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Ovarian cancer (OV) is a highly fatal malignant disease that commonly manifests at an advanced stage. Drug resistance, particularly platinum resistance, is a leading cause of treatment failure because first-line systemic chemotherapy primarily relies on platinum-based regimens. By analyzing the gene expression levels in the Cancer Genome Atlas database, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets, we discerned that HOXB2 was highly expressed in OV and was associated with poor prognosis and cisplatin resistance. Immunohistochemistry and loss-of-function experiments on HOXB2 were conducted to explore its role in OV. We observed that suppressing HOXB2 could impair the growth and cisplatin resistance of OV in vivo and in vitro. Mechanical investigation and experimental validation based on RNA-Seq revealed that HOXB2 regulated ATP-binding cassette transporter members and the ERK signaling pathway. We further demonstrated that HOXB2 modulated the expression of long non-coding RNA DANCR, a differentiation antagonizing non-protein coding RNA, and thus influenced its downstream effectors ABCA1, ABCG1, and ERK signaling to boost drug resistance and cancer proliferation. These results verified that high expression of HOXB2 correlated with platinum resistance and poor prognosis of OV. Therefore, targeting HOXB2 may be a promising strategy for OV therapy. [ABSTRACT FROM AUTHOR]

Background: Gestational diabetes mellitus (GDM) is the most common medical complication associated with pregnancy, which may impose risks on both mother and fetus. Micro RNAs (miRNAs) and long noncoding RNAs (lncRNAs) are implied as vital regulators in GDM. A recent paper revealed dysregulation of miR-33a-5p in placental tissues of GDM patients. However, the biological function of miR-33a-5p in GDM remains elusive. This study focused on exploring the function and underlying mechanisms of miR-33a-5p in GDM. Methods: 12 GDM pregnancies and 12 healthy pregnancies were enrolled in the study. INS-1 cell line was applied in in vitro experiments. The expression levels of miR-33a-5p, lnc-DANCR (Differentiation Antagonizing Non-Protein Coding RNA), and ABCA1 (ATP-binding cassette transporter 1) mRNA were determined by RT-qPCR assay. Glucose and insulin levels were measured by ELISA assay. Luciferase reporter assay and western blot assay were applied to validate the target of miR-33a-5p. Results: miR-33a-5p was upregulated in the blood samples from GDM, and was positively correlated with blood glucose (p < 0.0001). Overexpression or inhibition of miR-33a-5p significantly inhibited or promoted cell growth and insulin production of INS-1 cells (p < 0.01). Furthermore, ABCA1 is a direct target of miR-33a-5p, and lnc-DANCR functions as a sponge for miR-33a-5p to antagonize the function of miR-33a-5p in INS-1 cells. Conclusion: Our study demonstrated that lnc-DANCR-miR-33a-5p-ABCA1 signaling cascade plays a crucial role in the regulation of the cellular function of INS-1 cells. [ABSTRACT FROM AUTHOR]

Background: Glioma is the most common and aggressive primary brain tumor with high mortality rate around the world. LncRNAs have been identified to play key roles in tumorigenesis in various cancers, including glioma. However, the precise mechanism of DANCR in progression of glioma remains poorly defined. Methods: The expression levels of DANCR, miR-135a-5p and BMI1 were measured by qRT-PCR in glioma tissues and cells. Cell proliferation, migration and invasion were detected by CCK-8 assay and transwell assay, respectively. The possible binding sites of miR-135a-5p and DANCR or BMI1 were predicted by online software and verified using luciferase report assay and RNA immunoprecipitation (RIP) assay. Western blot analysis was carried out to detect the protein of BMI1 expression. A xenograft tumor model was established to investigate the functions of DANCR in glioma progression in vivo. Results: DANCR was upregulated and miR-135a-5p was downregulated in glioma tissues and cells. Knockdown of DANCR inhibited cell proliferation, migration and invasion in glioma cells. In addition, miR-135a-5p was a direct target of DANCR, and its elevated expression could reverse miR-135a-5p inhibition-mediated progression of glioma. Moreover, miR-135a-5p could specially bind to BMI1, and the expression of BMI1 was obviously elevated in glioma tissues and cells. Furthermore, DANCR acted as a ceRNA to regulate BMI1 expression and BMI1-mediated effects on progression of glioma by sponging miR-135a-5p. Besides, inhibition of DANCR limited tumor growth by regulating miR-135a-5p and BMI1 expression in vivo. Conclusion: DANCR knockdown inhibited cell proliferation, migration and invasion in glioma cells through regulating miR-135a-5p/BMI1 axis, providing viable therapeutic avenues for treatment of glioma. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are emerging as important regulators of numerous biological processes, especially in cancer development. Aberrantly expressed and specifically located in tumor cells, they exert distinct functions in different cancers via regulating multiple downstream targets such as chromatins, RNAs, and proteins. Differentiation antagonizing non-protein coding RNA (DANCR) is a cytoplasmic lncRNA that generally works as a tumor promoter. Mechanically, DANCR promotes the functions of vital components in the oncogene network by sponging their corresponding microRNAs or by interacting with various regulating proteins. DANCR's distinct expression in tumor cells and collective involvement in pro-tumor pathways make it a promising therapeutic target for broad cancer treatment. Herein, we summarize the functions and molecular mechanism of DANCR in human cancers. Furthermore, we introduce the use of CRISPR/Cas9, antisense oligonucleotides and small interfering RNAs as well as viral, lipid, or exosomal vectors for onco-lncRNA targeted treatment. Conclusively, DANCR is a considerable promoter of cancers with a bright prospect in targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is one of the available options for prostate cancer (PC). However, the acquisition of chemoresistance has become a major cause of chemotherapy failure. The long noncoding RNA DANCR is demonstrated to serve as an oncogene in various human cancers, including PC. However, the potential role of DANCR in docetaxel (DTX) resistance of PC and its underlying mechanism remains unclear. Methods: The abundance of DANCR, miR-34a-5p, and JAG1 mRNA was examined by quantitative reverse transcription PCR. The Cell Counting Kit-8 (CCK8) was used to determine the 50% inhibitory concentration value. Cell viability was evaluated by CCK8 and colony-formation assays. Transwells were utilized to analyze cell migration and invasion ability. The protein levels of LRP, P-gp, MRP1, and JAG1 were measured by Western blot assay. The target relationship between DANCR and miR-34a-5p, as well as miR-34a-5p and JAG1, was demonstrated by dual-luciferase, RNA immunoprecipitation, and RNA pull-down analysis. Tumor xenograft was undertaken to confirm the effect of DANCR on DTX resistance in PC. Results: DANCR and JAG1 were significantly upregulated, but miR-34a-5p was downregulated in DTX-resistant PC. Silencing of DANCR improved the DTX efficacy in DTX-resistant PC cells. DANCR served as a competing endogenous RNA of miR-34a-5p, leading to the derepression of miR-34a-5p target JAG1, which eventually triggered the resistance to DTX in DTX-tolerated PC. Conclusion: The DANCR/miR-34a-5p axis enhanced DTX resistance of PC via targeting JAG1, providing a novel insight to improve chemotherapy for PC. [ABSTRACT FROM AUTHOR]

Long noncoding RNA (lncRNA) differentiation antagonizing nonprotein coding RNA (DANCR) has been identified as an oncogene in several cancers. However, the biological function and role of DANCR in hepatocellular carcinoma (HCC) remain unclear. Our current study aimed to investigate the detailed mechanism of DANCR in HCC. We found that DANCR was significantly upregulated in HCC cell lines in comparison to LO2 cells. Then, we observed that knockdown of DANCR could greatly inhibit Huh7 and HepG2 cell proliferation. In addition, HCC cell apoptosis was increased by silence of DANCR and meanwhile, cell cycle progression was blocked in G1 phase. Apart from these, downregulation of DANCR repressed HCC cell migration and invasion ability obviously. As predicted by the bioinformatics analysis, microRNA‐216a‐5p (miR‐216a‐5p) could serve as a direct target of DANCR. MiR‐216a‐5p has been reported to be involved in many cancers. Here, the correlation between miR‐216a‐5p and DANCR was confirmed using dual‐luciferase reporter assay and radioimmunoprecipitation assay. Subsequently, Kruppel‐like factor 12 (KLF12) exerts an important role in different tumor types. KLF12 can function as a downstream target of miR‐216a‐5p. Finally, the in vivo experiments were used and the data proved that DANCR also strongly suppressed HCC tumor growth in vivo via targeting miR‐216a‐5p and KLF12. In conclusion, our study indicated that DANCR might provide a new perspective for HCC treatment. We reported that the DANCR exhibited an oncogenic role in hepatocellular carcinoma (HCC). Our data indicated that DANCR was involved in HCC progression and it could function as a biomarker for HCC. [ABSTRACT FROM AUTHOR]

Background: Abnormal expression of long non-coding RNA anti-differentiation noncoding RNA (lncRNA DANCR) can frequently be detected in cancer. Because of this, it is of vital necessity to perform a meta-analysis to clarify the value of lncRNA DANCR as a prognostic marker in malignant tumors. Methods: Related studies were retrieved from electronic databases including Web of Science, PubMed, and OVID, from inception to November 21, 2018. The HRs and corresponding 95% CIs were also calculated to explore the relationship of lncRNA DANCR expression with patient survival. Moreover, ORs were computed to assess the association of lncRNA DANCR expression with the pathological parameters. Results : A total of 14 studies involving 1,117 patients were included in this meta-analysis. The pooled HR suggested that high lncRNA DANCR expression was correlated with poor overall survival (OS; HR =1.85, 95% CI: 1.56–2.18) and disease-free survival (DFS; HR =2.49, 95% CI: 1.75–3.56) in cancer patients. Besides, High lncRNA DANCR expression was related to poor histological grade (PHG; OR =2.01, 95% CI: 1.08–3.75), high tumor stage (HTS; OR =3.52, 95% CI: 1.67–7.43), lymph node metastasis (LNM; OR =3.47, 95% CI: 1.42–8.49), and distant metastasis (DM; OR =4.76, 95% CI: 2.39–9.51). However, no evidence of obvious asymmetry was found for DFS (Pr>|z|=0.308), PHG (Pr>|z|=0.707), LNM (Pr>|z|=0.174), and DM (Pr>|z|=0.734) using Begg's funnel plot. Conclusion: Our findings suggest that high lncRNA DANCR expression can predict poor OS, DFS, PHG, HTS, LNM, and DM in cancer patients, implying that high lncRNA DANCR expression may potentially serve as a new indicator for poor prognosis and metastasis in cancer. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) play important roles in human cancers. However, the functional roles of lncRNAs in non-small-cell lung cancer (NSCLC) and the underlying mechanisms are not well understood. Methods: We examined the expression of lncRNA DANCR in NSCLC by qRT-PCR and explored its biological roles in NSCLC progression by cell and molecular biology studies. Results: DANCR expression level was increased in human NSCLC. The knockdown of DANCR inhibited NSCLC cell proliferation by inducing cell apoptosis and cell cycle arrest. In addition, DANCR knockdown suppressed NSCLC cell migration and invasion via inhibition of epithelial–mesenchymal transition (EMT). On the contrary, DANCR overexpression had the opposite effects. DANCR knockdown inhibited EZH-2-mediated epigenetic silencing of p21 promoter and increased p21 expression. Moreover, DANCR knockdown inhibited NSCLC cell proliferation, migration, and invasion in a p21-dependent manner. Conclusion: DANCR plays oncogenic roles in NSCLC and may provide a novel biomarker for NSCLC diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Long non‐coding RNAs (lncRNAs) have been identified to play vital roles in cancers, including human retinoblastoma (RB). However, the deepgoing mechanism is still ambiguous. In present study, we investigate the biological role of lncRNA DANCR (differentiation antagonizing non‐protein coding RNA) in carcinogenesis of RB. Results revealed that DANCR was up‐regulated in RB tissue and cell lines. Moreover, the ectopic overexpression of DANCR indicated poor overall survivals and disease free survival (DFS) for RB patients. In vitro and in vivo experiments, DANCR knockdown suppress the proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) correlated protein (N‐cadherin, Vimentin) of RB cells. Bioinformatics analysis predicted that miR‐34c and miR‐613 targeted with 3′‐UTR of DANCR, besides, miR‐34c and miR‐613 also targeted with 3′‐UTR of MMP‐9, which was validated by luciferase reporter assay. Functional experiments demonstrated that miR‐34c and miR‐613 could reverse the oncogenic function of DANCR in RB tumorigenesis. In conclusion, our results reveal that DANCR function as competing endogenous RNA (ceRNA) for miR‐34c and miR‐613 to modulate progression and metastasis in RB oncogenesis via targeting MMP‐9, presenting the in‐depth regulation of DANCR in RB and providing a novel insight for ceRNA mechanism for RB. [ABSTRACT FROM AUTHOR]

Long non-coding RNA DANCR has been certified to act as an effective regulator in the tumorigenesis of several types of tumors. In this study, the special role of DANCR in glioma progression was explored. It was speculated that high expression of DANCR in glioma tissues and cells might be an oncogenic factor. To understand the correlation between the expression pattern of DANCR and the overall survival of glioma patients, the Kaplan Meier method was used for analysis. The result showed that high expression of DANCR might be a poor prognostic factor in glioma patients. The effects of DANCR expression on proliferation and migration of glioma cells were detected through performing MTT assay, colony formation assay and transwell assays. Results of loss-of function assay suggested that downregulated DANCR could inhibited glioma cell proliferation and migration. Additionally, western blot assay was conducted in glioma cells to demonstrate that the protein levels of the Wnt/β-catenin pathway related proteins was negatively modulated by si-DANCR. Finally, and the increased proliferation and migration of glioma cells were observed after the Wnt/β-catenin signals were activated. However, this tendency was reduced by si-DANCR. In conclusion, DANCR positively affected glioma progression via activating Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Long non‐coding RNAs (lncRNAs) have emerged as new and important regulators of pathological processes including tumour development. In this study, we demonstrated that differentiation antagonizing non‐protein coding RNA (DANCR) was up‐regulated in lung adenocarcinoma (ADC) and that the knockdown of DANCR inhibited tumour cell proliferation, migration and invasion and restored cell apoptosis rescued; cotransfection with a miR‐496 inhibitor reversed these effects. Luciferase reporter assays showed that miR‐496 directly modulated DANCR; additionally, we used RNA‐binding protein immunoprecipitation (RIP) and RNA pull‐down assays to further confirm that the suppression of DANCR by miR‐496 was RISC‐dependent. Our study also indicated that mTOR was a target of miR‐496 and that DANCR could modulate the expression levels of mTOR by working as a competing endogenous RNA (ceRNA). Furthermore, the knockdown of DANCR reduced tumour volumes in vivo compared with those of the control group. In conclusion, this study showed that DANCR might be an oncogenic lncRNA that regulates mTOR expression through directly binding to miR‐496. DANCR may be regarded as a biomarker or therapeutic target for ADC. [ABSTRACT FROM AUTHOR]

lncRNAs regulate the initiation and progression of osteosarcoma, although the mechanism by which this occurs remains unknown. The present study shows that over-expression of the lncRNA DANCR increased osteosarcoma cell proliferation, migration, and invasion in vitro, as well as promoted xenograft tumor growth and lung metastasis in vivo. Mechanistically, DANCR promoted osteosarcoma progression by mediating cancer stem cells (CSCs) features. Moreover, pull-down assays and luciferase reporter assays indicated that DANCR upregulated expression of the receptor tyrosine kinase AXL by competitively binding to miR-33a-5p. Furthermore, DANCR enhanced the expression of proteins downstream of the AXL-Akt pathway. DANCR was consistently significantly increased in osteosarcoma tissues, and its expression was positively correlated with tumor size and metastasis as an independent poor prognostic factor. Furthermore, both in patient tumors and xenograft tumors, DANCR expression was positively related to AXL and negatively related to miR-33a-5p. Taken together, our results suggest that DANCR is a crucial upregulator of osteosarcoma and an independent predictor of prognosis. DANCR increases CSCs function by upregulating AXL via competitively binding to miR-33a-5p, and this function is sequentially performed through the PI3K-Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Cartilage tissues have limited capacity for repair after damage and then cause osteoarthritis, so finding alternative treatment is ongoing. Mesenchymal stem cells (MSCs) have become a promising therapy for cartilage damage and diseases due to the advantages of easy separation, high proliferative potentiality, and genetic stability. Synovium-derived MSCs (SMSCs) have been recognized as an ideal source for cartilage repair. In our previous study, we found that Sox4 promoted proliferation and chondrogenesis of SMSCs through upregulation of long noncoding RNA (lncRNA) DANCR. However, the exact molecular mechanism by which DANCR promotes proliferation and chondrogenesis of SMSCs remains unknown. In the present study, we investigated the effect of lncRNA DANCR on the proliferation and chondrogenesis of SMSCs. We found that overexpression of DANCR could promote proliferation and chondrogenesis of SMSCs, while knockdown of DANCR had the opposite effect. Moreover, our data demonstrated that DANCR directly interacted with myc, Smad3, and STAT3 mRNA to regulate their stability. Finally, we found that the promotion of SMSC proliferation induced by DANCR depended on myc. Also, DANCR activated chondrogenesis of SMSCs via upregulation of Smad3 and STAT3 expression. Our growing knowledge of the role of DANCR is pointing toward its potential use as a novel therapeutic approach for cartilage damage and diseases. [ABSTRACT FROM AUTHOR]

Healing of large calvarial bone defects in adults adopts intramembranous pathway and is difficult. Implantation of adipose-derived stem cells (ASC) that differentiate towards chondrogenic lineage can switch the bone repair pathway and improve calvarial bone healing. Long non-coding RNA DANCR was recently uncovered to promote chondrogenesis, but its roles in rat ASC (rASC) chondrogenesis and bone healing stimulation have yet to be explored. Here we first verified that DANCR expression promoted rASC chondrogenesis, thus we harnessed CRISPR activation (CRISPRa) technology to upregulate endogenous DANCR, stimulate rASC chondrogenesis and improve calvarial bone healing in rats. We generated 4 different dCas9-VPR orthologues by fusing a tripartite transcription activator domain VPR to catalytically dead Cas9 (dCas9) derived from 4 different bacteria, and compared the degree of activation using the 4 different dCas9-VPR. We unveiled surprisingly that the most commonly used dCas9-VPR derived from Streptococcus pyogenes barely activated DANCR. Nonetheless dCas9-VPR from Staphylococcus aureus (SadCas9-VPR) triggered efficient activation of DANCR in rASC. Delivery of SadCas9-VPR and the associated guide RNA into rASC substantially enhanced chondrogenic differentiation of rASC and augmented cartilage formation in vitro. Implantation of the engineered rASC remarkably potentiated the calvarial bone healing in rats. Furthermore, we identified that DANCR improved the rASC chondrogenesis through inhibition of miR-203a and miR-214. These results collectively proved that DANCR activation by SadCas9-VPR-based CRISPRa provides a novel therapeutic approach to improving calvarial bone healing. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated that long non-coding RNAs (lncRNAs) play critical roles in cancer development and progression. However, the mechanism by which lncRNAs contribute to colorectal cancer remains unclear. In this study, we identified the lncRNA, DANCR , which was upregulated in colorectal cancer. The upregulation of DANCR expression was associated with shorter patient survival time. DANCR depletion decreased cell proliferation, cell cycle progression, and tumorigenesis in a subcutaneous mouse xenograft model system. We further demonstrated that DANCR bound with lysine acetyltransferase 6A. This binding was essential for KAT6A acetyltransferase activity and thus, it influenced the expression of KAT6A target genes. Our data indicated that DANCR functions as an oncogenic lncRNA that promotes tumor development and progression. Therefore, DANCR may be a target molecule for colorectal cancer treatment. • In the present study, we observed that DANCR was upregulated in colorectal cancer compared with normal colorectal tissues and that it predicted poor patient survival. • DANCR promoted colorectal cancer cell proliferation and cell cycle arrest by activating the H3K23 acetyltransferase, KAT6A, and by activating cell cycle-related proteins. • Collectively, our results identified a new regulatory mechanism by which DANCR promotes colorectal cancer progression, providing a potential therapeutic target and prognostic factor for colorectal cancer. [ABSTRACT FROM AUTHOR]

Increasing evidence displays that microRNAs (miRNAs) participate in the development of various human malignancies, including esophageal squamous cell carcinoma (ESCC). MicroRNA-33a-5p (miR-33a-5p) has recently been reported to function as a tumor suppressor in many human cancers. However, the expression and role of miR-33a-5p in ESCC remains largely unknown. Herein, we discovered that miR-33a-5p was down-regulated in both ESCC tissues and cell lines, compared with their normal counterparts, and decreased expression of miR-33a-5p was found to be closely associated with poor patient prognosis of ESCC. Moreover, functional experiments revealed that up-regulation of miR-33a-5p inhibited cell proliferation and metastasis of ESCC cells. In addition, the expression level of miR-33a-5p was found to be negatively correlated with the long non-coding RNA (lncRNA) differentiation antagonizing non-protein coding RNA (DANCR), in both ESCC tissues and cell lines. Furthermore, zinc-finger-enhancer binding protein 1 (ZEB1) was predicted and confirmed to be a direct target of miR-33a-5p in ESCC. Further mechanistic investigation indicated that DANCR may function as a competing endogenous RNA (ceRNA) to sponge miR-33a-5p, and thereby up-regulate ZEB1 expression in ESCC. This study highlights the functions of miR-33a-5p in the progression of ESCC and suggests that the DANCR/miR-33a-5p/ZEB1 axis may be a potential prognostic and therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidences have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers that play key roles in tumor development and progression. Differentiation antagonizing non-protein noding RNA (DANCR) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancers. However, the clinical significance and molecular mechanism of DANCR in bladder cancer is still unknown. Methods: The relative expression level of DANCR was determined by Real-Time qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell lines. Loss-of-function experiments were performed to investigate the biological roles of DANCR on bladder cancer cell proliferation, migration, invasion and tumorigenicity. Comprehensive transcriptional analysis, RNA-FISH, dual-luciferase reporter assay and western blot were performed to explore the molecular mechanisms underlying the functions of DANCR. Results: In this study, we found that DANCR was significantly up-regulated in bladder cancer. Moreover, increased DANCR expression was positively correlated with higher histological grade and advanced TNM stage. Further experiments demonstrated that knockdown of DANCR inhibited malignant phenotypes and epithelial-mesenchymal transition (EMT) of bladder cancer cells. Mechanistically, we found that DANCR was distributed mostly in the cytoplasm and DANCR functioned as a miRNA sponge to positively regulate the expression of musashi RNA binding protein 2 (MSI2) through sponging miR-149 and subsequently promoted malignant phenotypes of bladder cancer cells, thus playing an oncogenic role in bladder cancer pathogenesis. Conclusion: This study is the first to demonstrate that DANCR plays a critical regulatory role in bladder cancer cell and DANCR may serve as a potential diagnostic biomarker and therapeutic target of bladder cancer. [ABSTRACT FROM AUTHOR]