Function of hsa_circ_0006646 as a competing endogenous RNA to promote progression in gastric cancer by regulating the miR-665–HMGB1 axis
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Background: Mounting evidences indicate that circular RNAs (circRNAs) are a novel class of non-coding RNAs and play vital roles in the tumorigenesis and aggressiveness including gastric cancer (GC). Nevertheless, the precise functions and underlying mechanisms of circRNAs in GC remain largely unknown. Methods: The Gene Expression Omnibus (GEO) data set GSE163416 was analyzed to screen the key circRNAs in GC. hsa_circ_0006646 was chosen for further study. GC tissues and matched adjacent normal gastric mucosal epithelial tissues were obtained from the Fourth Hospital of Hebei Medical University. The expressions of hsa_circ_0006646 was detected using quantitative real-time polymerase chain reaction (qRT-PCR). hsa_circ_0006646 was knocked down to identify its effects on GC cells. Bioinformatics algorithms were analyzed to predict the microRNA (miRNAs) potentially sponged by hsa_circ_0006646 and its target genes. Fluorescence in situ hybridization (FISH) was conducted to determine the subcellular location of hsa_circ_0006646 and the predicted miRNA. Then, qRT-PCR, luciferase reporter assay, radioimmunoprecipitation assay, Western blotting, and miRNA rescue experiments were used to confirm the hsa_circ_0006646–related regulatory axis in GC. Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell experiments were performed to determine the effect of the hsa_circ_0006646–related regulatory axis on GC cells' malignant behaviors in vitro. The xenograft tumor mouse model was established to evaluate the effect of hsa_circ_0006646 in vivo. Results: hsa_circ_0006646 exhibited a high expression in GC tissues as compared to corresponding adjacent normal gastric mucosal epithelial tissues and its high expression was positively correlated with TNM stage, lymph node invasion and poor prognosis (P<0.05). Knockdown of hsa_circ_0006646 suppressed the proliferation, colony formation, migration, and invasion in GC cells (all P<0.05). hsa_circ_0006646 upregulated high mobility group box 1 (HMGB1) by sponging miR-665 in GC cells (P<0.05). The hsa_circ_0006646–miR-665–HMGB1 axis promoted malignant behaviors and epithelial–mesenchymal transition (EMT) in GC cells by activating the Wnt/β-catenin pathway (P<0.05). The existence of hsa_circ_0006646–miR-665–HMGB1 axis was confirmed in GC specimens (P<0.05). Consequently, down-regulated hsa_circ_0006646 inhibited the progression and EMT of GC cells in vivo (P<0.05). Conclusions: For the first time, we demonstrated that hsa_circ_0006646–miR-665–HMGB1 axis exerted its tumor-promoting effects in GC, which suggested that hsa_circ_0006646 could be potentially targeted for GC treatment.Keywords:
Competing Endogenous RNA
HMGB1
Background and Aims: Pancreatic adenocarcinoma (PAAD) is the most lethal cancer type around the world. With the in-depth exploration of the function of long non‐coding RNAs (lncRNAs), the competing endogenous RNA (ceRNA) mechanism has shown its potential to partially reveal the pathogenesis of PAAD. This study aimed to construct a lncRNA‐associated ceRNA network and explore ceRNA regulatory axes with experimental and prognostic value in PAAD. Methods: First, we applied differential expression analysis in the TCGA_PAAD dataset. Then, interaction analysis and survival analysis in multiple RNA interaction databases were conducted to construct a ceRNA network. Finally, a potential regulatory axis was validated using clinical samples and cell lines by quantitative realtime PCR (qRT‐PCR). Results: A ceRNA network comprising 13 lncRNAs, 96 miRNAs, and 30 mRNAs was successfully constructed. Survival analysis further narrowed this network to five lncRNAs, three miRNAs, and seven mRNAs, which were significantly associated with patients' overall survival. A potential regulatory axis CASC8-miR-129-5p-TOB1 was further experimentally validated. The expression of these genes was associated with clinicopathological factors and their expression trend was consistent with ceRNA mechanism. Specifically, knockdown of lncRNA-CASC8 led to the overexpression of miR-129-5p and down-regulation of TOB1, while overexpression of CASC8 showed opposite effects. Conclusion: This novel ceRNA regulatory network could provide new insight into the pathogenesis of PAAD. The new regulatory axis CASC8-miR-129-5p-TOB1 might serve as a potential therapeutic target for patients. Keywords: pancreatic adenocarcinoma, competing endogenous RNA, long non‐coding RNA, The Cancer Genome Atlas, bioinformatics analysis
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Recent findings have identified competing endogenous RNAs (ceRNAs) as the drivers in many disease conditions, including cancers. The ceRNAs indirectly regulate each other by reducing the amount of microRNAs (miRNAs) available to target messenger RNAs (mRNAs). The ceRNA interactions mediated by miRNAs are modulated by a titration mechanism, i.e. large changes in the ceRNA expression levels either overcome, or relieve, the miRNA repression on competing RNAs; similarly, a very large miRNA overexpression may abolish competition. The ceRNAs are also called miRNA "decoys" or miRNA "sponges" and encompass different RNAs competing with each other to attract miRNAs for interactions: mRNA, long non-coding RNAs (lncRNAs), pseudogenes, or circular RNAs. Recently, we developed a computational method for identifying ceRNA-ceRNA interactions in breast invasive carcinoma. We were interested in unveiling which lncRNAs could exert the ceRNA activity. We found a drastic rewiring in the cross-talks between ceRNAs from the physiological to the pathological condition. The main actor of this dysregulated lncRNA-associated ceRNA network was the lncRNA PVT1, which revealed a net biding preference towards the miR-200 family members in normal breast tissues. Despite its up-regulation in breast cancer tissues, mimicked by the miR-200 family members, PVT1 stops working as ceRNA in the cancerous state. The specific conditions required for a ceRNA landscape to occur are still far from being determined. Here, we emphasized the importance of the relative concentration of the ceRNAs, and their related miRNAs. In particular, we focused on the withdrawal in breast cancer tissues of the PVT1 ceRNA activity and performed a gene expression and sequence analysis of its multiple isoforms. We found that the PVT1 isoform harbouring the binding site for a representative miRNA of the miR-200 family shows a drastic decrease in its relative concentration with respect to the miRNA abundance in breast cancer tissues, providing a plausibility argument to the breakdown of the sponge program orchestrated by the oncogene PVT1.
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Introduction Long non-coding RNAs (lncRNAs) functioning as competing endogenous RNAs (ceRNAs) play critical roles in tumour progression. However, prognosis-related ceRNA networks in lung adenocarcinoma (LUAD) have not been well characterised. Material and methods LUAD datasets were downloaded from the TCGA database, and the patients were divided into metastasis and non-metastasis groups. The differential expression of lncRNAs (DELs), miRNAs (DEMs), and mRNAs (DEGs) was analysed using the Limma package. Next, interactions between miRNA, lncRNA, and mRNA were predicted by miRcode, miRTarBase, miRDB, and TargetScan. The ceRNA network was constructed based on these interactions using Cytoscape software. DEG enrichment analysis was performed by GO and KEGG. After the prognosis analysis, we further screened molecules and constructed the prognosis-related ceRNA network. Moreover, the interactions between lncRNA, miRNA, and mRNA were validated by biological experiments. Results 854 DELs, 150 DEMs, and 2211 DEGs between metastasis and non-metastasis LUAD patients were identified. Functional enrichment analysis suggested that DEGs were closely related to key biological processes involved in LUAD progression. The prognosis-related ceRNA network included 1 miRNA, 2 lncRNAs, and 4 mRNAs. In this network, MIR155HG and ADAMTS9-AS2 can function as ceRNAs of miR-212 to regulate EPM2AIP1, LAX1, PRICKLE2, and CD226. Moreover, our study confirmed that MIR155HG inhibited the proliferation, migration, and invasion of LUAD cells by sponging miR-212-3p to regulate CD226. Conclusions This ceRNA network contributes to understanding the pathogenesis of LUAD. Furthermore, the molecules in the network are valuable predictive factors for LUAD prognosis as well as potential therapeutic biomarkers.
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In recent years, advances in bioinformatics approaches have allowed a systematic characterization of circular RNAs (circRNAs) across a variety of cell types. Demonstration of cell type specificity, regulated expression, and conservation between species all suggest that circRNAs have functional importance. Especially, investigators have begun focusing on the possibility that circRNAs operate as part of competing endogenous RNA (ceRNA) regulatory networks that are proposed to play critical roles in normal development and in pathologic conditions like cancer.
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Abstract Background There is a growing body of evidence suggesting that long non-coding RNAs(lncRNAs) can function as a microRNA(miRNA) sponge in various diseases including oral cancer. However, we are still not very clear about the pathophysiological function of lncRNAs. Methods We constructed a lncRNA-miRNA-mRNA network in oral cancer based on the competitive endogenous RNA(ceRNA) theory with the human expression profiles GSE74530 from the Gene Expression Omnibus (GEO) database and used topological analysis to determine the hub lncRNAs in the regulatory ceRNA network. Then, function enrichment analysis was performed by R package Cluster Profiler. Results A total of 238 potential co-dysregulated competing triples were obtained in the lncRNA-assoicated ceRNA network of oral cancer, which consisted of 10 lncRNA nodes, 41 miRNA nodes, and 122 mRNA nodes. Additionally, we found three lncRNAs( HCP5 , AGAP11 , HCG22 ) exhibiting superior potential as diagnostic and prognostic markers of oral cancer. Conclusions Our findings will provide novel insights for understanding the ceRNA regulation in oral cancer and identify three novel lncRNAs as potential molecular biomarkers.
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High mobility group box-1 (HMGB1) is an evolutionarily conserved protein, which widely exists in mammals. HMGB1 contains the nucleus localization sequences. Intracellular and extracellular HMGB1 shows different biological functions. Extracellular HMGB1 is closely related to sepsis, cancer, rheumatoid immune, atherosclerosis, ischemia-reperfusion injury and so on. The mobilization of HMGB1 from the nucleus to the cytoplasm and subsequent release involves the processes of post-translation modification, active secretion and nuclear localization.高迁移率族蛋白B1(high mobility group box-1，HMGB1)是一种在哺乳动物中广泛存在、进化中高度保守的蛋白质。细胞核定位序列的存在使得生理状态下的HMGB1主要存在于细胞核内，但其在细胞内外的不同位置具有不同的生物学功能。细胞外的HMGB1与脓毒症、肿瘤、风湿免疫、动脉粥样硬化及缺血再灌注损伤等多种疾病密切相关。HMGB1由细胞核内迁移至细胞质再释放到细胞外的过程，涉及核定位序列的翻译后修饰、主动分泌或被动释放等机制。.
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Pancreatic cancer is one of the most common gastrointestinal malignancies,and the main unsolved obstacles,which we must figure out,are the early detection and diagnosis,and the improvement in treatments.The ceRNA (competing endogenous RNA,ceRNA) hypothesis provides significant clues and a novel direction for understanding the mechanisms of tumor occurrence and progression,microRNAs and lncRNAs (long non coding RNAs,lncRNAs) are important components in ceRNA hypothesis.Researches have discovered that both overexpression and silence of miRNAs and abnormal expression of some lncRNAs are related to the occurrence and progression of pancreatic cancer.This paper reviewed the contents and mechanisms of ceRNA hypothesis,members of ceRNA network as well as the role of ceRNAs in pancreatic neoplasms.
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Pancreatic neoplasms; ceRNA; MicroRNAs; lncRNAs; PTEN
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Competitive endogenous RNA (ceRNA) hypothesis proposes that RNA transcripts, both coding and non-coding, crosstalk with and coregulate each other using microRNA response elements (MREs). CeRNA analysis tremendously expands functional information of coding and non-coding RNAs. Mounting evidence have shown that various types of RNAs, including pseudogenes, long non-coding RNAs, circular RNAs, and messenger RNAs, can function as ceRNAs in distinct physiological and pathophysiological states. Many validated ceRNA pairs participate in the initiation and progression of cancers, and systemic ceRNA network analyses revealing potential of ceRNAs in diagnosis, therapy, and prognosis of cancers have also been performed. Areas covered: This review concisely introduces ceRNA hypothesis and characteristics of ceRNA regulations. The major sections focus on representative examples of both protein coding and non-coding RNA transcripts acting as ceRNAs. CeRNA prediction programs and databases and implications of ceRNA network in cancers are then discussed. In the end, we surmise potential implications of ceRNA network for SLE. Expert opinion: The role of ceRNA network in systemic lupus erythematosus (SLE) remains undefined. We speculate that dissecting ceRNA network in SLE may help expand our comprehension of roles of transcriptome, particularly non-coding transcripts, and richen our knowledge of pathogenesis, diagnosis, and therapy of SLE.
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Competing endogenous RNAs (ceRNAs) refer to RNA transcripts, such as mRNAs, non-coding RNAs, pseudogene transcripts, and circular RNAs, that can regulate each other by competing for the same pool of miRNAs. ceRNAs involve in the pathogenesis of several common cancers such as prostate cancer, liver cancer, breast cancer, lung cancer, gastric cancer, endometrial cancer, and so on. ceRNA activity is determined by factors such as miRNA/ceRNA abundance, ceRNAs binding affinity to miRNAs, RNA editing, and RNA-binding proteins. The alteration of any of these factors may lead to ceRNA network imbalance and thus contribute to cancer initiation and progression. There are generally three steps in ceRNA research conductions: ceRNA prediction, ceRNA validation, and ceRNA functional investigation. Deciphering ceRNA interplay in cancer provides new insight into cancer pathogenesis and opportunities for therapy exploration. In this review, we try to give readers a concise and reliable illustration on the mechanism, functions, research approaches, and perspective of ceRNA in cancer.
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Bladder urothelial cancer (BUC) has become one of the most frequently occurring malignant tumors worldwide and it is of great importance to explore the molecular pathogenesis of bladder cancer. Emerging evidence has demonstrated that dysregulation of noncoding RNAs is critically involved in the tumorigenesis and progression of BUC. Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression and therefore form a competing endogenous RNA (ceRNA) network. ceRNA networks have been proven to play vital roles during tumorigenesis and progression. Elements involved in the ceRNA network have also been identified as potential therapeutic targets and prognostic biomarkers in various tumors. Understanding the regulatory mechanisms and functional roles of the ceRNA system will help understand tumorigenesis, progression mechanisms of BUC and develop therapeutics against cancer.In this study, we utilized the TCGA database and analyzed the multilevel expression profile of BUC. ceRNA regulatory networks were constructed by integrating tumor progression and prognosis information. RNA immunoprecipitation (RIP) and qRT-PCR were applied to verify the identified ceRNA networks. KEGG enrichment analysis was implemented to infer the biological functions of the regulatory system.We identified a lncRNA-miRNA-mRNA regulatory ceRNA network containing two lncRNAs, one miRNA and 14 mRNAs. The ceRNA network we identified showed significant roles in BUC tumorigenesis, progression, and metastases.The proposed ceRNA network may help explain the regulatory mechanism by which lncRNAs function as ceRNAs and improve our understanding of the pathogenesis of BUC. Moreover, the candidate elements involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for BUC.
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