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DDX23-Linc00630-HDAC1 axis activates the Notch pathway to promote metastasis.

ABSTRACT: Emerging studies demonstrated the roles of long non-coding RNAs (LncRNAs) are being implicated in the progression of many cancers. Here we report the discovery of a critical role for the linc00630 in the development of Non-Small-Cell Lung Cancers (NSCLCs). Screening from the microarray of six paired NSCLCs and adjacent non-tumor tissues, linc00630 showed a significantly higher RNA levels in NSCLCs. With the higher level confirmed in a separate cohort 90 NSCLCs patients, overexpressed of linc00630 also positive associated with tumor size, TNM tumor stage, lymph node status positive and overall patient outcomes. Linc00630 overexpression increased cell proliferation and metastasis in vitro and in vivo whereas linc00630 silencing had opposite effects. By RNA pull-down and mass spectrometry we identified Histone deacetylases 1 (HDAC1) and DEAD-box helicase 23 (DDX23) as the linc00630-binding protein that associated with mechanism of linc00630. DDX23 can specific bind with the promoter of Linc00630 to up-regulate the RNA level and high level of linc00630 strength the protein stability of HDAC1 to regulate the downstream pathway.Our study demonstrates the effectiveness of Linc00630 oligonucleotide-based promotion of NSCLCs metastasis and proliferation, illuminating a new basis of DDX23-Linc00630-HDAC1 signal axis for understanding its pathogenicity, which could be further developed as a valuable therapeutic strategy.

SUBMITTER: Mao G

PROVIDER: S-EPMC5503584 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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DDX23-Linc00630-HDAC1 axis activates the Notch pathway to promote metastasis.

Mao Guozhang G Jin Hui H Wu Liuguang L

Oncotarget 20170601 24

Emerging studies demonstrated the roles of long non-coding RNAs (LncRNAs) are being implicated in the progression of many cancers. Here we report the discovery of a critical role for the linc00630 in the development of Non-Small-Cell Lung Cancers (NSCLCs). Screening from the microarray of six paired NSCLCs and adjacent non-tumor tissues, linc00630 showed a significantly higher RNA levels in NSCLCs. With the higher level confirmed in a separate cohort 90 NSCLCs patients, overexpressed of linc0063 ...[more]

PMID: 28473661

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Project description:BackgroundCancer-associated fibroblasts (CAFs) orchestrate a supportive niche that fuels cancer metastatic development in non-small cell lung cancer (NSCLC). Due to the heterogeneity and plasticity of CAFs, manipulating the activated phenotype of fibroblasts is a promising strategy for cancer therapy. However, the underlying mechanisms of fibroblast activation and phenotype switching that drive metastasis remain elusive.MethodsThe clinical implications of fibroblast activation protein (FAP)-positive CAFs (FAP+CAFs) were evaluated based on tumor specimens from NSCLC patients and bioinformatic analysis of online databases. CAF-specific circular RNAs (circRNAs) were screened by circRNA microarrays of primary human CAFs and matched normal fibroblasts (NFs). Survival analyses were performed to assess the prognostic value of circNOX4 in NSCLC clinical samples. The biological effects of circNOX4 were investigated by gain- and loss-of-function experiments in vitro and in vivo. Fluorescence in situ hybridization, luciferase reporter assays, RNA immunoprecipitation, and miRNA rescue experiments were conducted to elucidate the underlying mechanisms of fibroblast activation. Cytokine antibody array, transwell coculture system, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the downstream effectors that promote cancer metastasis.ResultsFAP+CAFs were significantly enriched in metastatic cancer samples, and their higher abundance was correlated with the worse overall survival in NSCLC patients. A novel CAF-specific circRNA, circNOX4 (hsa_circ_0023988), evoked the phenotypic transition from NFs into CAFs and promoted the migration and invasion of NSCLC in vitro and in vivo. Clinically, circNOX4 correlated with the poor prognosis of advanced NSCLC patients. Mechanistically, circNOX4 upregulated FAP by sponging miR-329-5p, which led to fibroblast activation. Furthermore, the circNOX4/miR-329-5p/FAP axis activated an inflammatory fibroblast niche by preferentially inducing interleukin-6 (IL-6) and eventually promoting NSCLC progression. Disruption of the intercellular circNOX4/IL-6 axis significantly suppressed tumor growth and metastatic colonization in vivo.ConclusionsOur study reveals a role of the circRNA-induced fibroblast niche in tumor metastasis and highlights that targeting the circNOX4/FAP/IL-6 axis is a promising strategy for the intervention of NSCLC metastasis.

Dataset Information

DDX23-Linc00630-HDAC1 axis activates the Notch pathway to promote metastasis.

Publications

DDX23-Linc00630-HDAC1 axis activates the Notch pathway to promote metastasis.

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