Dataset Information

LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization.

ABSTRACT:

Background

Gastric cancer remains the leading cause of cancer death in the world. It is increasingly evident that long non-coding RNAs (lncRNAs) transcribed from the genome-wide association studies (GWAS)-identified gastric cancer risk loci act as a key mode of cancer development and disease progression. However, the biological significance of lncRNAs at most cancer risk loci remain poorly understood.

Methods

The biological functions of LINC00240 in gastric cancer were investigated through a series of biochemical assays. Clinical implications of LINC00240 were examined in tissues from gastric cancer patients.

Results

In the present study, we identified LINC00240, which is transcribed from the 6p22.1 gastric cancer risk locus, functioning as a novel oncogene. LINC00240 exhibits the noticeably higher expression in gastric cancer specimens compared with normal tissues and its high expression levels are associated with worse survival of patients. Consistently, LINC00240 promotes malignant proliferation, migration and metastasis of gastric cancer cells in vitro and in vivo. Importantly, LINC00240 could interact and stabilize oncoprotein DDX21 via eliminating its ubiquitination by its novel deubiquitinating enzyme USP10, which, thereby, promote gastric cancer progression.

Conclusions

Taken together, our data uncovered a new paradigm on how lncRNAs control protein deubiquitylation via intensifying interactions between the target protein and its deubiquitinase. These findings highlight the potentials of lncRNAs as innovative therapeutic targets and thus lay the ground work for clinical translation.

SUBMITTER: Zhang N

PROVIDER: S-EPMC10111703 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization.

Zhang Nasha N Wang Bowen B Ma Chi C Zeng Jiajia J Wang Teng T Han Linyu L Yang Ming M

Journal of experimental & clinical cancer research : CR 20230418 1

<h4>Background</h4>Gastric cancer remains the leading cause of cancer death in the world. It is increasingly evident that long non-coding RNAs (lncRNAs) transcribed from the genome-wide association studies (GWAS)-identified gastric cancer risk loci act as a key mode of cancer development and disease progression. However, the biological significance of lncRNAs at most cancer risk loci remain poorly understood.<h4>Methods</h4>The biological functions of LINC00240 in gastric cancer were investigate ...[more]

PMID: 37072811

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Project description:BackgroundHypoxia has long been considered as a hallmark of solid tumors and is closely associated with tumor progression. Circular RNAs (circRNAs) have been identified as a critical modulator in various cancers. However, the connections between hypoxia and circRNAs are largely unknown.MethodsHere, we investigated the expression profile of circRNAs in breast cancer (BC) MCF-7 cells under hypoxia and normoxia using microarray. We identified a novel hypoxia-responsive circRNA named circWSB1, whose expression pattern, potential diagnostic value and prognostic significance were assessed by qRT-PCR and in situ hybridization. Loss- and gain-of-function investigations in vivo and in vitro were performed to determine the biological functions of circWSB1. Mechanistically, chromatin immunoprecipitation and dual luciferase reporter assays were carried out to analyze the biogenesis of circWSB1. Furthermore, biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescent in situ hybridization, RNA electrophoretic mobility shift, deletion-mapping, co-immunoprecipitation assays and rescue experiments were applied to investigate the interaction between circWSB1 and Ubiquitin-specific peptidase 10 (USP10) as well as the relationship between USP10 and p53.ResultsWe found that the expression of circWSB1 was significantly upregulated in BC tissues and correlated with poor clinical outcomes, which might serve as an independent prognostic factor for BC patients. Ectopic expression of circWSB1 promoted the proliferation of BC cell in vitro and in vivo. Mechanistically, circWSB1 was transcriptionally upregulated by HIF1α in response to hypoxia and could competitively bind to deubiquitinase USP10 to prevent the access of p53 to USP10 in BC cells, leading to degradation of p53 and tumor progression of BC.ConclusionsTaken together, our findings disclose a novel mechanism that hypoxia-inducible circWSB1 could interact with USP10 to attenuate USP10 mediated p53 stabilization and promote the progression of BC, providing an alternative prognostic biomarker and therapeutic target for BC.

Dataset Information

LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization.

Background

Methods

Results

Conclusions

Publications

LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization.

Similar Datasets

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