The Rejuvenation and Functional Restoration of Aged Adipose Stem Cells by DUXAP10 Knockdown via the Regulation of the miR-214-3p/RASSF5 Axis.

Adipose stem cell (ASC)-based therapies provide an encouraging option for tissue repair and regeneration. However, the function of these cells declines with aging, which limits their clinical transformation. Recent studies have outlined the involvement of long non-coding RNAs in stem cell aging. Here, we reanalyzed our published RNA sequencing (RNA-seq) data profiling differences between ASCs from young and old donors and identified a lncRNA named double homeobox A pseudogene 10 (DUXAP10) as significantly accumulated in aged ASCs. Knocking down DUXAP10 promoted stem cell proliferation and migration and halted cell senescence and the secretion of proinflammatory cytokines. In addition, DUXAP10 was located in the cytoplasm and functioned as a decoy for miR-214-3p. miR-214-3p was downregulated in aged ASCs, and its overexpression rejuvenated aged ASCs and reversed the harm caused by DUXAP10. Furthermore, Ras Association Domain Family Member 5 (RASSF5) was the target of miR-214-3p and was upregulated in aged ASCs. Overexpressing DUXAP10 and inhibiting miR-214-3p both enhanced RASSF5 content in ASCs, while DUXAP10 knockdown promoted the therapeutic ability of aged ASCs for skin wound healing. Overall, this study offers new insights into the mechanism of age-related ASC dysfunction and names DUXAP10 and miR-214-3p as potential targets for energizing aged stem cells.

The pseudogene DUXAP10 contributes to gefitinib resistance in NSCLC by repressing OAS2 expression.

Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI),is the currently recommended first-line therapy for advanced EGFR-mutant lung cancer, and understanding the mechanism of resistance is the key to formulating therapeutic strategies for EGFR-TKIs. In this study, we evaluate the expression patterns and potential biological functions of the pseudogene DUXAP10 in gefitinib resistance. We find that pseudogene DUXAP10 expression is significantly upregulated in NSCLC gefitinib-resistant cells and tissues. Gain and loss of function assays reveal that knockdown of DUXAP10 by siRNA reverses gefitinib resistance both in vitro and in vivo. Furthermore, DUXAP10 interacts with the histone methyltransferase enhancer of zeste homolog 2 (EZH2) to repress the expression of 2',5'-oligoadenylate synthetase (OAS2). Overall, our study highlights the pivotal role of DUXAP10 in gefitinib resistance, and the DUXAP10/EZH2/OAS2 axis might be a promising therapeutic target to overcome acquired gefitinib resistance in NSCLC.

Long non-coding RNA DUXAP10 exerts oncogenic properties in osteosarcoma by recruiting HuR to enhance SOX18 mRNA stability.

Recent studies have demonstrated that several long non-coding RNAs (lncRNAs) play an important role in the occurrence and development of osteosarcoma (OS). However, more lncRNAs and their mechanisms in regulating growth and migration of OS cells remain to be investigated. In this study, we identified an lncRNA called DUXAP10 by analysis of GEO data, which was significantly up-regulated in OS tissues and cell lines. Experiments in vitro revealed that lncRNA DUXAP10 promoted proliferation, migration, and invasion of OS cells and inhibited their apoptosis. We also demonstrated that DUXAP10 promoted the formation and growth of OS by tumor formation assay. Furthermore, SOX18 was identified as a critical downstream target of DUXAP10 by transcriptome RNA-seq. Mechanistically, DUXAP10 mainly localized in cytoplasm and could specifically bind to HuR to increase the stability of SOX18 mRNA. Meanwhile, SOX18 knockdown largely reversed increased proliferation of OS cells induced by DUXAP10 overexpression. Findings from this study indicate that lncRNA DUXAP10 can act as an oncogene in osteosarcoma by binding HuR to up-regulate the expression of SOX18 at a post-transcriptional level, which may provide a new target for OS clinical diagnosis and treatment.

The LncRNA DUXAP10 Could Function as a Promising Oncogene in Human Cancer.

Cancer is one of the most prevalent and deadliest diseases globally, with an increasing morbidity of approximately 14 million new cancer cases per year. Identifying novel diagnostic and prognostic biomarkers for cancers is important for developing cancer therapeutic strategies and lowering mortality rates. Long noncoding RNAs (lncRNAs) represent a group of noncoding RNAs of more than 200 nucleotides that have been shown to participate in the development of human cancers. The novel lncRNA DUXAP10 was newly reported to be abnormally overexpressed in several cancers and positively correlated with poor clinical characteristics of cancer patients. Multiple studies have found that DUXAP10 widely regulates vital biological functions related to the development and progression of cancers, including cell proliferation, apoptosis, invasion, migration, and stemness, through different molecular mechanisms. The aim of this review was to recapitulate current findings regarding the roles of DUXAP10 in cancers and evaluate the potential of DUXAP10 as a novel biomarker for cancer diagnosis, treatment, and prognostic assessment.

LncRNA DUXAP10 Upregulation and the Hedgehog Pathway Activation Are Critically Involved in Chronic Cadmium Exposure-Induced Cancer Stem Cell-Like Property.

Cadmium (Cd) is a well-known lung carcinogen. However, the mechanism of Cd carcinogenesis remains to be clearly defined. Cd has been shown to act as a weak mutagen, suggesting that it may exert tumorigenic effect through nongenotoxic ways, such as epigenetic mechanisms. Long noncoding RNAs (lncRNAs) refer to RNA molecules that are longer than 200 nucleotides in length but lack protein-coding capacities. Regulation of gene expressions by lncRNAs is considered as one of important epigenetic mechanisms. The goal of this study is to investigate the mechanism of Cd carcinogenesis focusing on the role of lncRNA dysregulations. Cd-induced malignant transformation of human bronchial epithelia BEAS-2B cells was accomplished by a 9-month low-dose Cd (CdCl2, 2.5 µM) exposure. The Cd-exposed cells formed significantly more colonies in soft agar, displayed cancer stem cell (CSC)-like property, and formed tumors in nude mice. Mechanistically, chronic low-dose Cd exposure did not cause significant genotoxic effects but dysregulated lncRNA expressions. Further Q-PCR analysis confirmed the significant upregulation of the oncogenic lncRNA DUXAP10 in Cd-transformed cells. DUXAP10 knockdown in Cd-transformed cells significantly reduced their CSC-like property. Further mechanistic studies showed that the Hedgehog pathway is activated in Cd-transformed cells and inhibition of this pathway reduces Cd-induced CSC-like property. DUXAP10 knockdown caused the Hedgehog pathway inactivation in Cd-transformed cells. Furthermore, Pax6 expression was upregulated in Cd-transformed cells and Pax6 knockdown significantly reduced their DUXAP10 levels and CSC-like property. In summary, these findings suggest that the lncRNA DUXAP10 upregulation may play an important role in Cd carcinogenesis.

Long noncoding RNA DUXAP10 promotes the stemness of glioma cells by recruiting HuR to enhance Sox12 mRNA stability.

Long noncoding RNA (lncRNA) DUXAP10 has been shown to act as an oncogene in various tumors; however, its roles in glioma progression have never been established. Here, we show that DUXAP10 is overexpressed in glioma tissues and cells. Loss of function experiments reveal that DUXAP10 knockdown has little effects on glioma cell viability, but significantly reduces the stemness of glioma cells, which is characterized as the decrease of stemness marker expression, tumor sphere-forming ability, and ALDH activity. RNA immunoprecipitation and immunofluorescence assays indicate that DUXAP10 can directly interact with HuR protein and suppress the cytoplasm-nuclear translocation of HuR, which subsequently enhances Sox12 mRNA stability in cytoplasm and thus increases Sox12 expression. Further rescuing experiments show that the HuR/Sox12 axis is responsible for DUXAP10-mediated effects on glioma cell stemness.

Oncogenic pseudogene DUXAP10 knockdown suppresses proliferation and invasion and induces apoptosis of papillary thyroid carcinoma cells by inhibition of Akt/mTOR pathway.

Pseudogenes, another novel group of non-coding segments without protein-coding capacity, are closely associated with tumourigenesis and cancer progression. Double homeoboxA pseudogene 10 (DUXAP10) is reported to be robustly expressed in thyroid carcinoma. However, the functional role and underlying mechanism of DUXAP10 in papillary thyroid carcinoma (PTC) progression remain undefined. DUXAP10 expression in PTC cells was detected by qRT-PCR. Cell proliferation and invasion were determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell invasion assay, respectively. Apoptosis was evaluated using flow cytometry. Protein expression of matrix metalloproteinase (MMP)-2, MMP-9, protein kinase B (Akt), phosphorylated Akt, mammalian target of rapamycin (mTOR), and phosphorylated mTOR was examined by western blot. Results showed that DUXAP10 was significantly overexpressed in PTC cells compared with normal thyroid follicular epithelium cells. DUXAP10 silencing suppressed cell proliferation and invasive ability, reduced the expression of MMP-2 and MMP-9, and increased apoptotic rate and caspase-3 activity in PTC cells. Additionally, the Akt/mTOR pathway was inhibited following DUXAP10 knockdown in PTC cells. Activation of the Akt/mTOR pathway by 740Y-P and MHY1485 attenuated DUXAP10 knockdown-induced proliferation reduction, invasion suppression and apoptosis in PTC cells. In conclusion, DUXAP10 knockdown suppressed proliferation and invasion and induced apoptosis in PTC cells at least partially by inhibition of the Akt/mTOR pathway.

microRNA-1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39-mediated PI3K/AKT/mTOR pathway in HCC.

Increasing studies have confirmed that abnormally expressed microRNAs (miRNAs) take part in the carcinogenesis as well as the aggravation of hepatocellular carcinoma (HCC). However, little information is currently available about miR-1914 in HCC. Here, we first confirmed that miR-1914 inhibition in HCC cell lines and tumour specimens correlates with tumour size and histological grade. In a series of functional experiments, miR-1914 inhibited tumour proliferation and colony formation, resulting in cell cycle arrest and increased apoptosis. Moreover, miR-1914 mediated its functional effects by directly targeting GPR39 in HCC cells, leading to PI3K/AKT/mTOR repression. Restoring GPR39 expression incompletely counteracted the physiological roles of miR-1914 in HCC cells. In addition, down-regulation of AKT phosphorylation inhibited the effects of miR-1914 in HCC. Furthermore, the overexpression of lncRNA DUXAP10 negatively correlated with the expression of miR-1914 in HCC; thus, lncRNA DUXAP10 regulated miR-1914 expression and modulated the GPR39/PI3K/AKT-mediated cellular behaviours. In summary, the present study demonstrated for the first time that lncRNA DUXAP10-regulated miR-1914 plays a functional role in inhibiting HCC progression by targeting GPR39-mediated PI3K/AKT/mTOR pathway, and this miRNA represents a novel therapeutic target for patients with HCC.

Pseudogene DUXAP10 acts as a diagnostic and prognostic marker and promotes cell proliferation by activating PI3K/AKT pathway in hepatocellular carcinoma.

Background: Recently, the pseudogene DUXAP10 was shown to be overexpressed in various human cancers and emerged as a key cancer regulator. However, the roles of DUXAP10 in hepatocellular carcinoma (HCC) tumorigenesis and progression remain uncharacterized. Methods: Comprehensive analyses were performed to investigate DUXAP10 expression patterns, potential biologic functions, and clinical significance in HCC based on the data downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. DUXAP10 expression levels in HCC tissue sections and cells were verified using quantitative real-time PCR analysis. DUXAP10-siRNA was used to silence DUXAP10 in the Hep3B cell line to determine the roles of DUXAP10 in HCC cell proliferation. Results: DUXAP10 was significantly overexpressed in HCC, and DUXAP10 upregulation was closely associated with poor prognoses in HCC patients. DUXAP10 knockdown decreased cell proliferation and arrested HCC cells in the G1 phase of the cell cycle. Western blot analysis showed that DUXAP10 knockdown decreased p-AKT expression in HCC cells. Conclusion: Our study demonstrates that pseudogene DUXAP10 promotes HCC cell proliferation by activating PI3K/AKT pathway and could act as a potential diagnostic and prognostic biomarker for HCC patients.

Pseudogene DUXAP10 can be used as a diagnostic and prognostic biomarker in human cancers.

The pseudogene DUXAP10 is overexpressed in numerous types of human cancers. However, the diagnostic and prognostic value of DUXAP10 in cancers has yet to be characterized. PubMed, EMBASE, Web of Science, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus databases were comprehensively searched in this study. A total of 50 studies comprising 11,292 patients were collected in this integrated analysis. DUXAP10 was confirmed to be significantly overexpressed in various human cancers (p < .05). Summary receiver operating characteristic (SROC) curve analysis was implemented, which indicated that DUXAP10 was a potential diagnostic biomarker for human cancers (area under the curve [AUC] of SROC curve = 0.81 [0.77-0.84]; pooled sensitivity = 0.69 [0.62-0.75]; pooled specificity = 0.81 [0.73-0.87]). In addition, hazard ratios (HRs) with 95% confidence intervals (CIs) were obtained to evaluate the association of DUXAP10 expression with overall survival (OS) time of cancer patients. Outcomes of meta-analysis suggested that upregulation of DUXAP10 was closely associated with poor OS (pooled HR = 1.11 [1.03-1.18]). Our study revealed that the pseudogene DUXAP10 was upregulated in multiple types of cancers and could be a potential biomarker with good diagnostic and prognostic value for human cancers.

DUXAP10 inhibition attenuates the proliferation and metastasis of hepatocellular carcinoma cells by regulation of the Wnt/ß-catenin and PI3K/Akt signaling pathways.

The long non-coding RNA DUXAP10 has been involved in the development, progression, and metastasis in several human cancers, but its biological function and underlying mechanism in hepatocellular carcinoma (HCC) still undetermined. The present study was proposed to explore the effect of DUXAP10 on the growth and metastasis of HCC cells and the potential mechanisms involved. The results showed that DUXAP10 is dramatically elevated in HCC tumor tissues and cell lines. Knockdown of DUXAP10 by DUXAP10 si-RNA significantly inhibited the cell viability, proliferation and induce the apoptosis of HCC cell line. Meanwhile, inhibition of DUXAP10 attenuates the cell migration, invasion, and epithelial-mesenchymal transition (EMT) process. No significant change of JNK MAPK pathway was detected in DUXAP10 siRNA transfected HCC cell lines. The ß-catenin and pAkt levels were decreased in the Hep G2+DUXAP10 siRNA and SMMC7721+DUXAP10 siRNA groups, while the activation of Wnt/ß-catenin or PI3K/Akt suppressed the inhibition of DUXAP10 siRNA on cell proliferation and migration. Collectively, DUXAP10 plays a critical role in regulating HCC development, potentially by regulating EMT and cell proliferation through the PI3K/Akt and Wnt/ß-catenin signaling. Inhibition of DUXAP10 in HCC HepG2 cells could attenuate the EMT and cell proliferation and invasion. Therefore, DUXAP10 might be a promising therapy target to inhibit the growth of HCC.

LncRNA DUXAP10 modulates cell proliferation in esophageal squamous cell carcinoma through epigenetically silencing p21.

Esophageal Squamous Cell Carcinoma (ESCC) belongs to malignant tumor of human digestive system. It has greatly threatened human health both mentally and physically. Long non-coding RNAs have been discovered to be special molecular regulators in various cancers, including ESCC. LncRNA DUXAP10 is a newfound RNA, which is able to improve the progression of cancers 1-3 . In this study, DUXAP10 was certified to be upregulated in ESCC tissues and cells. Besides, it was positively correlated with short survival time. Moreover, down-expression of DUXAP10 contributed to decreased cell proliferation and metastasis. Silenced DUXAP10 led to increased apoptosis rate and stagnation of cell cycle. Results of mechanism experiments suggested that DUXAP10 motivated ESCC progression through recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p21. Our findings suggested that the pseudogene-derived from lncRNA DUXAP10 drove the biological progression of ESCC. DUXAP10 was likely to be a potential therapeutic target for ESCC.

Over-expression of oncigenic pesudogene DUXAP10 promotes cell proliferation and invasion by regulating LATS1 and ß-catenin in gastric cancer.

BACKGROUND: Recently, the pesudogenes have emerged as critical regulators in human cancers tumorigenesis and progression, and been identified as a key revelation in post-genomic biology. However, the expression pattern, biological function and mechanisms responsible for these molecules in human gastric cancer (GC) are not fully understood. METHODS: In this study, we globally assessed the transcriptomic differences of pesudogenes in gastric cancer using publicly available microarray data. DUXAP10 expression levels in GC tissues and cells was detected using quantitative real-time PCR (qPCR). DUXAP10 siRNAs and over-expression vector were transfected into GC cells to down-regulate or up-regulate DUXAP10 expression. Loss- and gain-of function assays were performed to investigate the role of DUXAP10 in GC cells cell proliferation, and invasion. RIP, RNA pulldown, and ChIP assays were used to determine the mechanism of DUXAP10's regulation of underlying targets. RESULTS: The pesudogene DUXAP10 is the only pseudogene that significantly over-expressed in all four GEO datasets, and frequently over-expressed in many other cancers including Liver Hepatocellular carcinoma, Bladder cancer, and Esophageal Cancer. High DUXAP10 expression is associated with GC patients poor prognosis, and knockdown of DUXAP10 significantly inhibits cells proliferation, migration and invasion in GC. Mechanistic investigation shows that DUXAP10 can interact with PRC2 and LSD1 to repress LATS1 expression at transcriptional level, and bind with HuR to maintain the stability of ß-catenin mRNA and increase its protein levels at post-transcriptional level. CONCLUSIONS: Overall, our findings illuminate how increased DUXAP10 confers an oncogenic function in GC development and progression that may serve as a candidate prognostic biomarker and target for clinical management of GC.

Knockdown of pseudogene derived from lncRNA DUXAP10 inhibits cell proliferation, migration, invasion, and promotes apoptosis in pancreatic cancer.

Current evidence suggests that pseudogene derived lncRNAs may be important players in human cancer progression. Our previous study showed that DUXAP10 could promote cell proliferation in colorectal cancer. However, the clinical significance and potential role of DUXAP10 in human pancreatic cancer (PC) has not been uncovered. In this study, we found that DUXAP10 was overexpressed in PC tissues compared with normal tissues. DUXAP10 expression was significantly higher in patients with an advanced TNM stage and positive lymph node metastasis. Bioinformatic analysis showed that cell cycle progression was increased in patients with high DUXAP10 expression. In vitro and in vivo assays of DUXAP10 alterations revealed a complex integrated phenotype affecting cell growth, apoptosis, migration, and invasion. Mechanistic studies revealed that DUXAP10 has a crucial role in G2/M arrest. We further showed that DUXAP10 regulated PC cell proliferation through interact with RNA-binding protein EZH2 and LSD1. Overall, our findings indicates that DUXAP10 is an oncogenic lncRNA that promotes PC proliferation and metastasis.

Overexpression of long non-coding RNAs DUXAP9 and DUXAP10 is associated with prognosis in patients with hepatocellular carcinoma after hepatectomy.

AIM: Hepatocellular carcinoma (HCC) is a common and aggressive malignant tumor with an especially high prevalence in Asian populations. This study aimed to identify differentially expressed lncRNAs using expression microarray and to explore the association between differential expression of lncRNAs and prognosis of HCC. METHODS: We retrospectively reviewed 63 patients with primary HCC that underwent a curative liver resection at the Department of General Surgery, Jingmen First People's Hospital. The expression level of lncRNAs DUXAP9 and DUXAP10 were detected by real-time PCR. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: By microarray profiling of lncRNAs, 256 were found to be differentially expressed, including 162 upregulated and 94 downregulated (P<0.05, fold change >2). Two candidate lncRNAs were determined as targets in this study, including DUXAP9 (upregulated by 6.35 fold) and DUXAP10 (upregulated by 4.53 fold). DUXAP9 and DUXAP10 were downregulated in the normal liver cell lines Chang liver, HL7702, THLE-2, THLE-3, FL62891, and AML12, which were significantly lower than HCC cell lines SMMC-7721, Hep3B, HuH7, MHCC-97H, HCC-LM, and SK-Hep-1 (P<0.05). Overexpression of lncRNAs DUXAP9 and DUXAP10 were associated with decreasing OS rates, respectively (P=0.0263 and P=0.0285). Meanwhile, Overexpression of DUXAP9 and DUXAP10 was associated with decreasing PFS rates, respectively (P=0.0174 and P=0.0041). After adjusting for competing risk factors, we identified microvascular invasion (P=0.014), tumor size (P=0.026), and lncRNAs DUXAP9 (P=0.001) and DUXAP10 (P=0.036) expression levels as independent prognostic factors associated with prognosis of patients with HCC. CONCLUSIONS: We found that lncRNAs DUXAP9 and DUXAP10 are expressed significantly higher in HCC tissues compared with non-tumorous tissues. Overexpression of DUXAP9 and DUXAP10 were independent risk factors associated with prognosis of patients with HCC.

The pseudogene DUXAP10 promotes an aggressive phenotype through binding with LSD1 and repressing LATS2 and RRAD in non small cell lung cancer.

Pseudogenes have been considered as non-functional transcriptional relics of human genomic for long time. However, recent studies revealed that they play a plethora of roles in diverse physiological and pathological processes, especially in cancer, and many pseudogenes are transcribed into long noncoding RNAs and emerging as a novel class of lncRNAs. However, the biological roles and underlying mechanism of pseudogenes in the pathogenesis of non small cell lung cancer are still incompletely elucidated. This study identifies a putative oncogenic pseudogene DUXAP10 in NSCLC, which is located in 14q11.2 and 2398 nt in length. Firstly, we found that DUXAP10 was significantly up-regulated in 93 human NSCLC tissues and cell lines, and increased DUXAP10 was associated with patients poorer prognosis and short survival time. Furthermore, the loss and gain of functional studies including growth curves, migration, invasion assays and in vivo studies verify the oncogenic roles of DUXAP10 in NSCLC. Finally, the mechanistic experiments indicate that DUXAP10 could interact with Histone demethylase Lysine specific demethylase1 (LSD1) and repress tumor suppressors Large tumor suppressor 2 (LATS2) and Ras-related associated with diabetes (RRAD) transcription in NSCLC cells. Taken together, these findings demonstrate DUXAP10 exerts the oncogenic roles through binding with LSD1 and epigenetic silencing LATS2 and RRAD expression. Our investigation reveals the novel roles of pseudogene in NSCLC, which may serve as new target for NSCLC diagnosis and therapy.