Dataset Information

N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1.

ABSTRACT: BACKGROUND:Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive. METHODS:Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation. FINDINGS:TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7. INTERPRETATION:Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1. FUNDING:This work was financially supported by grants of NSFC (81001192, 81672658 and 81972521) and National Key Research Project of Science and Technology Ministry (2016YFC0106204).

SUBMITTER: Zhou C

PROVIDER: S-EPMC7452680 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1.

Zhou Chenliang C Zhang Zhichang Z Zhu Xiaoshi X Qian Guowei G Zhou Yan Y Sun Yong Y Yu Wenxi W Wang Jiahui J Lu Haiyang H Lin Feng F Shen Zan Z Zheng Shuier S

EBioMedicine 20200824

<h4>Background</h4>Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive.<h4>Methods</ ...[more]

PMID: 32853985

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Project description:Background: The role of N6-methyladenosine (m6A)-related long non-coding RNAs (lncRNAs) in osteosarcoma (OS) has not been fully studied yet. We aimed to identify m6A-related lncRNAs that could act as prognostic biomarkers for OS. Methods: Pearson correlation was performed to identify m6A-related lncRNAs. Univariate and multivariate Cox regression analyses were performed to construct the risk model and assess whether the risk score was an independent prognostic factor for patients with OS. Gene Set Enrichment Analysis (GSEA) was performed to analyze the functions of genes in high-risk and low-risk groups. StarBase and Cytoscape were used to construct a competing endogenous RNA (ceRNA) network based on m6A-related prognostic lncRNA signature. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze the function of genes involved in the ceRNA network. Results: We extracted 122 common lncRNAs from TCGA and Gene Expression Omnibus (GEO) databases. Pearson correlation results revealed 59 significant m6A-related lncRNAs in The Cancer Genome Atlas (TCGA) database, from which 2 were screened to construct a risk signature in TCGA dataset, which was then validated in the GEO dataset. A corresponding risk score was calculated and shown to be an independent prognostic factor for patients with OS. Enrichment analysis indicated that cell proliferation-related biological processes were more common in the high-risk group, while immune-related biological processes were more common in the low-risk group. Moreover, we established a nomogram that had a good ability to predict the overall survival of patients with OS. Additionally, a ceRNA network based on small nucleolar RNA host gene 7 (SNHG7) and small nucleolar RNA host gene 12 (SNHG12) was constructed, with genes that were enriched in hepatocellular carcinoma, gastric cancer, and non-small-cell lung cancer pathways. Conclusion: Our study revealed the prognostic role of m6A-related lncRNAs in OS and identified SNHG7 and SNHG12 as potential biomarkers for predicting the prognosis of patients with OS. These findings have enriched our understanding of the role of m6A modification in the dysregulation of lncRNAs in OS.

Dataset Information

N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1.

Publications

N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1.

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