds and, therefore, promote cartilage regeneration. However, the profile and mechanisms of E7 peptide in cartilage regeneration remain elusive. In this study, we examined the effect of E7 peptide on the BMSC phenotype, including adhesion, viability and chondrogenic differentiation, and its underlying mechanism. The konjac glucomannan microsphere (KGM), a carrier material that is free of BMSC adhesion ability, was used as the solid base of E7 peptide to better explore the independent role of E7 peptide in BMSC behavior. The results showed that E7 peptide could support BMSC adhesion and viability in a comparable manner to RGD and promote superior chondrogenic differentiation to RGD. We examined differentially expressed genes of BMSCs induced by E7 compared to RGD. Subsequently, a real-time PCR validated the significantly upregulated expression of lncRNA H19, and the knockdown of lncRNA H19 or miR675, a downstream functional unit of H19, could significantly obscure the chondrogenic differentiation induced by E7. In conclusion, this study confirmed the independent role of E7 in the adhesion and viability of BMSCs and revealed the pro-chondrogenic effect of E7 on BMSCs via the H19/miR675 axis. These results could help establish new therapeutic strategies based on employing endogenous BMSCs for cartilage tissue regeneration.

M1 macrophage-derived exosomes promote autoimmune liver injury by transferring long noncoding RNA H19 to hepatocytes.

Exosomes mediate intercellular communication by transmitting active molecules. The function of long noncoding RNA (lncRNA) H19 in autoimmune liver injury is unclear. Concanavalin A (ConA)-induced liver injury is well-characterized immune-mediated hepatitis. Here, we showed that lncRNA H19 expression was increased in the liver after ConA treatment, accompanied by increased exosome secretion. Moreover, injection of AAV-H19 aggravated ConA-induced hepatitis, with an increase in hepatocyte apoptosis. However, GW4869, an exosome inhibitor, alleviated ConA-induced liver injury and inhibited the upregulation of lncRNA H19. Intriguingly, lncRNA H19 expression in the liver was significantly downregulated, after macrophage depletion. Importantly, the lncRNA H19 was primarily expressed in type I macrophage (M1) and encapsulated in M1-derived exosomes. Furthermore, H19 was transported from M1 to hepatocytes via exosomes, and exosomal H19 dramatically induced hepatocytes apoptosis both in vitro and vivo. Mechanistically, H19 upregulated the transcription of hypoxia-inducible factor-1 alpha (HIF-1α), which accumulated in the cytoplasm and mediated hepatocyte apoptosis by upregulating p53. M1-derived exosomal lncRNA H19 plays a pivotal role in ConA-induced hepatitis through the HIF-1α-p53 signaling pathway. These findings identify M1 macrophage-derived exosomal H19 as a novel target for the treatment of autoimmune liver diseases.