Long non-coding RNA linc00665 promotes lung adenocarcinoma progression and functions as ceRNA to regulate AKR1B10-ERK signaling by sponging miR-98
Zhuang‐Zhuang CongYifei DiaoYang XuXiaokun LiZhisheng JiangChenye ShaoSaiguang JiYi ShenWei DeQiang Yong
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Abstract Long non-coding RNAs (lncRNAs) are frequently dysregulated in multiple malignancies, demonstrating their potential oncogenic or tumor-suppressive roles in tumorigenesis. Herein, we reported the identification of a novel lncRNA, linc00665 (ENST00000590622), which was markedly upregulated in lung adenocarcinoma (LUAD) tissues and might serve as an independent predictor for poor prognosis. Functional assays indicated that linc00665 reinforced LUAD cell proliferation and metastasis in vitro and in vivo. Mechanistically, transcription factor SP1 induced the transcription of linc00665 in LUAD cells, which exerted its oncogenic role by functioning as competing endogenous RNA (ceRNA) for miR-98 and subsequently activating downstream AKR1B10-ERK signaling pathway. Together, our study elucidates oncogenic roles of linc00665–miR98–AKR1B10 axis in LUAD tumorigenesis, which may serve as potential diagnostic biomarkers and therapeutic targets.Keywords:
Competing Endogenous RNA
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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Abstract Long non-coding RNAs (lncRNAs) are frequently dysregulated in multiple malignancies, demonstrating their potential oncogenic or tumor-suppressive roles in tumorigenesis. Herein, we reported the identification of a novel lncRNA, linc00665 (ENST00000590622), which was markedly upregulated in lung adenocarcinoma (LUAD) tissues and might serve as an independent predictor for poor prognosis. Functional assays indicated that linc00665 reinforced LUAD cell proliferation and metastasis in vitro and in vivo. Mechanistically, transcription factor SP1 induced the transcription of linc00665 in LUAD cells, which exerted its oncogenic role by functioning as competing endogenous RNA (ceRNA) for miR-98 and subsequently activating downstream AKR1B10-ERK signaling pathway. Together, our study elucidates oncogenic roles of linc00665–miR98–AKR1B10 axis in LUAD tumorigenesis, which may serve as potential diagnostic biomarkers and therapeutic targets.
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Accumulating evidence suggested that lncRNA MALAT1 plays critical roles in the commencement and progression of malignant cancers. Nevertheless, the function of MALAT1 in colorectal cancer (CRC) remains largely unknown. In the present study, we reported that MALAT1 expression is significantly upregulated in CRC and correlated with advanced TNM stage, lymph node metastasis, and worse prognosis in patients. Functional assays revealed that MALAT1 knockdown reduced CRC cell growth and invasion abilities in vitro. Mechanistically, we discovered that MALAT1 may serve as a competing endogenous RNA (ceRNA) to miR-508-5p in CRC progression. Bioinformatics analysis and luciferase assays confirmed that RAB14 acts as a target of miR-508-5p. In addition, downregulation of RAB14 reduced the progression of CRC. Collectively, our findings indicated that MALAT1 could promote CRC progress by sponging miR-508-5p and enhancing RAB14 expression, which provides a therapeutic target in CRC treatment.
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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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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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Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Dysregulation of mRNAs and non-coding RNAs (ncRNAs) plays critical roles in the progression of HCC. Here, we investigated HCC samples by RNA-seq and identified a series of dysregulated RNAs in HCC. Various bioinformatics analyses established long non-coding RNA (lncRNA)-mRNA co-expression and competing endogenous RNA (ceRNA) networks in circRNA-miRNA-mRNA axis, indicating the potential cis and/or trans regulatory roles of lncRNAs and circRNAs. Moreover, GO pathway analysis showed that these identified RNAs were associated with many biological processes that were related to tumorigenesis and tumor progression. In conclusion, we systematically established functional networks of lncRNA-mRNA, circRNA-miRNA-mRNA to further unveil the potential interactions and biological processes in HCC. These results provide further insights into gene expression network of HCC and may assist future diagnosis of HCC.
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Abstract Recent evidence highlights the crucial regulatory roles of long noncoding RNAs (lncRNA) in tumor biology. In colorectal cancer (CRC), the expression of several lncRNAs is dysregulated and play essential roles in CRC tumorigenesis. However, the potential biological roles and regulatory mechanisms of the novel human lncRNA, CASC2 (cancer susceptibility candidate 2), in tumor biology are poorly understood. In this study, CASC2 expression was significantly decreased in CRC tissues and CRC cell lines, and decreased expression was significantly more frequent in patients with advanced tumor-node-metastasis stage disease (TNM III and IV) ( P = 0.028). Further functional experiments indicate that CASC2 could directly upregulate PIAS3 expression by functioning as a competing endogenous RNA (ceRNA) for miR-18a. This interactions leads to the de-repression of genes downstream of STAT3 and consequentially inhibition of CRC cell proliferation and tumor growth in vitro and in vivo by extending the G 0 /G 1 -S phase transition. Taken together, these observations suggest CASC2 as a ceRNA plays an important role in CRC pathogenesis and may serve as a potential target for cancer diagnosis and treatment.
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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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It has been extensively reported that long noncoding RNAs (lncRNAs) were closely associated with multiple malignancies. The aim of our study was to investigate the effects and mechanism of lncRNA POU6F2-AS1 in lung adenocarcinoma (LADC).The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets provided us the information of LADC clinical samples. High-regulation of POU6F2-AS1 was presented in LADC tissues compared with adjacent normal tissues, which was correlated with poor outcome of LADC patients. Functional experiments in Calu-3 and NCI-H460 cells showed that POU6F2-AS1 significantly promoted LADC cell proliferation, colony formation, invasion and migration. Moreover, through online prediction, luciferase reporter assay and Pearson's correlation analysis, we found that POU6F2-AS1 may act as a competing endogenous RNA (ceRNA) of miR-34c-5p and facilitated the expression of potassium voltage-gated channel subfamily J member 4 (KCNJ4). The promoting effect of cell aggressiveness induced by POU6F2-AS1 was enhanced by KCNJ4, whilst was abrogated due to the overexpression of miR-34c-5p. Collectively, POU6F2-AS1 might function as a ceRNA through sponging miR-34c-5p to high-regulate KCNJ4 in LADC, which indicates that POU6F2-AS1 might be a promising therapeutic target with significant prognostic value for LADC treatment.
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Abstract Long noncoding RNAs (lncRNAs) are aberrantly expressed in various cancers types and can function as competing endogenous RNAs (ceRNAs), which promote and maintain tumor initiation and progression. In this study, we explored the functional roles and regulatory mechanisms of lncRNAs as ceRNAs in colorectal cancer and their clinical potential as biomarkers. The RNA sequencing profiles of patients with colorectal cancer were downloaded from TCGA database, and 62 lncRNAs, 30miRNAs, and 59 mRNAs were identified to comprise the ceRNA network (fold change > 2, P < 0.01). Functional enrichment analysis suggested that the target genes of the ceRNA network may be involved in the pathways related to cancer, including the signaling pathway that regulates the pluripotency of stem cells, wnt signaling pathway, hippo signaling pathway, basal cell carcinoma, and colorectal cancer. Univariate and multivariate Cox's proportional hazard regression model revealed that five (H19, MIR31HG, HOTAIR, WT1‐AS, and LINC00488) out of 62 lncRNAs were closely related to the overall survival (OS) ( P < 0.05). Furthermore, the five‐lncRNA model could be an independent prognostic model in colorectal cancer. We computed for the risk function and constructed a risk score based on the five lncRNAs. Results showed that patients with high‐risk scores have poor survival rates. Additionally, combing the risk score and other clinicopathological features, we can better predict the patient's survival probabilities. Furthermore, we validate our model in the GSE38832 dataset. Collectively, our study has provided a deeper understanding of the lncRNA‐related ceRNA regulatory mechanism in CRC and identified five‐lncRNA model, which could be considered as candidate prognostic biomarkers and therapeutic targets.
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