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Long non-coding RNA FOXD1-AS1 promotes the progression and glycolysis of nasopharyngeal carcinoma by sustaining FOXD1 expression.

ABSTRACT: Long non-coding RNAs (lncRNAs) play a vital role in the progression of several cancers, including nasopharyngeal carcinoma (NPC). However, the mechanism of lncRNA involvement in the progression of NPC remains to be elucidated. Hence, we conducted in vivo and in vitro experiments to determine the molecular mechanism of FOXD1-AS1. We found that FOXD1-AS1 was over-expressed in NPC cells and tissues, and was significantly associated with poor survival rate in patients with NPC. We also found that FOXD1-AS1 promotes cellular proliferation, migration, invasion, and glycolysis, and inhibits apoptosis by upregulating the expression of FOXD1. Furthermore, FOXD1 could transcriptionally up-regulate the expression of key glycolytic genes to promote the glycolysis levels of NPC. The identified FOXD1-AS1 may serve as a potential prognostic biomarker and therapeutic target for patients with NPC.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7716144 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Long non-coding RNA FOXD1-AS1 promotes the progression and glycolysis of nasopharyngeal carcinoma by sustaining FOXD1 expression.

Wang Zhanwang Z Cheng Yaxin Y Zhu Yuxing Y Hu Xueying X Jin Yi Y Gong Lian L Xiao Mengqing M Xiang Liang L Zeng Qinghai Q Liu Jianye J Chen Xingyu X Zhang Yeyu Y Liu Xiaoming X Deng Liping L He Dong D Cao Ke K

American journal of cancer research 20201101 11

Long non-coding RNAs (lncRNAs) play a vital role in the progression of several cancers, including nasopharyngeal carcinoma (NPC). However, the mechanism of lncRNA involvement in the progression of NPC remains to be elucidated. Hence, we conducted in vivo and in vitro experiments to determine the molecular mechanism of FOXD1-AS1. We found that FOXD1-AS1 was over-expressed in NPC cells and tissues, and was significantly associated with poor survival rate in patients with NPC. We also found that FO ...[more]

PMID: 33294261

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Project description:BackgroundLong non-coding RNAs (lncRNAs) are widely involved in human cancers' progression by regulating tumor cells' various malignant behaviors. MAPKAPK5-AS1 has been recognized as an oncogene in colorectal cancer. However, the biological role of MAPKAPK5-AS1 in hepatocellular carcinoma (HCC) has not been explored.MethodsQuantitative real-time PCR was performed to detect the level of MAPKAPK5-AS1 in HCC tissues and cell lines. The effects of MAPKAPK5-AS1 on tumor growth and metastasis were assessed via in vitro experiments, including MTT, colony formation, EdU, flow cytometry, transwell assays, and nude mice models. The western blotting analysis was carried out to determine epithelial-mesenchymal transition (EMT) markers and AKT signaling. The interaction between MAPKAPK5-AS1, miR-154-5p, and PLAGL2 were explored by luciferase reporter assay and RNA immunoprecipitation. The regulatory effect of HIF-1? on MAPKAPK5-AS1 was evaluated by chromatin immunoprecipitation.ResultsMAPKAPK5-AS1 expression was significantly elevated in HCC, and its overexpression associated with malignant clinical features and reduced survival. Functionally, MAPKAPK5-AS1 knockdown repressed the proliferation, mobility, and EMT of HCC cells and induced apoptosis. Ectopic expression of MAPKAPK5-AS1 contributed to HCC cell proliferation and invasion in vitro. Furthermore, MAPKAPK5-AS1 silencing suppressed, while MAPKAPK5-AS1 overexpression enhanced HCC growth and lung metastasis in vivo. Mechanistically, MAPKAPK5-AS1 upregulated PLAG1 like zinc finger 2 (PLAGL2) expression by acting as an endogenous competing RNA (ceRNA) to sponge miR-154-5p, thereby activating EGFR/AKT signaling. Importantly, rescue experiments demonstrated that the miR-154-5p/PLAGL2 axis mediated the function of MAPKAPK5-AS1 in HCC cells. Interestingly, we found that hypoxia-inducible factor 1? (HIF-1?), a transcript factor, could directly bind to the promoter to activate MAPKAPK5-AS1 transcription. MAPKAPK5-AS1 regulated HIF-1? expression through PLAGL2 to form a hypoxia-mediated MAPKAPK5-AS1/PLAGL2/HIF-1? signaling loop in HCC.ConclusionsOur results reveal a MAPKAPK5-AS1/PLAGL2/HIF-1? signaling loop in HCC progression and suggest that MAPKAPK5-AS1 could be a potential novel therapeutic target of HCC.

Project description:BackgroundHigh glycolysis efficiency in tumor cells can promote tumor growth. lncRNAs play an important role in the proliferation, metabolism and migration of cancer cells, but their regulation of tumor glycolysis is currently not well researched.MethodsWe analyzed the co-expression of glycolysis-related genes and lncRNAs in The Cancer Genome Atlas (TCGA) database to screen glycolysis-related lncRNAs. Further prognostic analysis and differential expression analysis were performed. We further analyzed the relationship between lncRNAs and tumor immune infiltration. Since WAC antisense RNA 1 (WAC-AS1) had the greatest effect on the prognosis among all screened lncRNAs and had a larger coefficient in the prognostic model, we chose WAC-AS1 for further verification experiments and investigated the function and mechanism of action of WAC-AS1 in hepatocellular carcinoma.ResultsWe screened 502 lncRNAs that have co-expression relationships with glycolytic genes based on co-expression analysis. Among them, 112 lncRNAs were abnormally expressed in liver cancer, and 40 lncRNAs were related to the prognosis of patients. Eight lncRNAs (WAC-AS1, SNHG3, SNHG12, MSC-AS1, MIR210HG, PTOV1-AS1, AC145207.5 and AL031985.3) were used to established a prognostic model. Independent prognostic analysis (P<0.001), survival analysis (P<0.001), receiver operating characteristic (ROC) curve analysis (AUC=0.779) and clinical correlation analysis (P<0.001) all indicated that the prognostic model has good predictive power and that the risk score can be used as an independent prognostic factor (P<0.001). The risk score and lncRNAs in the model were found to be related to a variety of immune cell infiltration and immune functions. WAC-AS1 was found to affect glycolysis and promote tumor proliferation (P<0.01). WAC-AS1 affected the expression of several glycolysis-related genes (cAMP regulated phosphoprotein 19 (ARPP19), CHST12, MED24 and KIF2A) (P<0.01). Under hypoxic conditions, WAC-AS1 regulated ARPP19 by sponging miR-320d to promote glucose uptake and lactate production (P<0.01).ConclusionWe constructed a model based on glycolysis-related lncRNAs to evaluate the prognostic risk of patients. The risk score and lncRNAs in the model were related to immune cell infiltration. WAC-AS1 can regulate ARPP19 to promote glycolysis and proliferation by sponging miR-320d.

Dataset Information

Long non-coding RNA FOXD1-AS1 promotes the progression and glycolysis of nasopharyngeal carcinoma by sustaining FOXD1 expression.

Publications

Long non-coding RNA FOXD1-AS1 promotes the progression and glycolysis of nasopharyngeal carcinoma by sustaining FOXD1 expression.

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