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CircTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1.

ABSTRACT: Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the role of circRNA in lung squamous cell carcinoma (LUSC) remains largely unknown. Herein, we explore the expression profiles of circRNA and mRNA in 5 paired samples of LUSC. By analyzing the co-expression network of differentially expressed circRNAs and dysregulated mRNAs, we identify that a cell cycle-related circRNA, circTP63, is upregulated in LUSC tissues and its upregulation is correlated with larger tumor size and higher TNM stage in LUSC patients. Elevated circTP63 promotes cell proliferation both in vitro and in vivo. Mechanistically, circTP63 shares miRNA response elements with FOXM1. circTP63 competitively binds to miR-873-3p and prevents miR-873-3p to decrease the level of FOXM1, which upregulates CENPA and CENPB, and finally facilitates cell cycle progression.

SUBMITTER: Cheng Z

PROVIDER: S-EPMC6642174 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1.

Cheng Zhuoan Z Yu Chengtao C Cui Shaohua S Wang Hui H Jin Haojie H Wang Cun C Li Botai B Qin Meilin M Yang Chen C He Jia J Zuo Qiaozhu Q Wang Siying S Liu Jun J Ye Weidong W Lv Yuanyuan Y Zhao Fangyu F Yao Ming M Jiang Liyan L Qin Wenxin W

Nature communications 20190719 1

Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the role of circRNA in lung squamous cell carcinoma (LUSC) remains largely unknown. Herein, we explore the expression profiles of circRNA and mRNA in 5 paired samples of LUSC. By analyzing the co-expression network of differentially expressed circRNAs and dysregulated mRNAs, we identify that a cell cycle-related circRNA, circTP63, is upregulated in LUSC tissues and its upregulation is correlated with la ...[more]

PMID: 31324812

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is a common invasive malignancy worldwide with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been reported to be involved in cancer development. However, lncRNAs that are functional in ESCC and the underlying molecular mechanisms remain largely unknown.MethodsTranscriptomic analysis was performed to identify dysregulated lncRNAs in ESCC tissue samples. The high expression of LINC00680 in ESCC was validated by RT-qPCR, and the oncogenic functions of LINC00680 was investigated by cell proliferation, colony formation, migration and invasion assays in ESCC cells in vitro and xenografts derived from ESCC cells in mice. RNA-seq, competitive endogenous RNA (ceRNA) network analysis, and luciferase reporter assays were carried out to identify LINC00680 target genes and the microRNAs (miRNAs) bound to LINC00680. Antisense oligonucleotides (ASOs) were used for in vivo treatment.ResultsTranscriptome profiling revealed that a large number of lncRNAs was dysregulated in ESCC tissues. Notably, LINC00680 was highly expressed, and upregulation of LINC00680 was associated with large tumor size, advanced tumor stage, and poor prognosis. Functionally, knockdown of LINC00680 restrained ESCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, LINC00680 was found to act as a ceRNA by sponging miR-423-5p to regulate PAK6 (p21-activated kinase 6) expression in ESCC cells. The cell viability and motility inhibition induced by LINC00680 knockdown was significantly reversed upon PAK6 restoration and miR-423-5p inhibition. Furthermore, ASO targeting LINC00680 substantially suppressed ESCC both in vitro and in vivo.ConclusionsAn oncogenic lncRNA, LINC00680, was identified in ESCC, which functions as a ceRNA by sponging miR-423-5p to promote PAK6 expression and ESCC. LINC00680/miR-423-5p/PAK6 axis may serve as promising diagnostic and prognostic biomarkers and therapeutic targets for ESCC.

Project description:BACKGROUND:Circular RNAs (circRNAs), a new type of noncoding RNA (ncRNA), have been identified as significant gene expression regulators and are involved in cancer progression. However, the roles of circRNAs in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS:Here, the expression profile of circRNAs in a pair of NPC cell lines with different metastatic abilities (S18 and S26 cells) was analyzed by RNA-sequencing. Quantitative reverse transcription PCR was used to detect the expression level of circCRIM1 in NPC cells and tissues. Then, function experiments in vitro and in vivo were performed to evaluate the effects of circCRIM1 on NPC metastasis and EMT. Mechanistically, RNA immunoprecipitation, luciferase reporter assay, pull-down assay with biotinylated miRNA, fluorescent in situ hybridization were performed to confirm the interaction between circCRIM1 and miR-422a in NPC. The clinical value of circCRIM1 was evaluated in NPC metastasis and chemosensitivity. RESULTS:We identified that circCRIM1 was upregulated in highly metastatic NPC cells. CircCRIM1 was also overexpressed in NPC tissues with distant metastasis, and its overexpression promoted NPC cell metastasis and EMT. Mechanistically, circCRIM1 competitively bound to miR-422a and prevented the suppressive effects of miR-422a on its target gene FOXQ1, which finally led to NPC metastasis, EMT and docetaxel chemoresistance. Furthermore, high circCRIM1 expression was associated with unfavorable survival in NPC patients. We established a prognostic model based on circCRIM1 expression and N stage that effectively predicted the risk of distant metastasis and treatment response to docetaxel-containing induction chemotherapy in NPC patients. CONCLUSIONS:Our findings reveal the critical role of circCRIM1 specifically in promoting NPC metastasis and chemoresistance via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for prognosis and treatment resistance in NPC patients.

Project description:Background: Gastric cancer (GC) is one of the main mortality cause worldwide. Previously, we found Forkhead box protein (FOXM1) or Urokinase-type plasminogen activator (PLAU) are independent prognostic markers of GC. This study aims to explore the combining prognostic efficacy and the potential insights underlying additive effect of FOXM1 to PLAU in GC progression through in-silico analyses. Method: The expression of FOXM1 and PLAU were profiled in 33 cancer types using public data. A merged GC expression dataset containing 598 samples was used for evaluating prognostic significance of FOXM1/PLAU. Gene Set Enrichment Analysis (GSEA) was performed to elucidate the mechanisms underlying FOXM1/PLAU promoted GC progression. The Cancer Genome Atlas (TCGA) was used for analyzing the association between FOXM1/PLAU and tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were also computed using TCGA GC data. Drugs targeting FOXM1/PLAU associated gene expression pattern was analyzed using LINCs database. Results: FOXM1 and PLAU are overexpressed in 17/33 cancer types including GC. Kaplan-Meier analyses indicate that the FOXM1+PLAU+ subgroup have the worst prognosis, while FOXM1-PLAU- subgroup have the best survival. Bioinformatics analysis indicated that FOXM1+PLAU+ associated genes are enriched in TGF-beta, DNA repair and drug resistance signaling pathways; FOXM1 and PLAU expression are negatively correlated with tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were presented. Data mining from LINCs suggested several chemicals or drugs that could target the gene expression pattern of FOXM1+PLAU+ patients. Conclusion: FOXM1+PLAU+ can serve as effective prognostic biomarkers and potential therapeutic targets for GC. Due to the additive effect of these two genes, screening for drugs or chemicals that targeting the expression patterns PLAU+FOXM1+ subgroup may exert important clinical impact on GC management.

Dataset Information

CircTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1.

Publications

circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1.

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