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CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p.

ABSTRACT: BACKGROUND:Circular RNAs (circRNAs), a novel type of noncoding RNA (ncRNA), are covalently linked circular configurations that form via a loop structure. Accumulating evidence indicates that circRNAs are potential biomarkers and key regulators of tumor development and progression. However, the precise roles of circRNAs in renal cell carcinoma (RCC) remain unknown. METHODS:Through circRNA high-throughput sequencing of RCC cell lines, we identified the circRNA TLK1 (circTLK1) as a novel candidate circRNA derived from the TLK1 gene. qRT-PCR detected the mRNA, circRNA and miRNA expression levels in RCC tissues and cells. Loss-of function experiments were executed to detect the biological roles of circTLK1 in the RCC cell phenotypes in vitro and in vivo. RNA-FISH, RNA pull-down, dual-luciferase reporter, western blot and immunohistochemistry assays were used to investigate the molecular mechanisms underlying the functions of circTLK1. RESULTS:circTLK1 is overexpressed in RCC, and expression is positively correlated with distant metastasis and unfavorable prognosis. Silencing circTLK1 significantly inhibited RCC cell proliferation, migration and invasion in vitro and in vivo. circTLK1 was mainly distributed in the cytoplasm and positively regulated CBX4 expression by sponging miR-136-5p. Forced CBX4 expression reversed the circTLK1 suppression-induced phenotypic inhibition of RCC cells. Moreover, CBX4 expression was positively correlated with VEGFA expression in RCC tissues. CBX4 knockdown significantly inhibited VEGFA expression in RCC cells. CONCLUSION:Collectively, our findings demonstrate that circTLK1 plays a critical role in RCC progression by sponging miR-136-5p to increase CBX4 expression. circTLK1 may act as a diagnostic biomarker and therapeutic target for RCC.

SUBMITTER: Li J

PROVIDER: S-EPMC7275467 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p.

Li Jianfa J Huang Chenchen C Zou Yifan Y Ye Jing J Yu Jing J Gui Yaoting Y

Molecular cancer 20200605 1

<h4>Background</h4>Circular RNAs (circRNAs), a novel type of noncoding RNA (ncRNA), are covalently linked circular configurations that form via a loop structure. Accumulating evidence indicates that circRNAs are potential biomarkers and key regulators of tumor development and progression. However, the precise roles of circRNAs in renal cell carcinoma (RCC) remain unknown.<h4>Methods</h4>Through circRNA high-throughput sequencing of RCC cell lines, we identified the circRNA TLK1 (circTLK1) as a n ...[more]

PMID: 32503552

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Project description:BackgroundLung adenocarcinoma (LUAD) is currently the leading cause of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) play key roles in tumor occurrence and development as crucial cancer regulators. The present study aimed to explore the molecular mechanism and regulatory network of Linc00511 in LUAD and to identify new potential therapeutic targets for LUAD.MethodsReal-time quantitative polymerase chain reaction (RT-qPCR) was performed to determine the relative Linc00511 levels in LUAD tissues and cells. The proliferation, apoptosis, migration, and invasion abilities of LUAD cells were assessed by a Cell Counting Kit-8 (CCK-8) assay, a colony formation assay, flow cytometry, and a Transwell assay. Changes in hsa_miR-126-5p, hsa_miR-218-5p, and COL1A1 expression were analyzed using western blotting and RT-qPCR. Targeted binding between miR-126-5p/miR-218-5p and Linc00511 or COL1A1 was verified with a luciferase reporter system and confirmed by an RNA pulldown assay. The participation of the PI3K/AKT signaling pathway was confirmed via western blotting. Xenograft animal experiments were performed to detect the impact of Linc00511 on LUAD tumor growth in vivo.ResultsIn the present work, we observed that Linc00511 was upregulated in LUAD tissues and cells. Loss/gain-of-function experiments indicated that knockdown of Linc00511 significantly inhibited LUAD cell proliferation, migration and invasion and promoted LUAD cell apoptosis, whereas overexpression of Linc00511 showed the opposite effects. In addition, we determined that Linc00511 promoted COL1A1-mediated cell proliferation and cell motility by sponging miR-126-5p and miR-218-5p. Moreover, Linc00511 activated the PI3K/AKT signaling pathway through upregulation of COL1A1. Finally, silencing of Linc00511 inhibited LUAD tumor growth in vivo.ConclusionsLinc00511 acts as a competing endogenous RNA to regulate COL1A1 by targeting miR-126-5p and miR-218-5p, thereby promoting the proliferation and invasion of LUAD cells.

Project description:BackgroundCircular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC.MethodscircCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization.ResultsThe expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression.ConclusionsWe found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.

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CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p.

Publications

CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p.

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