[Corrigendum] Long non­coding RNA H19 regulates LASP1 expression in osteosarcoma by competitively binding to miR­29a­3p.

Following the publication of the above article, an interested reader drew to the authors' attention that, for the cell invasion assay experiments shown in Fig. 2D on p. 5, there appeared to be an overlapping section of data comparing between the Sao­2/Control and MG­63/siH19 panels, such that these data had been derived from the same original source where the panels were intended to portray the results from differently performed epxeriments. Upon examining their original data, the authors have realized that, in Fig. 2D, an inadvertent error was made in the copying and pasting of the two groups of pictures, resulting in the image belonging to the Saos­2 cell experiment being mistakenly pasted as the image for the MG­63 cell experiment. The authors carefully checked the original pictures and the experimental record, and found that the two groups of cells were close to the same morphology. The corrected version of Fig. 2, containing data from an alternatively performed experiment for Fig. 2D, is shown on the next page. Note that the error did not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this. They also apologize to the readership for any inconvenience caused. [Oncology Reports 46: 207, 2021; DOI: 10.3892/or.2021.8158].

Hypomethylation of the LncRNA H19 promoter accelerates osteogenic differentiation of vascular smooth muscle cells by activating the Erk1/2 pathways.

OBJECTIVE: Vascular calcification is a common chronic kidney disease complication. This study aimed to investigate the function of long non-coding RNA (LncRNA) H19 in vascular calcification to explore new therapeutic strategies. METHODS: We induced osteogenic differentiation and calcification of vascular smooth muscle cells (VSMCs) using ß-glycerophosphate. Then, we detected the LncRNA H19 promoter methylation status and Erk1/2 pathways using methylation-specific polymerase chain reaction and western blotting, respectively. RESULTS: Compared with the control group, high phosphorus levels induced VSMC calcification, accompanied by increases in LncRNA H19 and the osteogenic marker Runx2 and reduction of the contractile phenotype marker SM22a. LncRNA H19 knockdown inhibited osteogenic differentiation and calcification of VSMCs. However, the suppressed role of VSMC calcification caused by shRNA H19 was partially reversed by simultaneous activation of the Erk1/2 pathways. Mechanically, we found that the methylation rate of CpG islands in the LncRNA H19 promoter region was significantly lower in the high-phosphorus group, and the hypomethylation state elevated LncRNA H19 levels, which in turn regulated phosphorylated Erk1/2 expression. CONCLUSIONS: LncRNA H19 promoted osteogenic differentiation and calcification of VSMCs by regulating the Erk1/2 pathways. Additionally, hypomethylation of LncRNA H19 promoter CpG islands upregulated LncRNA H19 levels and subsequently activated Erk1/2 phosphorylation.

Danhongqing formula alleviates cholestatic liver fibrosis by downregulating long non-coding RNA H19 derived from cholangiocytes and inhibiting hepatic stellate cell activation.

OBJECTIVE: This study explores the mechanism of action of Danhongqing formula (DHQ), a compound-based Chinese medicine formula, in the treatment of cholestatic liver fibrosis. METHODS: In vivo experiments were conducted using 8-week-old multidrug resistance protein 2 knockout (Mdr2-/-) mice as an animal model of cholestatic liver fibrosis. DHQ was administered orally for 8 weeks, and its impact on cholestatic liver fibrosis was evaluated by assessing liver function, liver histopathology, and the expression of liver fibrosis-related proteins. Real-time polymerase chain reaction, Western blot, immunohistochemistry and other methods were used to observe the effects of DHQ on long non-coding RNA H19 (H19) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in the liver tissue of Mdr2-/- mice. In addition, cholangiocytes and hepatic stellate cells (HSCs) were cultured in vitro to measure the effects of bile acids on cholangiocyte injury and H19 expression. Cholangiocytes overexpressing H19 were constructed, and a conditioned medium containing H19 was collected to measure its effects on STAT3 protein expression and cell activation. The intervention effect of DHQ on these processes was also investigated. HSCs overexpressing H19 were constructed to measure the impact of H19 on cell activation and assess the intervention effect of DHQ. RESULTS: DHQ alleviated liver injury, ductular reaction, and fibrosis in Mdr2-/- mice, and inhibited H19 expression, STAT3 expression and STAT3 phosphorylation. This formula also reduced hydrophobic bile acid-induced cholangiocyte injury and the upregulation of H19, inhibited the activation of HSCs induced by cholangiocyte-derived conditioned medium, and decreased the expression of activation markers in HSCs. The overexpression of H19 in a human HSC line confirmed that H19 promoted STAT3 phosphorylation and HSC activation, and DHQ was able to successfully inhibit these effects. CONCLUSION: DHQ effectively alleviated spontaneous cholestatic liver fibrosis in Mdr2-/- mice by inhibiting H19 upregulation in cholangiocytes and preventing the inhibition of STAT3 phosphorylation in HSC, thereby suppressing cell activation. Please cite this article as: Li M, Zhou Y, Zhu H, Xu LM, Ping J. Danhongqing formula alleviates cholestatic liver fibrosis by downregulating long non-coding RNA H19 derived from cholangiocytes and inhibiting hepatic stellate cell activation. J Integr Med. 2024; 22(2): 188-198.

Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription.

BACKGROUND: Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whether tamoxifen played an anti-fibrotic role by affecting transcription factor ESR1. METHODS: ESR1 expression was detected in the human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks to establish PD-induced peritoneal fibrosis. Tamoxifen was administrated by daily gavage, at the dose of 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were performed to validate ESR1 bound H19 promoter. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of H19 on the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells (HPMCs). Intraperitoneal injection of nanomaterial-wrapped 2'-O-Me-modified small interfering RNA was applied to suppress H19 in the mouse peritoneum. RNA immunoprecipitation and RNA pull-down assays demonstrated binding between H19 and p300. Exfoliated peritoneal cells were obtained from peritoneal dialysis effluent to analyze the correlations between ESR1 (or H19) and peritoneal solute transfer rate (PSTR). RESULTS: ESR1 was increased significantly in the peritoneum after long-term exposure to PD dialysate. Tamoxifen treatment ameliorated high glucose-induced MMT of HPMCs, improved ultrafiltration rate, and decreased PSTR of mouse peritoneum. Tamoxifen reduced the H19 level by decreasing the ESR1 transcription of H19. Depletion of H19 reversed the pro-fibrotic effect of high glucose while ectopic expression of H19 exacerbated fibrotic pathological changes. Intraperitoneal injection of nanomaterial-wrapped 2'-O-Me-modified siRNAs targeting H19 mitigated PD-related fibrosis in mice. RNA immunoprecipitation (RIP) and RNA pull-down results delineated that H19 activated VEGFA expression by binding p300 to the VEGFA promoter and inducing histone acetylation of the VEGFA promoter. ESR1 and H19 were promising targets to predict peritoneal function. CONCLUSIONS: High glucose-induced MMT of peritoneal mesothelial cells in peritoneal dialysis via activating ESR1. In peritoneal mesothelial cells, ESR1 transcribed the H19 and H19 binds to transcription cofactor p300 to activate the VEGFA. Targeting ESR1/H19/VEGFA pathway provided new hope for patients undergoing peritoneal dialysis.

[Corrigendum] Roles of the H19/microRNA­675 axis in the proliferation and epithelial­mesenchymal transition of human cutaneous squamous cell carcinoma cells.

Following the publication of the above paper, a concerned reader drew to the authors' attention that, in Fig. 4C on p. 8, the 'Invasion, miR­675­inhibitor' data panel appeared to contain an overlapping section with the 'Invasion, mi­R675­inhibitor + pcDNA3.1­H19' data panel for the SCL1 cell line, such that the data were likely to have been derived from the same original source, even though they were intended to show the results from differently performed experiments. After having examined the original data, the authors also realized that the 'Inhibitor­NC' and 'miR­675­inhibitor' data panels showing the migration assay experiments for the A431 cell line in the same figure part had also inadvertently been derived from the same original source. After having been granted permission from the Editor of Oncology Reports to repeat the experiments shown in Fig. 4C, the revised version of Fig. 4, incorporating the new data for Fig. 4C, is shown on the next page. Note that these errors did not affect the overall conclusions reported in the study, and the repeated experiment yielded similar results to those obtained originally. The authors are grateful to the Editor for allowing them the opportunity to publish this corrigendum, and all the authors agree with the publication of this; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [Oncology Reports 45: 39, 2021; DOI: 10.3892/or.2021.7990].

Long Non-coding RNA H19 Recruits NFYB to Activate MBTD1 and Regulate Doxorubicin Resistance in Lymphoma Cells.

Doxorubicin (DOX) is a first-line chemo drug for lymphoma treatment. DOX resistance remains a major obstacle leading to treatment failure. This study explores the interactions of the long non-coding RNA H19 (H19)/nuclear transcription factor Y subunit beta (NFYB)/mbt domain containing 1 (MBTD1) axis in DOX resistance in lymphoma cells. Bioinformatics prediction indicated a correlation between MBTD1 and advanced lymphoma stage. Elevated MBTD1 expression was detected in lymphoma cells compared to normal lymphocytes, especially in DOX-resistant lymphoma cells (OCI-Ly8/DOX and SU-DHL-2/DOX). MBTD1 silencing weakened DOX resistance in the drug-resistant cells. Bioinformatics analysis further indicated a candidate H19/NFYB/MBTD1 axis in lymphoma. Luciferase and ChIP-qPCR assays validated that NFYB bound to MBTD1 promoter to activate the MBTD1 transcription. H19 recruited NFYB to increase MBTD1 expression without altering NFYB levels. H19 silencing suppressed growth of the DOX-resistant cells in vitro and in vivo. Either NFYB or MBTD1 activation restored the DOX resistance and malignant growth of the cells. In summary, this paper demonstrates that H19 activates MBTD1 transcription in a NFYB-dependent manner to promote DOX resistance in lymphoma cells.

Effects of H19/SAHH/DNMT1 on the oxidative DNA damage related to benzo[a]pyrene exposure.

The mechanisms that long noncoding RNA (lncRNA) H19 binding to S-adenosylhomocysteine hydrolase (SAHH) interacted with DNA methyltransferase 1 (DNMT1) and then regulated DNA damage caused by polycyclic aromatic hydrocarbons (PAHs) remain unclear. A total of 146 occupational workers in a Chinese coke-oven plant in 2014 were included in the final analyses. We used high-performance liquid chromatography mass spectrometry (HPLC-MS) equipped to detect urine biomarkers of PAHs exposure, including 2-hydroxynaphthalene (2-NAP), 2-hydroxyfluorene (2-FLU), 9-hydroxyphenanthrene (9-PHE) and 1-hydroxypyrene (1-OHP). The levels of SAM and SAH in plasma were detected by HPLC-ultraviolet. By constructing various BEAS-2B cell models exposed to 16 µM benzo[a]pyrene (BaP) for 24 h, toxicological parameters reflecting distinct mechanisms were evaluated. We documented that urinary 1-hydroxypyrene (1-OHP) levels were positively associated with blood H19 RNA expression (OR: 1.51, 95% CI: 1.03-2.19), but opposite to plasma SAHH activity (OR: 0.63, 95% CI: 0.41-0.98) in coke oven workers. Moreover, by constructing various BEAS-2B cell models exposed to benzo[a]pyrene (BaP), we investigated that H19 binding to SAHH exaggerated DNMT1 expressions and activity. Suppression of H19 enhanced the interaction of SAHH and DNMT1 in BaP-treated cells, decreased eight-oxoguanine DNA glycosylase 1 (OGG1) methylation, reduced oxidative DNA damage and lessened S phase arrest. However, SAHH or DNMT1 single knockdown and SAHH/DNMT1 double knockdown showed the opposite trend. A H19/SAHH/DNMT1 axis was involved in OGG1 methylation, oxidative DNA damage and cell cycle arrest by carcinogen BaP.

Targeting non-coding RNA H19: A potential therapeutic approach in pulmonary diseases.

Non-coding RNA is still one of the most popular fields in biology research. In recent years, people paid more attention to the roles of H19 in lung diseases, which expressed abnormally in various pathological process. Therefore, this review focus on the regulatory role of H19 in asthma, pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), lung injury, pneumonia, lung cancer, etc. And the potential therapeutic agents and molecular treatments of H19 are collected. The aim is to demonstrate its underlying mechanism in pulmonary diseases and to guide the basic research targeting H19 into clinical drug translation.

HHLA2 promotes tumor progression by long non­coding RNA H19 in human gallbladder cancer.

Advanced gallbladder cancer (GBC) is one of the most malignant of all types of biliary tract cancers that is associated with poor prognosis and high mortality. Accumulating evidence suggest that the B7 family of proteins serve an essential role in various types of cancers, including GBC. However, the potential function and regulatory mechanism of human endogenous retrovirus­H long terminal repeat­associating protein 2 (HHLA2; also known as B7­H7 or B7H5) in GBC remain poorly understood. In the present study, immunohistochemistry was used to examine the expression pattern of HHLA2 in samples from 89 patients with GBC. The possible association between HHLA2 expression and the clinicopathological parameters, including prognosis, were then assessed. Using lentiviruses, overexpression of HHLA2 plasmid or short­hairpin RNA (shRNA) of HHLA2 were transfected into GBC­SD cells to overexpress or knock down HHLA2 expression, respectively. The effects of HHLA2 overexpression and knockdown on the epithelial­mesenchymal transition (EMT) process on GBC­SD cells were measured by the western blotting and immunofluorescence staining of collagen I, N­cadherin, E­cadherin, vimentin and α­SMA. By contrast, changes in cell proliferation were measured using EdU assay. Cell invasion and migration were assessed using Transwell and wound­healing assays, respectively. In addition, a xenograft mouse model was established to evaluate the tumorigenic ability of the GBC cell line in vivo after stable transfection with lentivirus for HHLA2 overexpression or shRNA for HHLA2 knockdown. The regulatory relationships among TGF­ß1, long non­coding RNA (lncRNA) H19 (H19) and HHLA2 were then investigated. The mRNA expression of lncRNA H19 were assessed using reverse transcription­quantitative PCR, whereas the expression levels of HHLA2 were detected by western blotting and immunofluorescence staining. HHLA2 expression was found to gradually increase as the stages of the GBC samples become more advanced. In addition, the expression level of HHLA2 was calculated to be positively associated with the Nevin stage, American Joint Committee on Cancer stage, tumor invasion and regional lymph node metastasis but was negatively associated with the overall patient survival (OS). In vitro experiments demonstrated that overexpression of HHLA2 promoted GBC migration, invasion, proliferation and EMT, whereas in vivo experiments found a promoting role of HHLA2 overexpression on GBC tumor growth. After transfection with lentiviruses encoding the overexpression plasmid of lncRNA H19, GBC migration, invasion, proliferation and EMT were increased. By contrast, knocking down HHLA2 expression suppressed TGF­ß1­ or lncRNA H19 overexpression­induced GBC migration, invasion, proliferation and EMT. In addition, HHLA2 knockdown significantly reduced the sizes of the GBC tumors in vivo. These results suggest that HHLA2 overexpression can promote GBC progression. Conversely, ablation of HHLA2 expression inhibited both TGF­ß1­ and lncRNA H19­induced GBC progression, suggesting that HHLA2 is a potential therapeutic target for this disease.

Advanced glycation end products induce Aß1-42 deposition and cognitive decline through H19/miR-15b/BACE1 axis in diabetic encephalopathy.

OBJECTIVE: Diabetic encephalopathy (DE), a chronic complication of diabetes, is characterized by decline of cognitive function. The molecular mechanism of DE remains unclear. The purpose of this study is to evaluate the roles of advanced glycation end products (AGEs) in the pathogenesis of DE and investigate its underlying mechanisms in this process. METHODS: DE rats were developed by incorporating a high-fat diet and streptozotocin injection followed by the Morris Water Maze test. HT-22 cells were used to mimic the in vitro neuronal injuries of DE. Expression levels of long non-coding RNA H19, miR-15b and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA in the hippocampus of DE rats or HT-22 cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The levels of BACE1 proteins were analyzed by western blotting or immunohistochemical staining. The contents of Aß1-42 in supernatant of the cell culture were analyzed by enzyme-linked immu-nosorbent assay (ELISA). The relationship between H19 or BACE1 and miR-15b was verified with dual-luciferase reporter assay. RESULTS: We found that the accumulation of Aß1-42 and the phosphorylation of Tau (Ser404) were increased in the hippocampus CA3 regionof DE rats. MiR-15b was downregulated while H19 and BACE1 were upregulated in the hippocampus CA3 regionof DE rats and AGEs-treated HT-22 cells. The expression of BACE1 protein was negatively regulated by miR-15b at the post-transcriptional level in HT-22 cells. In vivo, administration of miR-15b mimics by the intranasal delivery markedly decreased the BACE1 protein in hippocampal CA3 region and improved the cognitive decline in DE rats. Besides, the luciferase activity assay confirmed the binding site of miR-15b to both the 3'-untranslated region (3'-UTR) of BACE1 mRNA and H19. Then, miR-15b inhibitor reversed H19 knockdown-mediated decrease of Aß1-42 level in AGEs-treated HT-22 cells. CONCLUSION: These results suggested that AGEs induced Aß1-42 deposition andcognitive decline through H19/miR-15b/ BACE1 axis in DE.

Long Non-Coding RNA H19 Prevents Lens Fibrosis through Maintaining Lens Epithelial Cell Phenotypes.

The integrity of lens epithelial cells (LECs) lays the foundation for lens function and transparency. By contrast, epithelial-mesenchymal transition (EMT) of LECs leads to lens fibrosis, such as anterior subcapsular cataracts (ASC) and fibrotic forms of posterior capsule opacification (PCO). However, the underlying mechanisms remain unclear. Here, we aimed to explore the role of long non-coding RNA (lncRNA) H19 in regulating TGF-ß2-induced EMT during lens fibrosis, revealing a novel lncRNA-based regulatory mechanism. In this work, we identified that lncRNA H19 was highly expressed in LECs, but downregulated by exposure to TGF-ß2. In both human lens epithelial explants and SRA01/04 cells, knockdown of H19 aggravated TGF-ß2-induced EMT, while overexpressing H19 partially reversed EMT and restored lens epithelial phenotypes. Semi-in vivo whole lens culture and H19 knockout mice demonstrated the indispensable role of H19 in sustaining lens clarity through maintaining LEC features. Bioinformatic analyses further implied a potential H19-centered regulatory mechanism via Smad-dependent pathways, confirmed by in vitro experiments. In conclusion, we uncovered a novel role of H19 in inhibiting TGF-ß2-induced EMT of the lens by suppressing Smad-dependent signaling, providing potential therapeutic targets for treating lens fibrosis.

Mechanism of lncRNA-H19 in Intestinal Injury of Mice with Ulcerative Colitis.

INTRODUCTION: Ulcerative colitis (UC) is a debilitating condition of the gastrointestinal system, and long non-coding RNA (lncRNA)-H19 emerges as a crucial player in inflammatory diseases. This study is designed to evaluate the mechanism of H19 in intestinal injury of UC mice and hint at a novel target for UC treatment. METHODS: UC mouse model was established, followed by injection of shH19, antagomir-331-3p, and tumor necrosis factor receptor-associated factor 4 (TRAF4) overexpression vector. H19, miR-331-3p, and TRAF4 expressions were detected via reverse transcription quantitative polymerase chain reaction. Intestinal injury was appraised via disease activity index (DAI), hematoxylin-eosin staining, and histopathological scoring. Interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-10 levels were detected via enzyme-linked immunosorbent assay. Binding relationships of H19 and miR-331-3p and TRAF4 were verified. RESULTS: H19 was highly expressed in colon tissues. Silencing H19 attenuated intestinal injury of UC mice, manifested by reductions in weight loss, DAI, histopathological scores, IL-1ß and TNF-α, and increases in colon length and IL-10. Mechanically, lncRNA-H19 is bound to miR-331-3p to inhibit its expression. TRAF4 is a target of miR-331-3p. Inhibition of miR-331-3p or overexpression of TRAF4 could reverse the alleviating role of lncRNA-H19 in intestinal injury of UC mice. CONCLUSION: LncRNA-H19 was highly expressed in UC mice and bound to miR-331-3p to promote TRAF4 transcription, thereby aggravating intestinal injury.

Long Non-coding RNA H19 Deteriorates Hypoxic-Ischemic Brain Damage by Interacting with MicroRNA-140-5p and STAT3.

OBJECTIVE: Even though extensive studies have surveyed long non-coding RNA (lncRNA)-related networks in hypoxic-ischemic brain damage (HIBD), the concrete function of lncRNA H19 (H19) in HIBD is still in ambiguity. Therein, this work intends to decipher H19-related network of microRNA (miR)-140-5p and signal transducer and activator of transcription 3 (STAT3) in HIBD. METHODS: Brain microvascular endothelial cells (BMECs) from BALB/c mice were isolated and induced by oxygen glucose deprivation (OGD). OGD-induced BMECs were transfected with depleted or restored H19, miR-140-5p or STAT3, and cell apoptosis, migration and angiogenesis were examined. H19, miR-140-5p and STAT3 expression and their internal connections were tested. RESULTS: H19 and STAT3 were overexpressed while miR-140-5p was down-regulated in OGD-induced BMECs. H19 or STAT3 knockdown, or miR-140-5p restoration repressed apoptosis and improved migration and angiogenesis of OGD-induced BMECs. MiR-140-5p restoration negated the impacts of up-regulated H19 on OGD-induced BMECs. H19 bound to miR-140-5p to modulate STAT3 expression. CONCLUSION: The work illustrates that depleting H19 or STAT3 or restoring miR-140-5p attenuates HIBD and supplies a novel perspective for HIBD management.

Anti-senescent effects of long non-coding RNA H19 on human dermal fibroblast cells through impairing microRNA-296-5p-dependent inhibition of IGF2.

Cell experiments were implemented in this research to investigate the molecular mechanism by which H19 affected senescence of human DFs (HDFs). By conducting luciferase assay, we analyzed the relations between H19 and miR-296-5p and between miR-296-5pand IGF2. Ectopic expression and silencing experiments were performed to assess their effects on the growth and senescence of HDFs. ß-Gal, DUSP6, p21, and p16 were utilized as markers for evaluating cell senescence. H19 and IGF2 were downregulated but miR-296-5p was upregulated in the aging HDFs. Mechanistic analysis showed that H19 bound to miR-296-5p to upregulate the miR-296-5p target, IGF2, and that activating the PI3K/mTOR pathway and upregulating AQP3 expression in HDFs. H19 upregulation or miR-296-5p downregulation facilitated the viability but restrained the senescence of HDFs, accompanied with reductions in the expression of cell senescence markers. Knockdown of IGF2 expression counteracted the effects induced by miR-296-5p inhibition, while inhibited PI3K/mTOR pathway reversed the impacts of IGF2 overexpression on HDFs. In summary, our data provided a novel insight into the anti-senescent mechanism of H19 in HDFs, offers a better understanding of cellular mechanisms during the process of aging.

Effects and early diagnostic value of lncRNA H19 on sepsis-induced acute lung injury.

Sepsis is an immune disease induced by microbial invasion. The molecular mechanism and value of long non-coding H19 (lncRNA H19) in sepsis remain largely unknown. The present study aimed to investigate the effects and early diagnostic value of lncRNA H19 on sepsis-induced acute lung injury (ALI). Serum samples from 85 septic patients and 76 healthy individuals were collected, and the expression of lncRNA H19 was assessed by the quantitative polymerase chain reaction (qPCR). Sprague-Dawley (SD) rats were subjected to cecal ligation and puncture (CLP) in order to construct models of sepsis-induced ALI. A total of 18 successfully modeled rats were randomly allocated into an lncRNA H19-ad group and a model group, and another 9 healthy SD rats from the same batch were selected as a control group. The samples of serum and lung tissue were collected. lncRNA H19 expression was quantified by qPCR, and levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-17, caspase-3, caspase-9, B-cell lymphoma-2 (Bcl-2), and BCL2-associated X (Bax) were measured by western blotting. A receiver operating characteristic (ROC) curve was employed to assess the diagnostic value of lncRNA H19 for septic patients. lncRNA H19 was downregulated in sepsis. Upregulation of lncRNA H19 inhibited TNF-α, IL-6, IL-17, caspase-3, caspase-9 and Bax and increased Bcl-2. The AUC of lncRNA H19 for early diagnosis of sepsis was 0.8197 (95% CI, 0.77 to 0.91). lncRNA H19 alleviated sepsis-induced ALI by inhibiting pulmonary apoptosis and inflammation, serving as a biochemical marker and therapeutic target for sepsis.

Long non-coding RNA H19 mediates N-acetyltransferase 1 gene methylation in the development of tamoxifen resistance in breast cancer.

Long non-coding RNA (lncRNA) H19 is associated with proliferation, invasion and metastasis in numerous types of cancer. H19 lncRNA has been demonstrated to be an estrogen-inducible gene, the expression of which is significantly increased in tamoxifen (TAM)-resistant MCF-7 breast cancer cells. The aim of the present study was to investigate the role and molecular mechanism of lncRNA H19 in the development of TAM resistance. TAM-resistant MCF-7 (MCF-7R) cells were developed by the treatment of wild-type MCF-7 cells with 4-hydroxytamoxifen. Analysis of H19 expression in the cells indicated that upregulation of H19 contributed to the resistance of the MCF-7R cell line. Furthermore, when H19 was knocked down in the MCF-7R cells, the sensitivity to 4-hydroxytamoxifen was markedly restored. The results further demonstrated that N-acetyltransferase 1 (NAT1) may serve an important role in TAM-resistant cells, as NAT1 expression was notably downregulated in the MCF-7R cells but significantly elevated following the knockdown of H19. In addition, lower expression of NAT1 and higher expression of H19 were indicated to be associated with poor prognosis in patients with breast cancer treated with TAM. The results of bisulfite genomic sequencing PCR analysis indicated that the methylation rate of NAT1 in MCF-7R cells was significantly higher compared with that in MCF-7 cells, while the methylation rate of NAT1 in TAM-resistant cells transfected with small interfering RNA against H19 was significantly lower than that in the corresponding untransfected cells. Therefore, the present study suggests that the H19 gene regulates NAT1 expression in TAM-resistant cells via the mediation of NAT1 promoter methylation.

Long non­coding RNA H19 regulates LASP1 expression in osteosarcoma by competitively binding to miR­29a­3p.

A prevalent type of bone tumor, osteosarcoma (OS) is prone to pulmonary metastasis, which results in a high relapse risk and poor prognosis for patients. The progression of OS is significantly associated with the expression of long non­coding (lnc)RNA H19. To the best of our knowledge, however, the exact molecular mechanism of this lncRNA has not been fully investigated. The present study verified the effect of H19 on the proliferation and invasion of osteosarcoma cells via in vivo and in vitro experiments, including Cell Counting Kit­8, western blot, reverse transcription­quantitative PCR, wound healing and Transwell assays. H19 was found to be overexpressed in OS compared with corresponding normal adjacent tissue. In addition, H19 served as a competing endogenous ncRNA targeting microRNA­29a­3p and activating LIM and SH3 domain protein 1 and modulating the OS cell phenotype. The results of the present study may improve understanding of OS pathogenesis.

Long non-coding RNA H19 and the underlying epigenetic function in response to DNA damage of lung cancer cells.

The purpose of the current study is to clarify the epigenetic function of long non-coding RNA (lncRNA) H19 in lung cancer as well as the relevant regulatory mechanism. We first determined H19 upregulation in A549 cells. DNA damage model was established in A549 cells by exposure to X-ray and then ionizing radiation (IR). The degree of DNA damage in the IR cell model was assessed by Comet assay. Gain- and loss-of-function assays were employed to clarify the roles of H19 and miR-675 in DNA damage of A549 cells. The results demonstrated that H19 knockdown inhibited the response of lung cancer cells to IR-induced DNA damage but promoted the damage repair. H19 could interact with miR-675, whereby aggravating IR-induced DNA damage. Furthermore, p62 was identified to be a downstream gene positively regulated by miR-675 while APEX1 was a target gene negatively regulated by miR-625-5p. Meanwhile, silencing of H19 could inhibit APEX1 expression by upregulating miR-625-5p, thereby accelerating DNA damage repair in A549 cells. In conclusion, H19 could function as a modulator of DNA damage response in lung cancer cells.

Long non-coding RNA H19 acts as a microRNA-194 sponge to inhibit the apoptosis and promote the proliferation of hypertrophic scar fibroblasts.

The effects of long non-coding RNAs (lncRNAs) on the proliferation of hypertrophic scars have been described, however, the underlying mechanisms are not well characterized. The present study aimed to investigate the mechanisms of lncRNA H19 in hypertrophic scars. The effects of the lncRNA H19 on the proliferation and apoptosis of hypertrophic scar fibroblasts (HSFs) were analyzed using 5'-ethynyl-2'-deoxyuridine staining, flow cytometry, and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The results revealed H19 promoted the proliferation and inhibited the apoptosis in HSF. In addition, the binding associations between H19 and microRNA-194 (miR-194), and miR-194 and insulin-like growth factor I receptor (IGF1R) were identified using bioinformatics screening and verified using dual-luciferase assays. Furthermore, the effects of the IGF1R knockdown on H19-induced HSF phenotypes and regulation over the p38 MAPK pathway were determined. Mechanistically, miR-194 was identified as the downstream effector of the H19-mediated phenotypes of HSFs through its ability to directly target IGF1R, thus modulating the p38 MAPK signaling pathway. In conclusion, the findings suggested that H19 may inhibit the apoptosis and promote the proliferation of HSFs through the miR-194/IGF1R/p38 MAPK signaling axis, thereby contributing to the progression of hypertrophic scars. These findings may provide novel targets for the treatment of hypertrophic scars.

Long non-coding RNA-H19 promotes ovarian cancer cell proliferation and migration via the microRNA-140/Wnt1 axis.

To explore the effect and underlying molecular mechanism of long non-coding RNA (lncRNA)-H19 on ovarian cancer (OC) cells, a total of 41 cases of OC and adjacent normal tissues were collected. H19 and microRNA (miR)-140 expressions in OC tissues and cells were detected using quantitative real-time polymerase chain reaction (qRT-RCR). The correlation between H19 expression and prognosis of OC patient was analyzed. siRNA (si)-H19 and si-negative control (NC) were transfected into OC cells. Cell proliferation was checked by cell counting kit-8 assay and colony formation assay, and cell migration and invasion were analyzed via Transwell assay. The targeted binding relationship between H19 and miR-140 was predicted and verified, miR-140 downstream gene was predicted and Wnt1 was screened out. The impact of in-miR-140 on the si-H19-induced decreased OC cell proliferation and migration was evaluated. H19 expression was upregulated in OC tissues and cells, and its overexpression was associated with a poor prognosis of OC. si-H19 remarkably reduced OC cell proliferation and migration. H19 upregulated Wnt1 expression through targeting miR-140 in OC cells. Altogether, miR-140 was notably downregulated in OC, and in-miR-140 partially inhibited the si-H19-induced decrease of OC cell proliferation and migration. H19 competitively bound to miR-140 to upregulate Wnt1, thereby promoting OC cell proliferation and migration.