Deleted In Lymphocytic Leukemia 2 Research Articles

Huaier suppresses cell viability, migration and invasion in human non-small cell lung cancer via lncRNA DLEU2/miR-212-5p/ELF3 axis.

Accumulating studies suggest that Huaier exerts anti-tumor effects through intricate mechanisms. Despite extensive research on its efficacy in lung cancer, further investigation is required to elucidate the molecular mechanism of Huaier. The involvement of long noncoding RNAs (lncRNAs) in the anti-lung cancer effects of Huaier remains unknown. In this study, we found Huaier suppressed cell viability, migration and invasion in non-small cell lung cancer (NSCLC) cells. LncRNA sequencing analysis revealed Deleted in lymphocytic leukemia 2 (DLEU2) to be significantly downregulated in Huaier-treated NSCLC cells. Furthermore, DLEU2 silencing was observed to suppress NSCLC progression, while DLEU2 overexpression attenuated the anti-tumor effects of Huaier in NSCLC, thereby promoting cell viability, migration and invasion of NSCLC. The ceRNA role of DLEU2 had been demonstrated in NSCLC, which directly interacted with miR-212-5p to rescue the repression of E74 Like ETS Transcription Factor 3 (ELF3) by this microRNA. Additionally, Huaier was found to regulate the expression of miR-212-5p and ELF3. Functionally, miR-212-5p inhibitor or ELF3 overexpression reversed the effects of DLEU2 silencing or Huaier treatment, resulting in increased colony formation, migration and invasion in NSCLC. Taken together, these results illuminate the mechanism underlying Huaier's anti-tumor effects via the DLEU2/miR-212-5p/ELF3 signaling pathway, which offers novel insights into the anti-tumor effects of Huaier and constitutes a promising therapeutic target for the treatment in NSCLC.

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.

LncRNA DLEU2 Accelerates Oral Cancer Progression via miR-30a-5p/RAP1B Axis to Regulate p38 MAPK Signaling Pathway.

Background Oral cancer (OC) is common cancer in the world. Long noncoding RNAs (lncRNAs) have been shown to be involved in cancer regulation, including oral cancer (OC). The aim of this study was to investigate the role of lncRNA deleted in lymphocytic leukemia 2 (DLEU2) in oral cancer. Method The Gene Expression Omnibus database was used to analyze differentially expressed lncRNA/microRNA (miRNA, miR)/mRNA. The expression levels of DLEU2, miR-30a-5p, and RAP1B in OC cells were detected by RT-qPCR. Dual-luciferase was used to analyze the binding of lncRNA/miRNA/mRNA. Cell Counting Kit-8 was used to measure cell proliferation. Transwell assay was used to inspect cell migration and invasion abilities. Western blot was used to detect MAPK pathway-related protein levels. Result Our research shows that, in contrast to miR-30a-5p, DLEU2 or RAP1B was upregulated in OC cells, and high expression of DLEU2 or RAP1B was associated with poorer overall survival. Inhibiting the expression of DLEU2 slowed the proliferation and reduced the ability of migration and invasion of Tca8113 and CAL-27 cells. miR-30a-5p was predicted to interact with DLEU2 or RAP1B by bioinformatics, and dual-luciferase analysis confirmed this interaction. Notably, si-DLEU2 suppressed RAP1B expression and protein level, and after overexpression of RAP1B in OC cells, reversal of suppressed DLEU2 expression was observed. Furthermore, the inhibitory effect of si-DLEU2 on MAPK signaling was reversed by overexpression of RAP1B. Therefore, si-DLEU2 regulates MAPK signaling through the miR-30a-5p/RAP1B axis and inhibits OC development. Conclusion DLEU2 contributed to proliferation, migration and invasion via miR-30a-5p/RAP1B axis to regulate MAPK signaling pathway in OC cells.

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

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. 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. 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 invivo. DLEU2 and HOXB2 were significantly highly expressed in primary Wilm's tumor tissues and invitro 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 invivo. 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.

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

ABSTRACT 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.

13q14 Deletion and Its Effect on Prognosis of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia affecting adults. CLL results due to uncontrolled accumulation of B lymphocytes in the body with the clinical spectrum ranging from comparatively benign disease to an aggressive form. The disease pathogenesis lies in molecular genetics, the most common alteration being the deletion in the long arm of chromosome 13, at position 14 (13q14) region. This deletion leads to the loss of important microRNAs which are involved in maintaining the critical balance of the apoptosis mechanism of cell death of B lymphocytes. As such, the imbalance contributes towards B cells' immortality and, thus, CLL arises. This significant 13q14 deletion contributes to CLL's pathogenesis and paves the way for CLL treatment, hence affecting the prognosis of the affected patients.Furthermore, the size of deletion of the long arm of chromosome 13 (13q) has a remarkable effect on its prognosis and therapeutic intervention. The minimal deleted region (MDR)/small deletion or long 13q loss/mutation, and biallelic 13q deletion or monoallelic 13q deletion are commonly seen. 13q14 deletion is an initiating defect targeting tumor suppressor gene locus deleted in lymphocytic leukemia 2 (DLEU2))/microRNA15A (MIR15A)/microRNA 16-1 (MIR 16-1). Regarding CLL treatment, conventional therapy with alkylating agents has been used for a long time, which reported low- to non-existent complete remission rates and adverse events after prolonged use. Moreover, research into the 13q14 deletion has also provided new insights into the molecular genetics and pathways that interact in such a way, making it possible to transform healthy cells into malignant cells in an entirely new fashion with a complete disregard to its original form, resulting in CLL.

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

IntroductionGastric 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. MethodsQuantitative 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. ResultsThe 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. ConclusionsIn 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.

ObjectiveConsidering the plight in thyroid cancer therapy, we aimed to find novel therapeutic targets from a molecular perspective.MethodsQuantitative 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.ResultsDLEU2 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.ConclusionlncRNA 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.

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.

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. 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. 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. 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.

Long noncoding RNA DLEU2 predicts a poor prognosis and enhances malignant properties in laryngeal squamous cell carcinoma through the miR-30c-5p/PIK3CD/Akt axis

Long noncoding RNAs (lncRNAs) have been identified as potential prognostic tools and therapeutic biomarkers for a variety of human cancers. However, the functional roles and underlying mechanisms of key lncRNAs affecting laryngeal squamous cell carcinomas (LSCCs) are largely unknown. Here, we adopted a novel subpathway strategy based on the lncRNA-mRNA profiles from the Cancer Genome Atlas (TCGA) database and identified the lncRNA deleted in lymphocytic leukemia 2 (DLEU2) as an oncogene in the pathogenesis of LSCCs. We found that DLEU2 was significantly upregulated and predicted poor clinical outcomes in LSCC patients. In addition, ectopic overexpression of DLEU2 promoted the proliferation and migration of LSCC cells both in vivo and in vitro. Mechanistically, DLEU2 served as a competing endogenous RNA to regulate PIK3CD expression by sponging miR-30c-5p and subsequently activated the Akt signaling pathway. As a target gene of DLEU2, PIK3CD was also upregulated and could predict a poor prognosis in LSCC patients. In conclusion, we found that the novel LSCC-related gene DLEU2 enhances the malignant properties of LSCCs via the miR-30c-5p/PIK3CD/Akt axis. DLEU2 and its targeted miR-30c-5p/PIK3CD/Akt axis may represent valuable prognostic biomarkers and therapeutic targets for LSCCs.

LncRNA DLEU2 aggravates the progression of hepatocellular carcinoma through binding to EZH2

To explore whether lncRNA deleted in lymphocytic leukemia 2 (DLEU2) could accelerate the migratory, invasive and proliferative abilities, thus influencing the progression of HCC. DLEU2 level in HCC tissues and adjacent normal tissues was firstly determined. Its level in HCC tissues with different tumor sizes (≤ 5 cm or > 5 cm), different tumor stages (stage I-II or III-IV) and either with vascular invasion or not was determined. Potential influences of DLEU2 on proliferative, migratory and invasive abilities of SMMC7721 and HCLM3 cells were assessed. The interaction between DLUE2 and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) was evaluated by RNA Binding Protein Immunoprecipitation (RIP) assay. Finally, the effect of DLEU2/EZH2 regulatory loop on proliferative ability of HCC cells was detected. DLEU2 was upregulated in HCC tissues, especially in those larger than 5 cm in tumor size, accompanied with vascular invasion and in worse tumor stage. Knockdown of DLEU2 attenuated proliferative, migratory and invasive abilities of SMMC7721 and HCLM3 cells. RIP assay proved that DLEU2 could interact with EZH2. Knockdown of EZH2 attenuated the inhibited proliferation in HCC cells with DLEU2 knockdown. DLEU2 accelerates the proliferative, migratory and invasive abilities of HCC cells via binding to EZH2, thus aggravating the progression of HCC.

MiR‑15a represses cancer cell migration and invasion under conditions of hypoxia by targeting and downregulating Bcl‑2 expression in human osteosarcoma cells.

Osteosarcoma is a common, high-risk primary bone malignancy that mostly affects the younger population. There has been no marked improvement in the clinical outcomes of osteosarcoma patients to date, and cancer recurrence and metastasis are common in high-grade osteosarcoma. Therefore, identifying new biomarkers and novel therapeutic targets is crucial for improving the prognosis of osteosarcoma patients. In the present study, the MG63 human osteosarcoma cell line was employed to examine the role of microRNA (miR)-15a in regulating cellular activities under hypoxic conditions. It was demonstrated that hypoxia stimulates migration and invasion in MG63 cells, which was correlated with the downregulation of miR-15a and upregulation of B-cell lymphoma 2 (Bcl-2) expression. Introduction of miR-15a or knockdown of endogenous Bcl-2 may reduce hypoxia-induced cell invasion and migration through the regulation of matrix metalloproteinases. Analysis of the expression of miR-15a indicated that hypoxia repressed the transcription of deleted in lymphocytic leukemia 2 (DLEU2), which is the host gene of miR-15a. These findings indicated that miR-15a may be a valuable target for the treatment of osteosarcoma, particularly for patients with high-grade cancer or heavy tumor burden.

A Human Long Non-Coding RNA ALT1 Controls the Cell Cycle of Vascular Endothelial Cells Via ACE2 and Cyclin D1 Pathway

Background/Aims: ALT1 is a novel long non-coding RNA derived from the alternatively spliced transcript of the deleted in lymphocytic leukemia 2 (DLEU2). To date, ALT1 biological roles in human vascular endothelial cells have not been reported. Methods: ALT1 was knocked down by siRNAs. Cell proliferation was analyzed by cck-8. The existence and sequence of human ALT1 were identified by 3’ rapid amplification of cDNA ends. The interaction between lncRNA and proteins was analyzed by RNA-Protein pull down assay, RNA immunoprecipitation, and mass spectrometry analysis. Results: ALT1 was expressed in human umbilical vein endothelial cells (HUVECs). The expression of ALT1 was significantly downregulated in contact-inhibited HUVECs and in hypoxia-induced, growth-arrested HUVECs. Knocking down of ALT1 inhibited the proliferation of HUVECs by G0/G1 cell cycle arrest. We observed that angiotensin converting enzyme Ⅱ(ACE2) was a direct target gene of ALT1. Knocking-down of ALT1 or its target gene ACE2 could efficiently decrease the expression of cyclin D1 via the enhanced ubiquitination and degradation, in which HIF-1α and protein von Hippel-Lindau (pVHL) might be involved. Conclusion: The results suggested the human long non-coding RNA ALT1 is a novel regulator for cell cycle of HUVECs via ACE2 and cyclin D1 pathway.

Eight genes are highly associated with BMD variation in postmenopausal Caucasian women

Low bone mineral density (BMD) is an important risk factor for skeletal fractures which occur in about 40% of women ≥50 years in the western world. We describe the transcriptional changes in 84 trans-iliacal bone biopsies associated with BMD variations in postmenopausal females (50 to 86 years), aiming to identify genetic determinants of bone structure. The women were healthy or having a primary osteopenic or osteoporotic status with or without low energy fractures. The total cohort of 91 unrelated women representing a wide range of BMDs, were consecutively registered and submitted to global gene Affymetrix microarray expression analysis or histomorphometry. Among almost 23,000 expressed transcripts, a set represented by ACSL3 (acyl-CoA synthetase long-chain family member 3), NIPSNAP3B (nipsnap homolog 3B), DLEU2 (Deleted in lymphocytic leukemia, 2), C1ORF61 (Chromosome 1 open reading frame 61), DKK1 (Dickkopf homolog 1), SOST (Sclerostin), ABCA8, (ATP-binding cassette, sub-family A, member 8), and uncharacterized (AFFX-M27830-M-at), was significantly correlated to total hip BMD (5% false discovery rate) explaining 62% of the BMD variation expressed as T-score, 53% when adjusting for the influence of age (Z-score) and 44% when further adjusting for body mass index (BMI). Only SOST was previously associated to BMD, and the majority of the genes have previously not been associated with a bone phenotype. In molecular network analyses, SOST shows a strong, positive correlation with DKK1, both being members of the Wnt signaling pathway. The results provide novel insight in the underlying biology of bone metabolism and osteoporosis which is the ultimate consequence of low BMD.