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The competing endogenous RNA (ceRNA)-based profiling has been extensively studied in carcinogenesis of lung adenocarcinoma (LUAD), while it has seldomly been applied to investigate the metastatic potential of LUAD. This study aims to examine the function and in-depth mechanism of GPR37-centered ceRNA network in LUAD. Cancer tissues and adjacent normal tissues from three LUAD patients were collected for high-throughput sequencing to screen for differentially expressed genes. A PPI network was constructed to screen the key gene GPR37, followed by analysis for the functions and pathways. Clinical data from LUAD patients were integrated with gene expression data in TCGA-LUAD dataset for survival analysis. Based on the miRNAs targeting_GPR37 and lncRNAs targeting_miRNAs, a lncRNA-miRNA-mRNA ceRNA network was established. GPR37 was up-regulated in LUAD tissue samples, and it may be a key gene involved in LUAD progression. GPR37 in LUAD was mainly enriched in the mitosis-related pathways. High GPR37 expression corresponded to poor prognosis in LUAD patients. Meanwhile, GPR37 could be used as an independent factor to predict the prognosis in LUAD patients. LncRNA DLEU1, up-regulated in LUAD tissue samples, may competitively bind to miR-4458 to up-regulate the expression of the miR-4458 downstream target GPR37. DLEU1 was associated with poor prognosis and tumor metastasis in LUAD patients. Altogether, our findings reveal a novel ceRNA network of DLEU1/miR-4458/GPR37 in LUAD growth and metastasis.

Objectives: APOC1 has been reported to promote tumor progression. Nevertheless, its impact on cell proliferation and glycolysis in gastric cancer (GC) remains to be probed. Hence, this study explored the related impacts and mechanisms. Methods: DLEU1, SMYD2, and APOC1 expression was detected in GC cells. Afterward, ectopic expression and knockdown experiments were conducted in GC cells, followed by measurement of cell proliferation, glucose uptake capability, lactic acid production, ATP content, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and GLUT1, HK2, and LDHA expression. In addition, interactions between DLEU1 and SMYD2 were analyzed with RIP and RNA pull down assays, and the binding of SMYD2 to APOC1 promoter and the methylation modification of SMYD2 in H3K4me3 were assessed with a ChIP assay. The ectopic tumor formation experiment in nude mice was conducted for in vivo validation. Results: DLEU1, SMYD2, and APOC1 were highly expressed in GC cells. The downregulation of DLEU1 or APOC1 inhibited glucose uptake capability, lactic acid production, ECAR, the expression of GLUT1, HK2, and LDHA, ATP contents, and proliferation but augmented OCR in GC cells, which was also verified in animal experiments. Mechanistically, DLEU1 interacted with SMYD2 and recruited SMYD2 to APOC1 promoter to promote H3K4me3 modification, thus facilitating APOC1 expression. Furthermore, the effects of DLEU1 silencing on GC cell proliferation and glycolysis were negated by overexpressing SMYD2 or APOC1. Conclusion: LncRNA DLEU1 recruited SMYD2 to upregulate APOC1 expression, thus boosting GC cell proliferation and glycolysis.

Abstract Oral squamous cell carcinoma (OSCC) is one of the most frequent malignancies found in head and neck cancers. Dysregulation of lncRNAs has been proposed to be related to the development of OSCC. Here, we investigated the function and probable mechanisms of lncRNA DLEU1 in OSCC. OSCC cell lines and human oral keratinocytes (HOKs) were cultured, while SCC‐25 and CAL‐27 cells were transfected with the corresponding plasmids. Reverse transcription quantitative PCR (RT‐qPCR) and western blot were carried out to measure the RNA and protein levels. Cell proliferation, migration and invasion were evaluated using MTT assays, wound healing and Transwell assays. The StarBase database predicted the interactions between DLEU1 and miR‐126‐5p, as well as miR‐126‐5p and GAB1, which were further validated using a dual‐luciferase reporter assay. Our results indicated that DLEU1 and GAB1 were upregulated, while miR‐126‐5p was downregulated in OSCC cells. Silencing DLEU1 reduced OSCC cell proliferation, migration, and invasion, while DLEU1 overexpression had the opposite effects. DLEU1 mediated biological effects in OSCC through binding to miR‐126‐5p, which directly targeted GAB1. miR‐126‐5p knockdown rescued the inhibitory function of DLEU1 depletion on proliferation, migration and invasion. Meanwhile, the miR‐126‐5p mimic exerted suppressive functions in the progression of OSCC, which were neutralized after GAB1 overexpression. In summary, lncRNA DLEU1 targets the miR‐126‐5p/GAB1 axis to aggravate OSCC progression, providing a novel target for treating OSCC.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is crucial to elucidate the mechanism underlying ferroptosis resistance in GBM. We used qRT-PCR to detect the level of DLEU1 and mRNAs of indicated genes, whereas protein levels were determined by Western blots. Fluorescence in situ hybridization assay (FISH) was applied to validate the sublocation of DLEU1 in GBM cells. Gene knockdown or overexpression was achieved by transient transfection. Ferroptosis markers were detected by indicated kits and transmission electron microscopy (TEM). RNA pull-down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (CHIP)-qPCR, and dual-luciferase assay were used to validate the direct interaction between indicated key molecules in the current study. We validated that the expression of DLEU1 was upregulated in GBM samples. DLEU1 knockdown exacerbated erastin-induced ferroptosis in LN229 and U251MG cells, as well as in the xenograft model. Mechanistically, we found that DLEU1 bound with ZFP36 and facilitated ZFP36 to degrade ATF3 mRNA, thus upregulating the expression of SLC7A11 to attenuate erastin-induced ferroptosis. Importantly, our results confirmed that cancer-associated fibroblasts (CAFs) conferred ferroptosis resistance in GBM. The stimulation of CAF-conditioned medium enhanced the activation of HSF1, and HSF1 transcriptionally increased the level of DLEU1 to regulate erastin-induced ferroptosis. This study identified DLEU1 as an oncogenic lncRNA that epigenetically downregulates ATF3 expression via binding with ZFP36 to facilitate ferroptosis resistance in GBM. The upregulation of DLEU1 in GBM might be attributed to CAF-induced HSF1 activation. Our study might provide a research basis for understanding CAF-induced ferroptosis resistance in GBM. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is one of the most frequent malignancies found in head and neck cancers. Dysregulation of lncRNAs has been proposed to be related to the development of OSCC. Here, we investigated the function and probable mechanisms of lncRNA DLEU1 in OSCC. OSCC cell lines and human oral keratinocytes (HOKs) were cultured, while SCC‐25 and CAL‐27 cells were transfected with the corresponding plasmids. Reverse transcription quantitative PCR (RT‐qPCR) and western blot were carried out to measure the RNA and protein levels. Cell proliferation, migration and invasion were evaluated using MTT assays, wound healing and Transwell assays. The StarBase database predicted the interactions between DLEU1 and miR‐126‐5p, as well as miR‐126‐5p and GAB1, which were further validated using a dual‐luciferase reporter assay. Our results indicated that DLEU1 and GAB1 were upregulated, while miR‐126‐5p was downregulated in OSCC cells. Silencing DLEU1 reduced OSCC cell proliferation, migration, and invasion, while DLEU1 overexpression had the opposite effects. DLEU1 mediated biological effects in OSCC through binding to miR‐126‐5p, which directly targeted GAB1. miR‐126‐5p knockdown rescued the inhibitory function of DLEU1 depletion on proliferation, migration and invasion. Meanwhile, the miR‐126‐5p mimic exerted suppressive functions in the progression of OSCC, which were neutralized after GAB1 overexpression. In summary, lncRNA DLEU1 targets the miR‐126‐5p/GAB1 axis to aggravate OSCC progression, providing a novel target for treating OSCC. [ABSTRACT FROM AUTHOR]

Abstract Background miR-146b-5p has been reported to participate in premature ovarian failure (POF) in mice. However, its role in POF patients is unclear. We predicted that miR-146b-5p might interact with lncRNA DLEU1, a crucial player in ovarian cancer. We then explored the interaction between DLEU1 and miR-146b-5p. Methods Expression of DLEU1 and miR-146b-5p in POF and control ovary tissues was determined by RT-qPCR. The subcellular location of DLEU1 in human KGN cells was analyzed using subcellular fractionation assays. The direct interaction between DLEU1 and miR-146b-5p was analyzed using RNA pull-down assays. The role of DLEU1 in miR-146a expression was analyzed using overexpression assay. Cell proliferation was analyzed using cell apoptosis assay. Results Increased DLEU1 expression and decreased miR-146b-5p expression were observed in POF. DLEU1 directly interacted with MiR-146b-5p and was expressed in both nuclear and cytoplasm samples of KGN cells. In KGN cells, DLEU1 and miR-146b-5p failed to regulate the expression of each other. However, DLEU1 promoted cell apoptosis and reduced the inhibitory effects of miR-146b-5p on cell apoptosis. Conclusions DLEU1 is overexpressed in POF and sponges miR-146b-5p to increase KGN cell apoptosis.

Objective To investigate the expression of LncRNA DLEU1 in ESCC tissues, and its effect on the proliferation and migration of ESCC cells. Methods We collected 58 cases of ESCC tissues and corresponding para-cancerous tissues. RT-qPCR was used to detect the relative expression levels of DLEU1 in ESCC tissues and cells. Log-rank test was used to analyze the relation between the expression of DLEU1 and clinicopathological features. Kaplan-Meier analysis was used to investigate the correlation between the expression of DLEU1 and the survival of ESCC patients. Multivariate Cox regression model was used to evaluate the effect of DLEU1 on the prognosis of ESCC patients. Effects of DLEU1 on the proliferation and migration of Eca9706 cells were evaluated by CCK-8 and wound healing assays, respectively. Results DLEU1 was highly expressed in ESCC tissues (P < 0.01) and significantly correlated with tumor size, TNM stage and lymph node metastasis (all P < 0.05). High expression of DLEU1 was negatively correlated with poor prognosis of ESCC patients (P < 0.01), and DLEU1 was also an independent prognostic risk factor (P < 0.05). Moreover, knockdown of DLEU1 significantly inhibited the proliferation and migration of Eca9706 cells, compared with the control group (P < 0.01). Conclusion DLEU1 is highly expressed in ESCC tissues. The expression of DLEU1 is an independent risk factor for the prognosis of ESCC patients and promotes ESCC cell proliferation and migration.

Abstract Background Neuropathic pain belongs to chronic pain and is caused by the primary dysfunction of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) have been reported to regulate neuronal functions and play significant roles in neuropathic pain. DLEU1 has been indicated to have close relationship with neuropathic pain. Therefore, our study focused on the significant role of DLEU1 in neuropathic pain rat models. Methods We first constructed a chronic constrictive injury (CCI) rat model. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were employed to evaluate hypersensitivity in neuropathic pain. RT-qPCR was performed to analyze the expression of target genes. Enzyme-linked immunosorbent assay (ELISA) was conducted to detect the concentrations of interleukin‐6 (IL-6), tumor necrosis factor‐α (TNF-α) and IL-1β. The underlying mechanisms of DLEU1 were investigated using western blot and luciferase reporter assays. Results Our findings showed that DLEU1 was upregulated in CCI rats. DLEU1 knockdown reduced the concentrations of IL‐6, IL‐1β and TNF‐α in CCI rats, suggesting that neuroinflammation was inhibited by DLEU1 knockdown. Besides, knockdown of DLEU1 inhibited neuropathic pain behaviors. Moreover, it was confirmed that DLEU1 bound with miR-133a-3p and negatively regulated its expression. SRPK1 was the downstream target of miR-133a-3p. DLEU1 competitively bound with miR-133a-3p to upregulate SRPK1. Finally, rescue assays revealed that SRPK1 overexpression rescued the suppressive effects of silenced DLEU1 on hypersensitivity in neuropathic pain and inflammation of spinal cord in CCI rats. Conclusion DLEU1 regulated inflammation of the spinal cord and mediated hypersensitivity in neuropathic pain in CCI rats by binding with miR-133a-3p to upregulate SRPK1 expression.

Long non-coding RNAs (LncRNAs) have been proven to be involved in the progression of osteosarcoma. LncRNA DLEU1 was found to act as an oncogene in various types of cancer. In this study, we aimed to explore the biological functions of DLEU1 in osteosarcoma and the specific mechanism. Our results showed that DLEU1 was highly expressed in osteosarcoma tissue specimens and cells. Downregulation of DLEU1 in osteosarcoma cells inhibited the cell proliferation, migration and invasion. Further mechanistic analysis and functional assays demonstrated that DLEU1 exerted its role by sponging microRNA (miR)-671-5p in osteosarcoma cells. Moreover, DEAD-box helicase 5 (DDX5) was confirmed as the target of miR-671-5p. Furthermore, rescue assays indicated that miR-671-5p inhibitor significantly reversed the effects of DLEU1 knockdown on osteosarcoma cell proliferation and invasion while restoration of DDX5 rescued the proliferation and invasion of osteosarcoma cells transfected with miR-671-5p mimics. In conclusion, DLEU1 acted as an oncogene in osteosarcoma by directly sponging miR-671-5p and regulating the expression of DDX5. These findings suggested that DLEU1 might be a novel therapeutic target in the treatment of osteosarcoma.

Background: miR-146b-5p has been reported to participate in premature ovarian failure (POF) in mice. However, its role in POF patients is unclear. We predicted that miR-146b-5p might interact with lncRNA DLEU1, a crucial player in ovarian cancer. We then explored the interaction between DLEU1 and miR-146b-5p. Methods: Expression of DLEU1 and miR-146b-5p in POF and control ovary tissues was determined by RT-qPCR. The subcellular location of DLEU1 in human KGN cells was analyzed using subcellular fractionation assays. The direct interaction between DLEU1 and miR-146b-5p was analyzed using RNA pull-down assays. The role of DLEU1 in miR-146a expression was analyzed using overexpression assay. Cell proliferation was analyzed using cell apoptosis assay. Results: Increased DLEU1 expression and decreased miR-146b-5p expression were observed in POF. DLEU1 directly interacted with MiR-146b-5p and was expressed in both nuclear and cytoplasm samples of KGN cells. In KGN cells, DLEU1 and miR-146b-5p failed to regulate the expression of each other. However, DLEU1 promoted cell apoptosis and reduced the inhibitory effects of miR-146b-5p on cell apoptosis. Conclusions: DLEU1 is overexpressed in POF and sponges miR-146b-5p to increase KGN cell apoptosis. [ABSTRACT FROM AUTHOR]

Objective: To explore the role of long non-coding RNA DLEU1 in the tumorigenesis and progression of non-small cell lung cancer (NSCLC) and the underlying mechanisms. Methods: The expression of DLEU1 in NSCLC tumor tissues and adjacent normal tissues was evaluated using bioinformatics analysis and qPCR. The effects of DLEU1 overexpression or deficiency on cell proliferation, apoptosis, migration and invasion were explored experimentally. Additionally, the impact of DLEU1 up-regulation on tumourigenesis was also assessed in vivo. Results: The expression of DLEU1 was up-regulated in NSCLC tumor tissues. DLEU1 overexpression promoted the proliferation, migration, and invasion, but inhibited the apoptosis of NSCLC cells by upregulating CDK1 expression, binding with SRC and altering the expression of P70(S6K), MMP2 and E-cadherin. Besides, xenograft tumors in nude mice demonstrated that DLEU1 overexpression accelerated tumor growth. Conclusions: DLEU1 promoted tumorigenesis and progression of NSCLC, and might be a promising therapeutic target for NSCLC.

Growing evidences suggest that long non-coding RNAs (lncRNAs) are closely correlated to the development of human cancer, such as colorectal cancer (CRC). A previous report suggested that DLEU1 accelerated CRC development. However, DLEU1’s underlying mechanism in CRC remains unclear. In our study, the level of DLEU1 in CRC tissues is investigated by qRT-PCR. Our data exhibited that DLEU1 level was observably increased in CRC tissues and CRC cell lines and was closely associated with bad prognosis of CRC patients. CRC cell proliferation was repressed by sh-LncRNA DLEU1, whereas cell apoptosis was markedly stimulated. Moreover, knockdown of DLEU1 inhibited cell migration and invasion. Mechanistically, through interacting with miR-320b in CRC, DLEU1 promoted the level of PRPS1 which was a target of miR-320b. The rescue experiment confirmed that knockdown of DLEU1 repressed cell proliferation, migration and invasion while stimulated cell apoptosis via miR-320b/phosphoribosyl pyrophosphate synthetase 1 (PRPS1) axis. Meanwhile, the data of xenograft model exhibited that inhibition of DLEU1 suppressed tumor growth in vivo. In summary, DLEU1 knockdown may repress PRPS1 expression via miR-320b, and then repress cell proliferation, migration and invasion while stimulate cell apoptosis. Our research may provide a novel target for the treatment of CRC.

Growing evidences suggest that long non-coding RNAs (lncRNAs) are closely correlated to the development of human cancer, such as colorectal cancer (CRC). A previous report suggested that DLEU1 accelerated CRC development. However, DLEU1's underlying mechanism in CRC remains unclear. In our study, the level of DLEU1 in CRC tissues is investigated by qRT-PCR. Our data exhibited that DLEU1 level was observably increased in CRC tissues and CRC cell lines and was closely associated with bad prognosis of CRC patients. CRC cell proliferation was repressed by sh-LncRNA DLEU1, whereas cell apoptosis was markedly stimulated. Moreover, knockdown of DLEU1 inhibited cell migration and invasion. Mechanistically, through interacting with miR-320b in CRC, DLEU1 promoted the level of PRPS1 which was a target of miR-320b. The rescue experiment confirmed that knockdown of DLEU1 repressed cell proliferation, migration and invasion while stimulated cell apoptosis via miR-320b/phosphoribosyl pyrophosphate synthetase 1 (PRPS1) axis. Meanwhile, the data of xenograft model exhibited that inhibition of DLEU1 suppressed tumor growth in vivo. In summary, DLEU1 knockdown may repress PRPS1 expression via miR-320b, and then repress cell proliferation, migration and invasion while stimulate cell apoptosis. Our research may provide a novel target for the treatment of CRC. [ABSTRACT FROM AUTHOR]

Abstract Background Accumulating evidences show that long noncoding RNAs (lncRNA) play essential roles in the development and progression of various malignancies. However, their functions remains poorly understood and many lncRNAs have not been defined in colorectal cancer (CRC). In this study, we investigated the role of DLEU1 in CRC. Methods Quantitative real-time PCR was used to detect the expression of DLEU1 and survival analysis was adopted to explore the association between DLEU1 expression and the prognosis of CRC patients. CRC cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effects of DLEU1 in BCa. Biotin-coupled probe pull down assay, RNA immunoprecipitation and Fluorescence in situ hybridization assays were conducted to confirm the relationship between DLEU1 and SMARCA1. Results Here we revealed that DLEU1 was crucial for activation of KPNA3 by recruiting SMARCA1, an essential subunit of the NURF chromatin remodeling complex, in CRC. DLEU1 was indispensible for the deposition of SMARCA1 at the promoter of KPNA3 gene. Increased expression of DLEU1 and KPNA3 was observed in human CRC tissues. And higher expression of DLEU1 or KPNA3 in patients indicates lower survival rate and poorer prognosis. DLEU1 knockdown remarkably inhibited CRC cell proliferation, migration and invasion in vitro and in vivo while overexpressing KPNA3 in the meantime reversed it. Conclusions Our results identify DLEU1 as a key regulator by a novel DLEU1/SMARCA1/KPNA3 axis in CRC development and progression, which may provide a potential biomarker and therapeutic target for the management of CRC.

Background: Cisplatin (DDP) resistance has become an obstacle to chemotherapy for nasopharyngeal carcinoma (NPC) patients. Recent evidences indicate that long noncoding RNAs (lncRNAs) are involved in tumorigenesis and chemoresistance. However, the potential role of lncRNAs in NPC progression remains largely unknown. Methods: First, lncRNA expression profiling in NPC was performed via microarray analysis. To explore the involvement of DLEU1 in DDP resistance, loss-of-function experiments were employed in vitro and in vivo. Bioinformatics analysis, luciferase reporter assay, qRT-PCR, and Western blot assays were used to investigate the underlying mechanisms. Results: Here, we identified 153 differentially expressed lncRNAs. Among them, DLEU1 was remarkably up-regulated in NPC tissues and associated with worse outcome. Knock-down of DLEU1 could sensitize NPC cells to DDP in vitro and in vivo. Further investigations revealed that DLEU1 positively regulated BIRC6 expression via its competing endogenous RNA (ceRNA) activity on miR-381-3p. We also observed that BIRC6 overexpression or miR-381-3p silence could significantly reverse DLEU1-dependent DDP resistance. Conclusion: Our data suggest that DLEU1 acts as an oncogene to promote DDP resistance and BIRC6 expression in NPC through interacting with miR-381-3p, which may help to develop new strategy against NPC chemoresistance. [ABSTRACT FROM AUTHOR]

Although accumulating evidence has shown the important function of long non-coding RNAs (lncRNAs) in tumor progression and chemotherapy resistance, the role of lncRNA DLEU1 in regulating proliferation, invasion, and chemoresistance of bladder cancer (BCA) cells remains largely unknown. Here, we found that DLEU1 was upregulated in BLCA tissues and BCA patients with high DLEU1 expression exhibited a shorter survival time. Furthermore, mechanistic analysis and functional assays validated that DLEU1 induced cell proliferation, invasion, and cisplatin resistance of BCA cells by de-repressing the expression of HS3ST3B1 through sponging miR-99b. Low miR-99b and high HS3ST3B1 levels were correlated with worse prognosis in patients with BCA. Ectopic expression of HS3ST3B1 or inhibition of miR-99b reversed DLEU1 knockdown-mediated suppression of cell proliferation, invasion, and cisplatin resistance. Thus, our study revealed a novel role for the DLEU1/miR-99b/HS3ST3B1 axis in regulating proliferation, invasion, and cisplatin resistance of BCA cells.

The competing endogenous RNA (ceRNA)-based profiling has been extensively studied in carcinogenesis of lung adenocarcinoma (LUAD), while it has seldomly been applied to investigate the metastatic potential of LUAD. This study aims to examine the function and in-depth mechanism of GPR37-centered ceRNA network in LUAD. Cancer tissues and adjacent normal tissues from three LUAD patients were collected for high-throughput sequencing to screen for differentially expressed genes. A PPI network was constructed to screen the key gene GPR37, followed by analysis for the functions and pathways. Clinical data from LUAD patients were integrated with gene expression data in TCGA-LUAD dataset for survival analysis. Based on the miRNAs targeting&#95;GPR37 and lncRNAs targeting&#95;miRNAs, a lncRNA-miRNA-mRNA ceRNA network was established. GPR37 was up-regulated in LUAD tissue samples, and it may be a key gene involved in LUAD progression. GPR37 in LUAD was mainly enriched in the mitosis-related pathways. High GPR37 expression corresponded to poor prognosis in LUAD patients. Meanwhile, GPR37 could be used as an independent factor to predict the prognosis in LUAD patients. LncRNA DLEU1, up-regulated in LUAD tissue samples, may competitively bind to miR-4458 to up-regulate the expression of the miR-4458 downstream target GPR37. DLEU1 was associated with poor prognosis and tumor metastasis in LUAD patients. Altogether, our findings reveal a novel ceRNA network of DLEU1/miR-4458/GPR37 in LUAD growth and metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Although growing evidence has demonstrated that the long non-coding RNA DLEU1 is involved in the progression of various cancers, its functional role and underlying mechanisms have not been explored in cervical cancer (CC). In this study, we found that DLEU1 was up-regulated in both CC tissues and CC cell lines, and overexpression of DLEU1 was significantly correlated with shorter patient survival. Knockdown of DLEU1 suppressed CC cell proliferation and invasion, whereas overexpression of DLEU1 promoted the proliferation and invasion of CC cells. Bioinformatics analysis was used to elucidate the potential correlation between DLEU1 and miR-381. Moreover, qRT-PCR analysis, luciferase reporter assay and RNA immunoprecipitation assay confirmed that DLEU1 inhibited the expression of miR-381, and revealed a direct interaction between DLEU1 and miR-381. In addition, we demonstrated that miR-381 directly targeted HOXA13 in CC cells. The restoration of HOXA13 expression reversed DLEU1 knockdown or miR-381 overexpression-mediated suppression of cell proliferation and invasion. These results suggested that DLEU1 can promote CC cell proliferation and invasion via the miR-381/HOXA13 axis.

Long non‐coding RNA (lncRNA) deleted in lymphocytic leukaemia 1 (DLEU1) was reported to be involved in the occurrence and development of multiple cancers. However, the exact expression, biological function and underlying mechanism of DLEU1 in hepatocellular carcinoma (HCC) remain unclear. In this study, real‐time quantitative polymerase chain reaction (qRT‐PCR) in HCC tissues and cell lines revealed that DLEU1 expression was up‐regulated, and the increased DLEU1 was closely associated with advanced tumour‐node‐metastasis stage, vascular metastasis and poor overall survival. Function experiments showed that knockdown of DLEU1 significantly inhibited HCC cell proliferation, colony formation, migration and invasion, and suppressed epithelial to mesenchymal transition (EMT) process via increasing the expression of E‐cadherin and decreasing the expression of N‐cadherin and Vimentin. Luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay demonstrated that DLEU1 could sponge miR‐133a. Moreover, miR‐133a inhibition significantly reversed the suppression effects of DLEU1 knockdown on HCC cells. Besides, we found that silenced DLEU1 significantly decreased insulin‐like growth factor 1 receptor (IGF‐1R) expression (a target of miR‐133a) and its downstream signal PI3K/AKT pathway in HCC cells, while miR‐133a inhibitor partially reversed this trend. Furthermore, DLEU1 knockdown impaired tumour growth in vivo by regulating miR‐133a/IGF‐1R axis. Collectively, these findings indicate that DLEU1 promoted HCC progression by sponging miR‐133a to regulate IGF‐1R expression. Deleted in lymphocytic leukaemia 1/miR‐133a/IGF‐1R axis may be a novel target for treatment of HCC. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNA (lncRNA) deleted in lymphocytic leukemia 1 (DLEU1) was reported to be involved in the development and progression of multiple cancers. However, the accurate expression pattern, biological function and potential molecular mechanism of DLEU1 in glioma are not yet known. The present study investigated the role of DLEU in the development and progression of glioma, as well as the potential mechanism played by DLEU1 in glioma. Materials and methods: The levels of DLEUI in glioma tissues and cell lines were examined using quantitative real-time PCR. The potential effects of DLEU1 on the proliferation, mobility, invasion and apoptosis of glioma cells were evaluated using corresponding in vitro experiments. The association between DLEU1 and microRNA (miR)-421 was also determined using luciferase reporter activity and RNA immunoprecipitation (RIP) assays. Results: The results revealed that DLEU1 was significantly upregulated in glioma tissues and cell lines. Increased DLEU1 was positively associated with the high-grade carcinoma (III–IV). Functional studies revealed that knockdown of DLEU1 expression by siRNA led to decreased proliferation, migration and invasion and increased apoptosis in human glioma cells. Furthermore, luciferase reporter activity and RIP assays confirmed that DLEUI could act as a competing endogenous RNA (ceRNA) for miR-421 that functioned as a tumor suppressor in glioma. Moreover, inhibition miR-421 partially restored the effect of DLEU1 knockdown on the glioma cells. DLEU1 could regulate myocyte enhancer factor 2D (MEF2D) expression, a known target of miR-421 in glioma cells. Conclusion: Taken together, these findings suggested that DLEU1 regulated MEF2D expression to promote glioma progression by sponging miR-421 and that DLEU1 might be a potential therapeutic target for glioma. [ABSTRACT FROM AUTHOR]

Although accumulating evidence has shown the important function of long non-coding RNAs (lncRNAs) in tumor progression and chemotherapy resistance, the role of lncRNA DLEU1 in regulating proliferation, invasion, and chemoresistance of bladder cancer (BCA) cells remains largely unknown. Here, we found that DLEU1 was upregulated in BLCA tissues and BCA patients with high DLEU1 expression exhibited a shorter survival time. Furthermore, mechanistic analysis and functional assays validated that DLEU1 induced cell proliferation, invasion, and cisplatin resistance of BCA cells by de-repressing the expression of HS3ST3B1 through sponging miR-99b. Low miR-99b and high HS3ST3B1 levels were correlated with worse prognosis in patients with BCA. Ectopic expression of HS3ST3B1 or inhibition of miR-99b reversed DLEU1 knockdown-mediated suppression of cell proliferation, invasion, and cisplatin resistance. Thus, our study revealed a novel role for the DLEU1/miR-99b/HS3ST3B1 axis in regulating proliferation, invasion, and cisplatin resistance of BCA cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Long non-coding RNA DLEU1 is up-regulated in NSCLC. • DLEU1 facilitates proliferation, migration, and invasion, but suppresses apoptosis of NSCLC cells. • DLEU1 exerts an oncogenic function in NSCLC both in vitro and in vivo. • DLEU1 regulates CDK1 expression, binds with SRC and alters the expression levels of P70(S6K), MMP2, and E-cadherin. Abstract Objective To explore the role of long non-coding RNA DLEU1 in the tumorigenesis and progression of non-small cell lung cancer (NSCLC) and the underlying mechanisms. Methods The expression of DLEU1 in NSCLC tumor tissues and adjacent normal tissues was evaluated using bioinformatics analysis and qPCR. The effects of DLEU1 overexpression or deficiency on cell proliferation, apoptosis, migration and invasion were explored experimentally. Additionally, the impact of DLEU1 up-regulation on tumourigenesis was also assessed in vivo. Results The expression of DLEU1 was up-regulated in NSCLC tumor tissues. DLEU1 overexpression promoted the proliferation, migration, and invasion, but inhibited the apoptosis of NSCLC cells by upregulating CDK1 expression, binding with SRC and altering the expression of P70(S6K), MMP2 and E-cadherin. Besides, xenograft tumors in nude mice demonstrated that DLEU1 overexpression accelerated tumor growth. Conclusions DLEU1 promoted tumorigenesis and progression of NSCLC, and might be a promising therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Objectives: APOC1 has been reported to promote tumor progression. Nevertheless, its impact on cell proliferation and glycolysis in gastric cancer (GC) remains to be probed. Hence, this study explored the related impacts and mechanisms., Methods: DLEU1, SMYD2, and APOC1 expression was detected in GC cells. Afterward, ectopic expression and knockdown experiments were conducted in GC cells, followed by measurement of cell proliferation, glucose uptake capability, lactic acid production, ATP content, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and GLUT1, HK2, and LDHA expression. In addition, interactions between DLEU1 and SMYD2 were analyzed with RIP and RNA pull down assays, and the binding of SMYD2 to APOC1 promoter and the methylation modification of SMYD2 in H3K4me3 were assessed with a ChIP assay. The ectopic tumor formation experiment in nude mice was conducted for in vivo validation., Results: DLEU1, SMYD2, and APOC1 were highly expressed in GC cells. The downregulation of DLEU1 or APOC1 inhibited glucose uptake capability, lactic acid production, ECAR, the expression of GLUT1, HK2, and LDHA, ATP contents, and proliferation but augmented OCR in GC cells, which was also verified in animal experiments. Mechanistically, DLEU1 interacted with SMYD2 and recruited SMYD2 to APOC1 promoter to promote H3K4me3 modification, thus facilitating APOC1 expression. Furthermore, the effects of DLEU1 silencing on GC cell proliferation and glycolysis were negated by overexpressing SMYD2 or APOC1., Conclusion: LncRNA DLEU1 recruited SMYD2 to upregulate APOC1 expression, thus boosting GC cell proliferation and glycolysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Recently, a large number of studies have focused on the important role of long non-coding RNAs (lnc RNAs) in metabolism and development and have found that abnormal lnc RNA expression is associated with the pathogenesis and development of many diseases. The lnc RNA DLEU1 is involved in many solid tumours and haematological malignancies. However, its role in epithelial ovarian carcinoma ( EOC) and the associated molecular mechanisms has not been reported. In this study, quantitative reverse transcription- PCR ( qRT- PCR) demonstrated higher lnc RNA DLEU1 expression in EOC tissues than in normal tissues. Plasmid transfection of DLEU1 to up-regulate its expression in the ovarian cancer cell lines A2780 and OVCAR3 increased cell proliferation, migration, and invasion, while inhibited apoptosis. Nude mouse xenograft assay demonstrated that DLEU1 overexpression promoted tumour growth in vivo. QRT- PCR showed decreased miR-490-3p expression, while Western blotting demonstrated increased its target genes CDK1, cyclinD 1 and SMARCD1, as well as matrix metalloproteinase-2 ( MMP2), Bcl- xL and P70S6K protein expression, respectively. Short interfering RNA silencing of DLEU1 produced opposite results, where qRT- PCR showed increased miR-490-3p expression. The dual-luciferase reporter assay revealed a direct interaction between DLEU1 and miR-490-3p. MiR-490-3p plays a tumour suppressor role in epithelial ovarian cancer by targeting CDK1 regulation and influencing SMARCD1 and cyclin D1 ( CCND1) expressions. Therefore, we suggest that through interaction with miR-490-3p, DLEU1 may influence the expression of CDK1, CCND1 and SMARCD1 protein, subsequently promoting the development and progression of EOC. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is crucial to elucidate the mechanism underlying ferroptosis resistance in GBM. We used qRT-PCR to detect the level of DLEU1 and mRNAs of indicated genes, whereas protein levels were determined by Western blots. Fluorescence in situ hybridization assay (FISH) was applied to validate the sublocation of DLEU1 in GBM cells. Gene knockdown or overexpression was achieved by transient transfection. Ferroptosis markers were detected by indicated kits and transmission electron microscopy (TEM). RNA pull-down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (CHIP)-qPCR, and dual-luciferase assay were used to validate the direct interaction between indicated key molecules in the current study. We validated that the expression of DLEU1 was upregulated in GBM samples. DLEU1 knockdown exacerbated erastin-induced ferroptosis in LN229 and U251MG cells, as well as in the xenograft model. Mechanistically, we found that DLEU1 bound with ZFP36 and facilitated ZFP36 to degrade ATF3 mRNA, thus upregulating the expression of SLC7A11 to attenuate erastin-induced ferroptosis. Importantly, our results confirmed that cancer-associated fibroblasts (CAFs) conferred ferroptosis resistance in GBM. The stimulation of CAF-conditioned medium enhanced the activation of HSF1, and HSF1 transcriptionally increased the level of DLEU1 to regulate erastin-induced ferroptosis. This study identified DLEU1 as an oncogenic lncRNA that epigenetically downregulates ATF3 expression via binding with ZFP36 to facilitate ferroptosis resistance in GBM. The upregulation of DLEU1 in GBM might be attributed to CAF-induced HSF1 activation. Our study might provide a research basis for understanding CAF-induced ferroptosis resistance in GBM.

Cholangiocarcinoma is an extremely malignant cancer with poor prognosis. Finding efficient diagnosis and treatment is the indispensable way to improve the prognosis of CCA patients. Therefore, exploring molecular abnormalities in CCA development is urgently needed. DLEU1 is a potential tumor-related lncRNA and abnormally expressed in multiple cancers. In this study, TCGA data analysis showed upregulation of DLEU1 expression in CCA. Furthermore, we confirmed that DLEU1 expression was increased in CCA tissues and cells compared with corresponding controls. Upregulated DLEU1 was related to poor clinicopathological characteristics. Functionally, silencing DLEU1 inhibited CCA proliferation, invasion, stemness maintenance and chemo-resistance, whereas amplifying DLEU1 promoted malignant biological behavior of CCA cells. Mechanistically, DLEU1 expression was transcriptionally facilitated by transcription factor YY1. Moreover, DLEU1 promoted oncogene YAP1 expression by functioning as a sponge to competitively bind to miR-149-5p. YAP1 promoted CCA proliferation, invasion and stemness maintenance, whereas miR-149-5p inhibited malignant biological behavior of CCA. Rescue experiments confirmed that the cancer-promoting effect of DLEU1 was saved by interfering miR-149-5p or YAP1. Furthermore, YAP1 promoted tumor stemness maintenance partly by acting as a transcriptional coactivator to promote TEAD2-induced SOX2 expression. These findings indicated that YY1-induced DLEU1 played a crucial role in CCA progression via miR-149-5p/YAP1/TEAD2/SOX2 axis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

We investigated the role of long non-coding RNA DLEU1 (deleted in lymphocytic leukemia 1) in the progression of papillary thyroid carcinoma (PTC). DLEU1 levels were higher in PTC cell lines (BHP5-16, TPC-1,8505C, and SW1736) and patient tissues (n=54) than in a human thyroid follicular epithelial cell line (Nthy-ori3-1) or adjacent normal thyroid tissues. High DLEU1 expression correlated positively with lymph node metastasis and advanced clinical stages in PTC patients. Bioinformatics, dual luciferase reporter, and RNA pulldown assays confirmed that DLEU1 directly binds to miR-421. Moreover, bioinformatics and dual luciferase reporter assays showed that miR-421 directly binds to the 3'untranslated region of the rho-related coiled-coil kinase 1 (ROCK1) in TPC-1 cells. PTC patient tissues and cell lines showed high ROCK1 mRNA and protein levels as well as low miR-421 levels. CCK-8, flow cytometry, wound healing, and Transwell invasion assays demonstrated that DLEU1 silencing decreases TPC-1 cell proliferation, survival and progression, but they can be rescued by miR-421 knockdown or ROCK1 overexpression. DLEU1 knockdown in TPC-1 cells decreased in vivo xenograft tumor size and weight compared to controls in nude mice. These findings demonstrate that DLEU1 promotes PTC progression by sponging miR-421 and increasing ROCK1 expression.

Mounting studies have revealed that long non-coding RNA (lncRNA) deleted in lymphocytic leukemia 1 (DLEU1) positively regulated the initiation and development of various human malignant tumors. Nevertheless, the function and mechanism of DLEU1 in human glioblastoma multiforme (GBM) remain elusive and ill-defined. The current study was designed to highlight the functional role and disclose the underlying molecular mechanism by which DLEU1 regulated GBM development. We found that DLEU1 was up-regulated in GBM and DLEU1 knockdown significantly inhibited GBM cell proliferation and induced apoptosis. As predicted by bioinformatics analysis and validated in mechanistic assays, SP1 could bind to the promoter region of DLEU1 to activate DLEU1 transcription. Additionally, miR-4429 was verified as a target gene of DLEU1 and negatively modulated by DLEU1. More importantly, miR-4429 overexpression repressed the mRNA and protein levels of SP1 via binding to the 3'UTR of SP1. Overexpression of SP1 or miR-4429 inhibitor could partly abolish the effect of DLEU1 knockdown on cell viability and apoptosis in GBM. Accordingly, our experimental data revealed that SP1-DLEU1-miR-4429 formed a feedback loop to promote GBM development, providing a new evidence for the role of DLEU1 in GBM., (© 2019 The Author(s).)

Long non-coding RNAs (LncRNAs) have been proven to be involved in the progression of osteosarcoma. LncRNA DLEU1 was found to act as an oncogene in various types of cancer. In this study, we aimed to explore the biological functions of DLEU1 in osteosarcoma and the specific mechanism. Our results showed that DLEU1 was highly expressed in osteosarcoma tissue specimens and cells. Downregulation of DLEU1 in osteosarcoma cells inhibited the cell proliferation, migration and invasion. Further mechanistic analysis and functional assays demonstrated that DLEU1 exerted its role by sponging microRNA (miR)-671-5p in osteosarcoma cells. Moreover, DEAD-box helicase 5 (DDX5) was confirmed as the target of miR-671-5p. Furthermore, rescue assays indicated that miR-671-5p inhibitor significantly reversed the effects of DLEU1 knockdown on osteosarcoma cell proliferation and invasion while restoration of DDX5 rescued the proliferation and invasion of osteosarcoma cells transfected with miR-671-5p mimics. In conclusion, DLEU1 acted as an oncogene in osteosarcoma by directly sponging miR-671-5p and regulating the expression of DDX5. These findings suggested that DLEU1 might be a novel therapeutic target in the treatment of osteosarcoma.

Although growing evidence has demonstrated that the long non-coding RNA DLEU1 is involved in the progression of various cancers, its functional role and underlying mechanisms have not been explored in cervical cancer (CC). In this study, we found that DLEU1 was up-regulated in both CC tissues and CC cell lines, and overexpression of DLEU1 was significantly correlated with shorter patient survival. Knockdown of DLEU1 suppressed CC cell proliferation and invasion, whereas overexpression of DLEU1 promoted the proliferation and invasion of CC cells. Bioinformatics analysis was used to elucidate the potential correlation between DLEU1 and miR-381. Moreover, qRT-PCR analysis, luciferase reporter assay and RNA immunoprecipitation assay confirmed that DLEU1 inhibited the expression of miR-381, and revealed a direct interaction between DLEU1 and miR-381. In addition, we demonstrated that miR-381 directly targeted HOXA13 in CC cells. The restoration of HOXA13 expression reversed DLEU1 knockdown or miR-381 overexpression-mediated suppression of cell proliferation and invasion. These results suggested that DLEU1 can promote CC cell proliferation and invasion via the miR-381/HOXA13 axis.

Following a multivariant analysis we demonstrated that children and adolescents with Burkitt lymphoma (BL) and a 13q14.3 deletion have a significant decrease in event free survival (EFS) despite identical short intensive multi-agent chemotherapy. However, how this deletion in the 13q14.3 region is associated with a significant decrease in EFS in children and adolescents with BL is largely unknown. The gene Deleted in Lymphocytic Leukemia 1 (DLEU1) is located in the region of 13q14.3. Here, we report that DLEU1 expression is implicated in the regulation of BL programmed cell death, cell proliferation, and expression of apoptotic genes in transcription activator-like effector nuclease (TALEN)s-induced DLEU1 knockdown and DLEU1 overexpressing BL cell lines. Furthermore, NSG mice xenografted with DLEU1 knockdown BL cells had significantly shortened survival (p < 0.05 and p < 0.005), whereas those xenografted with DLEU1 overexpressing BL cells had significantly improved survival (p < 0.05 and p < 0.0001), following treatment with rituximab and/or cyclophosphamide. These data suggest that DLEU1 may in part function as a tumor suppressor gene and confer chemoimmunotherapy resistance in children and adolescents with BL.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.