Therapeutic potential of ADSC-EV-derived lncRNA DLEU2: A novel molecular pathway in alleviating sepsis-induced lung injury via the miR-106a-5p/LXN axis.

This study investigates the molecular mechanisms by which extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSCs) promote M2 polarization of macrophages and thus reduce lung injury caused by sepsis. High-throughput sequencing was used to identify differentially expressed genes related to long non-coding RNA (lncRNA) in ADSC-derived EVs (ADSC-EVs) in sepsis lung tissue. Weighted gene co-expression network analysis (WGCNA) was employed to predict the downstream target genes of the lncRNA DLEU2. The RNAInter database predicted miRNAs that interact with DLEU2 and LXN. Functional and pathway enrichment analyses were performed using GO and KEGG analysis. A mouse model of sepsis was established, and treatment with a placebo or ADSC-EVs was administered, followed by RT-qPCR analysis. ADSC-EVs were isolated and identified. In vitro cell experiments were conducted using the mouse lung epithelial cell line MLE-12, mouse macrophage cell line RAW264.7, and mouse lung epithelial cell line (LEPC). ADSC-EVs were co-cultured with RAW264.7 and MLE-12/LEPC cells to study the regulatory mechanism of the lncRNA DLEU2. Cell viability, proliferation, and apoptosis of lung injury cells were assessed using CCK-8, EdU, and flow cytometry. ELISA was used to measure the levels of inflammatory cytokines in the sepsis mouse model, flow cytometry was performed to determine the number of M1 and M2 macrophages, lung tissue pathology was evaluated by H&E staining, and immunohistochemistry was conducted to examine the expression of proliferation- and apoptosis-related proteins. High-throughput sequencing and bioinformatics analysis revealed enrichment of the lncRNA DLEU2 in ADSC-EVs in sepsis lung tissue. Animal and in vitro cell experiments showed increased expression of the lncRNA DLEU2 in sepsis lung tissue after treatment with ADSC-EVs. Furthermore, ADSC-EVs were found to transfer the lncRNA DLEU2 to macrophages, promoting M2 polarization, reducing inflammation response in lung injury cells, and enhancing their viability, proliferation, and apoptosis inhibition. Further functional experiments indicated that lncRNA DLEU2 promotes M2 polarization of macrophages by regulating miR-106a-5p/LXN, thereby enhancing the viability and proliferation of lung injury cells and inhibiting apoptosis. Overexpression of miR-106a-5p could reverse the biological effects of ADSC-EVs-DLEU2 on MLE-12 and LEPC in vitro cell models. Lastly, in vivo animal experiments confirmed that ADSC-EVs-DLEU2 promotes high expression of LXN by inhibiting the expression of miR-106a-5p, further facilitating M2 macrophage polarization and reducing lung edema, thus alleviating sepsis-induced lung injury. lncRNA DLEU2 in ADSC-EVs may promote M2 polarization of macrophages and enhance the viability and proliferation of lung injury cells while inhibiting inflammation and apoptosis reactions, thus ameliorating sepsis-induced lung injury in a mechanism involving the regulation of the miR-106a-5p/LXN axis.

A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction.

Micropeptides encoded by short open reading frames (sORFs) within long noncoding RNAs (lncRNAs) are beginning to be discovered and characterized as regulators of biological and pathological processes. Here, we find that lncRNA Dleu2 encodes a 17-amino-acid micropeptide, which we name Dleu2-17aa, that is abundantly expressed in T cells. Dleu2-17aa promotes inducible regulatory T (iTreg) cell generation by interacting with SMAD Family Member 3 (Smad3) and enhancing its binding to the Foxp3 conserved non-coding DNA sequence 1 (CNS1) region. Importantly, the genetic deletion of Dleu2-17aa in mice by start codon mutation impairs iTreg generation and worsens experimental autoimmune encephalomyelitis (EAE). Conversely, the exogenous supplementation of Dleu2-17aa relieves EAE. Our findings demonstrate an indispensable role of Dleu2-17aa in maintaining immune homeostasis and suggest therapeutic applications for this peptide in treating autoimmune diseases.

LncRNA DLEU2 contributes to Taxol resistance of gastric cancer cells through regulating the miR-30c-5p-LDHA axis.

Gastric cancer (GC) is a human malignancy which is associated with high mortality rate and poor prognosis. In addition to surgery, chemo- and radio-therapies are effective strategies against GC at advanced or metastatic stage. Taxol is a traditionally anti-cancer drug which is applied to various types of cancer. However, development of drug resistance limited the anti-cancer effects of Taxol. Currently, the biological roles and mechanisms of non-coding RNA DLEU2 in Taxol resistant GC remain unclear. This study reported that DLEU2 was significantly upregulated and miR-30c-5p was remarkedly downregulated in gastric tumours and cell lines. Silencing DLEU2 or overexpression of miR-30c-5p effectively increased the Taxol sensitivity of GC cells. Through bioinformatics analysis, RNA pull-down and luciferase assay, we demonstrated that DLEU2 sponged miR-30c-5p to block its expression in GC cells. Moreover, from the established Taxol resistant GC cell line, we detected remarkedly upregulated DLEU2 and downregulated miR-30c-5p expressions and significantly elevated glucose metabolism. Under low glucose condition, Taxol resistant cells were more susceptible to Taxol. In addition, we showed overexpression of miR-30c-5p blocked glucose metabolism through inhibiting the LDHA, a glucose metabolism key enzyme by direct targeting the 3'UTR of LDHA. Finally, rescue experiments validated that restoration of miR-30c-5p in DLEU2-overexpressing Taxol resistant GC cells effectively overcame the DLEU2-promoted Taxol resistance. In summary, this study uncovered new roles and molecular mechanisms of the lncRNA DLEU2-promoted Taxol resistance of gastric cancer cells, presenting the DLEU2-miR-30c-5p-LDHA-glucose metabolism axis a potentially therapeutic target for treatment of Taxol resistant GC.

TiO2nanotubes promote osteogenic differentiation of human bone marrow stem cells via epigenetic regulation ofRMRP/DLEU2/EZH2 pathway.

TiO2nanotubes (TNTs) significantly promote osteogenic differentiation and bone regeneration of cells. Nevertheless, the biological processes by which they promote osteogenesis are currently poorly understood. Long non-coding RNAs (lncRNAs) are essential for controlling osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Epigenetic chromatin modification is one of the pathways in which lncRNAs regulate osteogenic differentiation. Here, we reported that TNTs could upregulate lncRNARMRP, and inhibition of lncRNARMRPin human BMSCs (hBMSCs) grown on TNTs could decrease runt-related transcription factor 2 (RUNX2), alkaline phosphatase, osteopontin, and osteocalcin (OCN) expression. Furthermore, we discovered that inhibiting lncRNARMRPelevated the expression of lncRNADLEU2, and lncRNADLEU2knockdown promoted osteogenic differentiation in hBMSCs. RNA immunoprecipitation experiments showed that lncRNADLEU2could interact with EZH2 to induce H3K27 methylation in the promoter regions of RUNX2 and OCN, suppressing gene expression epigenetically. According to these results, lncRNARMRPis upregulated by TNTs to promote osteogenic differentiation throughDLEU2/EZH2-mediated epigenetic modifications.

Deleted in lymphocytic leukemia 2 (DLEU2): a possible biomarker that holds promise for future diagnosis and treatment of cancer.

The mechanism of deleted in lymphocytic leukemia 2 (DLEU2)-long non-coding RNA in tumors has become a major point of interest in recent research related to the occurrence and development of a variety of tumors. Recent studies have shown that the long non-coding RNA DLEU2 (lncRNA-DLEU2) can cause abnormal gene or protein expression by acting on downstream targets in cancers. At present, most lncRNA-DLEU2 play the role of oncogenes in different tumors, which are mostly associated with tumor characteristics, such as proliferation, migration, invasion, and apoptosis. The data thus far show that because lncRNA-DLEU2 plays an important role in most tumors, targeting abnormal lncRNA-DLEU2 may be an effective treatment strategy for early diagnosis and improving the prognosis of patients. In this review, we integrated lncRNA-DLEU2 expression in tumors, its biological functions, molecular mechanisms, and the utility of DLEU2 as an effective diagnostic and prognostic marker of tumors. This study aimed to provide a potential direction for the diagnosis, prognosis, and treatment of tumors using lncRNA-DLEU2 as a biomarker and therapeutic target.

Long noncoding RNA DLEU2 regulates the progression of Wilm's tumor via miR-539-3p/HOXB2 axis.

BACKGROUND: Wilm's tumor is the most common renal cancer in the pediatric age group. Long noncoding RNAs (lncRNAs) are a kind of RNA transcripts longer than ∼200 nucleotides, which have been revealed to be involved in the progression of Wilm's tumor. OBJECTIVE: The purpose of this study was to investigate the function and molecular mechanism of deleted in lymphocytic leukemia 2 (DLEU2) lncRNA in Wilm's tumor progression. STUDY DESIGN: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of DLEU2, miR-539-3p and HOXB2 mRNA in Wilm's tumor tissues and cells. Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, transwell assay, and flow cytometry were applied to explore the function of DLEU2 in Wilm's tumor cell malignant phenotypes and the regulatory mechanism among DLEU2, miR-539-3p and HOXB2 in Wilm's tumor cells. Western blot examined the protein levels of Bax, Bcl-2 and HOXB2. The relationship between miR-539-3p and DLEU2 or HOXB2 was verified by dual-luciferase reporter assay. Xenograft models of Wilm's tumor were established to study the role of DLEU2 in vivo. RESULTS: DLEU2 and HOXB2 were significantly highly expressed in primary Wilm's tumor tissues and in vitro cell lines. Silencing of DLEU2 reduced the proliferation, migration and invasion of Wilm's tumor cells, and promoted cell apoptosis. MiR-539-3p was confirmed to be a target of DLEU2. DLEU2 silencing inhibited the malignant behaviors of Wilm's tumor cells by releasing miR-539-3p. In addition, HOXB2 was a target of miR-539-3p. Overexpression of HOXB2 partially restored the inhibitory effects of miR-539-3p on Wilm's tumor cell malignant behaviors. Animal experiments also confirmed the anti-tumor effects of DLEU2 silencing in vivo. CONCLUSION: DLEU2 up-regulates the expression of HOXB2 by targetedly repressing miR-539-3p, thereby at least partially promoting the development of Wilm's tumor, these findings provided novel therapeutic targets for Wilm's tumor.

Identification of lncRNA DLEU2 as a potential diagnostic biomarker and anti-inflammatory target for ulcerative colitis.

The incidence of ulcerative colitis (UC) in China has significantly increased over the past 10 years. Here we aim to explore potential diagnostic biomarkers and anti-inflammatory targets associated with UC. Patients with UC were enrolled in this study. The expression of lncRNAs and mRNAs in the nidus of the gut mucosa and adjacent normal mucosa samples was evaluated by RNA sequencing. The role of DLEU2 in inflammation and NF-κB signaling pathway was examined by RT-qPCR, Western blotting, and ELISA with human macrophage-like cells derived from THP-1. 564 lncRNAs and 859 mRNAs are significantly altered in the nidus of the gut mucosa of UC patients. Among the differentially expressed lncRNAs, DLEU2 changes the most. The expression of DLEU2 is negatively associated with inflammatory factors such as TNF-α, IL-1α, IL-1ß, IL-6, and NLRP3. Mechanistically, DLEU2 exerts anti-inflammatory activity by inhibiting the NF-κB signaling pathway. In conclusion, the lncRNA DLEU2 in the intestinal mucosa is dysregulated upon gut inflammation and may act as a diagnostic biomarker and a therapeutic target for UC.

Long noncoding RNA DLEU2 promotes growth and invasion of hepatocellular carcinoma by regulating miR-30a-5p/PTP4A1 axis.

Increasing data indicate that long noncoding RNA (lncRNA) DLEU2 is implicated in carcinogenesis in multiple malignancies including hepatocellular carcinoma (HCC). However, the role and molecular mechanism by which lncRNA DLEU2 contributes to HCC remain unknown. The association of lncRNA DLEU2 with clinicopathological characteristics and prognosis in patients with HCC was analyzed by qRT-PCR, and public TCGA dataset. CCK-8, colony formation and Transwell assays were performed to verify the role of lncRNA DLEU2 in HCC. RNA immunoprecipitation (RIP), luciferase gene report and qRT-PCR assays were employed to uncover lncRNA DLEU2-spevific binding with miR-30a-5p. The effect of lncRNA DLEU2 and (or) miR-30a-5p on PTP4A1 expression was examined by Western blot analysis. As a consequence, we found that lncRNA DLEU2 was upregulated in HCC tissue samples and associated with distant metastasis and poor survival in patients with HCC. Knockdown of lncRNA DLEU2 impaired HCC cell proliferation, colony formation and invasion, but ectopic expression of lncRNA DLEU2 abolished these effects. Furthermore, lncRNA DLEU2 harbored a negative correlation and specific binding with miR-30a-5p in HCC cells. Knockdown of lncRNA DLEU2 upregulated miR-30a-5p, but downregulated its target PTP4A1, and miR-30a-5p abrogated lncRNA DLEU2-induced tumor-promoting effects and PTP4A1 upregulation. Taken together, our findings demonstrate that lncRNA DLEU2 promotes growth and invasion of HCC cells by regulating miR-30a-5p/ PTP4A1 axis.

DLEU2 modulates proliferation, migration and invasion of platelet-derived growth factor-BB (PDGF-BB)-induced vascular smooth muscle cells (VSMCs) via miR-212-5p/YWHAZ axis.

DLEU2 has been proved to act as an oncogene in a variety of cancers, but its role in cardiovascular diseases is dearth of research. Thus, this study mainly discussed the effect and possible mechanism of DLEU2 on platelet-derived growth factor-BB (PDGF-BB)-triggered vascular smooth muscle cell (VSMC) injury. To obtain authentic results, the expressions of target genes in atherosclerosis serum were determined by reverse transcription quantitative PCR (RT-qPCR) and the protein levels were evaluated by Western blot. PDGF-BB was used to simply simulate the biological characteristics of VSMCs in vitro. The effect of DLEU2 on the biological behavior of PDGF-BB-induced VSMCs was analyzed by gain- and loss-of-function assays. Bioinformatics analysis, dual luciferase reporter assay, and Pearson correlation method were conducted to determine the relationship between target genes. The role of DLEU2/miR-212-5p/ YWHAZ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta) axis in PDGF-BB-induced VSMCs was verified by rescue experiments. As a result, DLEU2 and YWHAZ were up-regulated, and miR-212-5p was down-regulated in atherosclerosis serum. Overexpressed DLEU2 facilitated the biological behavior of PDGF-BB-induced VSMCs, whilst siDLEU2 did the opposite. Moreover, overexpressed DLEU2 promoted proliferating cell nuclear antigen (PCNA) expression but repressed α-smooth muscle actin (α-SMA) and Calponin expressions, while it also enhanced YWHAZ expression via suppressing miR-212-5p. MiR-212-5p mimic and siYWHAZ reversed the effects of overexpressed DLEU2 on above biological characteristics and protein expressions in PDGF-BB-induced VSMCs, while the regulatory effect of miR-212-5p mimic was partially offset by overexpressed YWHAZ. Collectively, DLEU2 modulates PDGF-BB-induced VSMC injury via miR-212-5p/YWHAZ axis in atherosclerosis.

Deleted in lymphocytic leukemia 2 induces retinoic acid receptor beta promoter methylation and mitogen activated kinase-like protein activation to enhance viability and mobility of colorectal cancer cells.

Abnormal expression of long non-coding RNAs (lncRNAs) is frequently linked to the pathogenesis of colorectal cancer (CRC). This work explored the function of lncRNA deleted in lymphocytic leukemia 2 (DLEU2) in CRC and the epigenetic mechanism. Candidate oncogenes in CRC were predicted using a GSE146587 dataset. DLEU2 was highly expressed in CRC according to the bioinformatic analysis and its high expression was detected in CRC cells compared to the normal colon epithelial cells (FHC). Downregulation of DLEU2 in CRC SW480 and HT29 cells suppressed viability, migration, invasiveness, and resistance to apoptosis of cells. The mRNA microarray analysis was performed to explore the key molecules mediated by DLEU2. Retinoic acid receptor beta (RARB) expression was elevated in cells after DLEU2 downregulation. The promoter methylation of RARB was enhanced in CRC cells compared to normal FHC cells. DLEU2 induced promoter methylation of RARB to downregulate its expression. Further silencing of RARB restored proliferation and invasiveness of cells blocked by sh-DLEU2. Upregulation of DLEU2 activated the mitogen activated kinase-like protein (MAPK) signaling pathway to trigger CRC progression. In conclusion, this study demonstrates that DLEU2 enhances viability and mobility of CRC cells by inducing RARB promoter methylation and activating the MAPK signaling pathway.

Prognostic Value of Long Noncoding RNA DLEU2 and Its Relationship with Immune Infiltration in Kidney Renal Clear Cell Carcinoma and Liver Hepatocellular Carcinoma.

BACKGROUND: DLEU2 is a long noncoding RNA considered important in the progression of many cancers. However, correlations between DLEU2 and kidney renal clear cell carcinoma (KIRC) and liver hepatocellular carcinoma (LIHC) have rarely been reported. METHODS: We first analysed the expression of DLEU2 across cancers and the correlation between DLEU2 and the clinical features of KIRC and LIHC by using the "ggplot2" package in R and searched the Oncomine database and Timer website platform. We verified the expression of DLEU2 in the GEO dataset (GSE105261 and GSE45267). Receiver operating characteristic (ROC) curves were drawn using the "pROC" and "ggplot2" packages in R, and we constructed a DLEU2-based prognostic nomogram for KIRC and LIHC by using the "survival" and "rms" packages in R. Then, we analysed the correlation between DLEU2 expression and prognosis in R as well as the correlation between DLEU2 and immune cell infiltration in the TIMER database. Finally, we explored the causes of DLEU2 upregulation in the UCSC Xena and UALCAN databases. RESULTS: We found that DLEU2 was upregulated in many cancers, including KIRC and LIHC. Expression of DLEU2 is associated with tumour stage, grade, lymphatic metastasis, and distant metastasis in KIRC as well as alpha-fetoprotein (AFP), tumour stage, grade, lymphatic metastasis, and distant metastasis in LIHC. DLEU2 is an adverse factor for the prognosis of KIRC and LIHC. In addition, DLEU2 has moderate accuracy in diagnosing KIRC and LIHC and predicting their prognosis. Moreover, we found that expression of DLEU2 correlated positively with immune cell infiltration in KIRC and LIHC, and upregulation of DLEU2 in KIRC and LIHC suggests a poor prognosis based on immune cells analysis. Genetic and epigenetic analyses of DLEU2 indicate that copy number variations (CNVs) and methylation contribute to the upregulation of DLEU2. CONCLUSION: The long noncoding RNA DLEU2 has the potential to predict the prognosis and immune infiltration of KIRC and LIHC.

Long non-coding RNA DLEU2 drives EMT and glycolysis in endometrial cancer through HK2 by competitively binding with miR-455 and by modulating the EZH2/miR-181a pathway.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) and aerobic glycolysis are fundamental processes implicated in cancer metastasis. Although increasing evidence demonstrates an association between EMT induction and enhanced aerobic glycolysis in human cancer, the mechanisms linking these two conditions in endometrial cancer (EC) cells remain poorly defined. METHODS: We characterized the role and molecular mechanism of the glycolytic enzyme hexokinase 2 (HK2) in mediating EMT and glycolysis and investigated how long noncoding RNA DLEU2 contributes to the stimulation of EMT and glycolysis via upregulation of HK2 expression. RESULTS: HK2 was highly expressed in EC tissues, and its expression was associated with poor overall survival. Overexpression of HK2 effectively promoted EMT phenotypes and enhanced aerobic glycolysis in EC cells via activating FAK and its downstream ERK1/2 signaling. Moreover, microRNA-455 (miR-455) served as a tumor suppressor by directly interacting with HK2 mRNA and inhibiting its expression. Furthermore, DLEU2 displayed a significantly higher expression in EC tissues, and increased DLEU2 expression was correlated with worse overall survival. DLEU2 acted as an upstream activator for HK2-induced EMT and glycolysis in EC cells through two distinct mechanisms: (i) DLEU2 induced HK2 expression by competitively binding with miR-455, and (ii) DLEU2 also interacted with EZH2 to silence a direct inhibitor of HK2, miR-181a. CONCLUSIONS: This study identified DLEU2 as an upstream activator of HK2-driven EMT and glycolysis in EC cells and provided significant mechanistic insights for the potential treatment of EC.

LncRNA DLEU2 is activated by STAT1 and induces gastric cancer development via targeting miR-23b-3p/NOTCH2 axis and Notch signaling pathway.

INTRODUCTION: Gastric cancer (GC) has severely affected the health of patients and caused high mortality around the world. Long non-coding RNAs (lncRNAs) have been validated to play significant roles in biological process of multiple cancers. METHODS: Quantitative real-time PCR (RT-qPCR) and western blot analysis were conducted to evaluate the expression levels and protein levels of related genes in GC cells. Functional assays were implemented to explore the effect of deleted in lymphocytic leukemia 2 (DLEU2). The upstream and downstream mechanisms of DLEU2 were verified by mechanism investigations. RESULTS: The expression of long non-coding RNA (lncRNA) DLEU2 was observably high in GC cells and tissues. DLEU2 silence depressed the capacities of proliferation, migration and invasion but promoted apoptosis in GC cells. Moreover, DLEU2 was activated by signal transducer and activator of transcription 1 (STAT1) and sequestered microRNA-23b-3p (miR-23b-3p) to modulate the expression of notch receptor 2 (NOTCH2), thereby stimulating Notch signaling pathway. More importantly, DLEU2 contributed to GC progression via targeting miR-23b-3p/NOTCH2 axis. CONCLUSIONS: In summary, our research identified the STAT1/DLEU2/miR-23b-3p/NOTCH2/Notch axis in GC development, indicating that DLEU2 might function as a novel biomarker in GC.

Long noncoding RNA DLEU2 drives the malignant behaviors of thyroid cancer through mediating the miR-205-5p/TNFAIP8 axis.

OBJECTIVE: Considering the plight in thyroid cancer therapy, we aimed to find novel therapeutic targets from a molecular perspective. METHODS: Quantitative real-time PCR (qRT-PCR) and Western blot assay were carried out to determine RNA and protein expression. Cell counting kit-8 (CCK8) assay, flow cytometry, transwell migration assay and aerobic glycolysis analysis were performed to analyze cell proliferation, apoptosis, migration and aerobic glycolysis of thyroid cancer cells. MiRcode and Starbase software were used to search the downstream genes of long noncoding RNA (lncRNA) deleted in lymphocytic leukemia 2 (DLEU2) and microRNA-205-5p (miR-205-5p), and the intermolecular combination was confirmed by dual-luciferase reporter assay. The in vivo role of DLEU2 in tumor growth was verified using the murine xenograft model. RESULTS: DLEU2 and tumor necrosis factor-α-induced protein 8 (TNFAIP8) were highly expressed in thyroid cancer tissues and cell lines. DLEU2 and TNRAIP8 promoted the proliferation, migration and aerobic glycolysis and restrained the apoptosis of thyroid cancer cells. DLEU2/miR-205-5p/TNFAIP8 signaling axis was identified in thyroid cancer cells. TNFAIP8 overexpression largely rescued the malignant phenotypes in DLEU2-silenced thyroid cancer cells. DLEU2 positively regulated TNFAIP8 expression by acting as miR-205-5p sponge in thyroid cancer cells. DLEU2 silencing blocked the growth of xenograft tumors in vivo. CONCLUSION: lncRNA DLEU2 exerted a pro-tumor role to promote proliferation, migration and aerobic glycolysis while repressing the apoptosis of thyroid cancer cells via miR-205-5p/TNFAIP8 axis.

Knockdown of long non­coding RNA DLEU2 suppresses idiopathic pulmonary fibrosis by regulating the microRNA­369­3p/TRIM2 axis.

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia with an increasing incidence. In the present study, Genome Expression Omnibus (GEO) datasets (GSE10667, GSE24206 and GSE32537) were applied to identify lncRNA DLEU2 in IPF. Through prediction using starBase, TargetScan, miRTarBase and miRDB, tripartite motif containing 2 (TRIM2) and prostaglandin F2 receptor inhibitor (PTGFRN) were found to be upregulated in IPF. DLEU2 expression, the mRNA expression of TRIM2 and PTGFRN, and miR­369­3p expression in A549 cells and lung tissues were detected by RT­qPCR. The protein expression of TRIM2 and PTGFRN in lung tissues and A549 cells was detected by western blot analysis. The proliferation and migration of A549 cells was respectively detected by CCK­8 assay and wound healing assay. The expression of collagen I, α­smooth muscle actin (SMA) and E­cadherin was detected by immunofluorescence assay in A549 cells, and collagen I expression was detected by immunohistochemistry assay in lung tissues. The expression of collagen I, α­SMA and E­cadherin was also detected by western blot analysis in A549 cells and lung tissues. Dual­luciferase reporter assay was used to confirm the association between DLEU2 and miR­369­3p, and miR­369­3p and TRIM2. As a result, DLEU2 expression was found to be upregulated in IPF and in transforming growth factor (TGF)­ß1­stimulated A549 cells. The silencing of DLEU2 inhibited the TGF­ß1­induced proliferation, migration and epithelial­mesenchymal transition (EMT) of A549 cells and bleomycin (BLM)­induced pulmonary fibrosis in mice. TRIM2 expression was increased and miR­369­3p expression was decreased in the lung tissues of mice with BLM­induced fibrosis and in TGF­ß1­stimulated A549 cells. DLEU2 directly targeted miR­369­3p. The effect of the silencing of DLEU2 on TGF­ß1­stimulated A549 cells was suppressed by the silencing of miR­369­3p. TRIM2 was the target protein of miR­369­3p. On the whole, the present study demonstrates that the silencing of DLEU2 suppressed IPF by upregulating miR­369­3p expression and downregulating TRIM2 expression.

LncRNA DLEU2 promotes cervical cancer cell proliferation by regulating cell cycle and NOTCH pathway.

Long noncoding RNAs (lncRNAs) are known to play a crucial role in the onset and progression of cervical cancer (CC). Here, the results of RNA microarray and RNA-sequencing dataset analysis showed that lncRNA DLEU2 was significantly upregulated in CC tissues. Clinicopathologic analysis indicated that lncRNA DLEU2 was closely related to tumor topography. Functional experiments and bioinformatics analysis revealed that lncRNA DLEU2 promoted CC cell proliferation and accelerated the cell cycle. Mechanistically, lncRNA DLEU2 promoted the progression of the cell cycle and inhibited the activity of the Notch signaling pathway by inhibiting p53 expression. Additionally, lncRNA DLEU2 probably interacted with ZFP36 Ring Finger Protein (ZFP36) to inhibit the expression of p53. In conclusion, this study revealed the function of lncRNA DLEU2 in CC tumorigenesis, suggesting new therapeutic targets in CC.

Comprehensive analysis to identify DLEU2L/TAOK1 axis as a prognostic biomarker in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors that are harmful to human health. Increasing evidence has underscored the critical role of the competitive endogenous RNA (ceRNA) regulatory networks among various human cancers. However, the complexity and behavior characteristics of the ceRNA network in HCC were still unclear. In this study, we aimed to clarify a phosphatase and tensin homolog (PTEN)-related ceRNA regulatory network and identify potential prognostic markers associated with HCC. The expression profiles of three RNAs (long non-coding RNAs [lncRNAs], microRNAs [miRNAs], and mRNAs) were extracted from The Cancer Genome Atlas (TCGA) database. The DLEU2L-hsa-miR-100-5p/ hsa-miR-99a-5p-TAOK1 ceRNA network related to the prognosis of HCC was obtained by performing bioinformatics analysis. Importantly, we identified the DLEU2L/TAOK1 axis in the ceRNA by using correlation analysis, and it appeared to become a clinical prognostic model by Cox regression analysis. Furthermore, methylation analyses suggested that the abnormal upregulation of the DLEU2L/TAOK1 axis likely resulted from hypomethylation, and immune infiltration analysis showed that the DLEU2L/TAOK1 axis may have an impact on the changes in the tumor immune microenvironment and the development of HCC. In summary, the current study constructing a ceRNA-based DLEU2L/TAOK1 axis might be a novel important prognostic factor associated with the diagnosis and prognosis of HCC.

Long noncoding RNA DLEU2 affects the proliferative and invasive ability of colorectal cancer cells.

Emerging evidence indicates that long noncoding RNAs (lncRNAs) are closely associated with colorectal cancer (CRC) tumorigenesis. One example is lncRNA Deleted in Lymphocytic Leukemia 2 (DLEU2). However, how DLEU2 contributes to CRC is still poorly understood. This study sought to investigate the effects of DLEU2 on CRC pathogenesis, and the underlying mechanism involved. Using a quantitative real-time polymerase chain reaction (qRT-PCR) assay, we demonstrated that the expression levels of DLEU2 in 45 pairs of CRC tissues were higher than those in the corresponding normal colon mucosal tissues. In addition, CRC patients with high DLEU2 expression levels exhibited poor overall survival (OS) and recurrence-free survival (RFS), as determined by analyses and measurements from the GEO and GEPIA databases. When DLEU2 was silenced using short interfering RNA (siRNA) in CRC cell line, the results demonstrated that DLEU2 silencing suppressed CRC cell tumorigenesis in vitro, which was associated with decreased expression of cyclin dependent kinase 6(CDK6), ZEB1, and ZEB2 as well as enhancing the expression of Cyclin-dependent kinase inhibitor 1A (CDKN1A). Taken together, the results of this study suggested that DLEU2 may play critical roles in the progression of CRC and may serve as a prognostic biomarker for CRC.

DLEU2: A Meaningful Long Noncoding RNA in Oncogenesis.

BACKGROUND: Long non-coding RNA (lncRNA) with little or no coding ability has shown a variety of biological functions in cancer, including epigenetic regulation, DNA damage, regulation of microRNAs, and participation in signal transduction pathways. LncRNA can be used as an oncogene and tumor suppressor gene through transcriptional regulation in cancer. For example, the over-expressed lncRNA DLEU2 promotes the occurrence of laryngeal cancer, lung cancer, hepatocellular carcinoma, etc., and inhibits the progression of chronic lymphocytic leukemia. Deleted in Lymphocytic Leukemia 2 (DLEU2), as one of the long non-coding RNAs, was first found in chronic lymphoblastic leukemia and drawn into the progress of innumerable cancers. The molecular mechanism of DLEU2 in multiple tumors will be revealed. METHODS: In this review, current studies on the biological functions and mechanisms of DLEU2 in tumors are summarized and analyzed; related researches are systematically retrieved and collected through PubMed. RESULTS: DLEU2, a novel cancer-related lncRNA, has been demonstrated to be abnormally expressed in various malignant tumors, including leukemia, esophageal cancer, lung cancer, glioma, hepatocellular carcinoma, malignant pleural mesothelioma, bladder cancer, pancreatic cancer, pharynx and throat cancer, renal clear cell carcinoma, breast cancer, osteosarcoma. Besides, lncRNA DLEU2 has been shown to be involved in the process of proliferation, migration, invasion and inhibition of apoptosis of cancer cells. CONCLUSION: Due to the biological functions and mechanisms involved in DLEU2, it may represent an available biomarker or potential therapeutic target in a variety of malignant tumors.

Deleted in lymphocytic leukemia 2 (DLEU2): An lncRNA with dissimilar roles in different cancers.

Deleted in lymphocytic leukemia 2" (DLEU2) is a long non-coding transcript with several splice variants. It has been identified through a comprehensive sequencing of a commonly deleted region in leukemia i.e. the 13q14 region. Afterwards, different investigations reported up-regulation of this long non-coding RNA in several types of cancers. Up-regulation of DLEU2 has been shown to determine poor survival in esophageal, pancreatic, laryngeal, renal, cervical and lung cancers. However, the diagnostic power of DLUE2 has only assessed in two studies; only one them exhibiting promising results. A limitation of most of studies is that they did not differentiate between transcript variants of this lncRNA. Therefore, it is not possible to attribute the observed functions to a certain alternate transcript. In this manuscript, we discuss the results of these studies in three different sections based on the type of experiments.