Competing endogenous RNAs (ceRNAs) are transcripts that can regulate each other at post-transcription level by competing for shared miRNAs. CeRNA networks link the function of protein-coding mRNAs with that of non-coding RNAs such as microRNA, long non-coding RNA, pseudogenic RNA and circular RNA. Given that any transcripts harbouring miRNA response element can theoretically function as ceRNAs, they may represent a widespread form of post-transcriptional regulation of gene expression in both physiology and pathology. CeRNA activity is influenced by multiple factors such as the abundance and subcellular localisation of ceRNA components, binding affinity of miRNAs to their sponges, RNA editing, RNA secondary structures and RNA-binding proteins. Aberrations in these factors may deregulate ceRNA networks and thus lead to human diseases including cancer. In this review, we introduce the mechanisms and molecular bases of ceRNA networks, discuss their roles in the pathogenesis of cancer as well as methods of predicting and validating ceRNA interplay. At last, we discuss the limitations of current ceRNA theory, propose possible directions and envision the possibilities of ceRNAs as diagnostic biomarkers or therapeutic targets.

https://jmg.bmj.com/content/jmedgenet/52/10/710.full.pdf

ceRNA in cancer: possible functions and clinical implications

Many RNA species have been identified as important players in the development of chronic diseases, including cancer. Over the past decade, numerous studies have highlighted how regulatory RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play crucial roles in the development of a disease state. It is clear that the aberrant expression of miRNAs promotes tumor initiation and progression, is linked with cardiac dysfunction, allows for the improper physiological response in maintaining glucose and insulin levels, and can prevent the appropriate integration of neuronal networks, resulting in neurodegenerative disorders. Because of this, there has been a major effort to therapeutically target these noncoding RNAs. In just the past 5 years, over 100 antisense oligonucleotide-based therapies have been tested in phase I clinical trials, a quarter of which have reached phase II/III. Most notable are fomivirsen and mipomersen, which have received FDA approval to treat cytomegalovirus retinitis and high blood cholesterol, respectively. The continued improvement of innovative RNA modifications and delivery entities, such as nanoparticles, will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Here we summarize the latest promises and challenges of targeting noncoding RNAs in disease.

/pdf/targeting-noncoding-rnas-in-disease-q0xbm4g645.pdf

Targeting noncoding RNAs in disease

Recently long non-coding RNAs (lncRNA) have emerged as new gene regulators and prognostic markers in several cancers including renal cell carcinoma (RCC). In this study, we investigated the contributions of the lncRNA MALAT1 in RCC with a specific focus on its transcriptional regulation and its interactions with Ezh2 and miR-205. We found that MALAT1 expression was higher in human RCC tissues where it was associated with reduced patient survival. MALAT1 silencing decreased RCC cell proliferation and invasion and increased apoptosis. Mechanistic investigations showed that MALAT1 was transcriptionally activated by c-Fos and that it interacted with Ezh2. After MALAT1 silencing, E-cadherin expression was increased while beta-catenin expression was decreased through Ezh2. Reciprocal interaction between MALAT1 and miR-205 was also observed. Lastly, MALAT1 bound Ezh2 and oncogenesis facilitated by MALAT1 was inhibited by Ezh2 depletion, thereby blocking epithelial-mesenchyme transition via E-cadherin recovery and beta-catenin downregulation. Overall, our findings illuminate how overexpression of MALAT1 confers an oncogenic function in RCC that may offer a novel theranostic marker in this disease.

https://cancerres.aacrjournals.org/content/canres/75/7/1322.full.pdf

Long noncoding RNA MALAT1 promotes aggressive renal cell carcinoma through Ezh2 and interacts with miR-205.

LncRNAs have attracted lots of attentions from researchers worldwide in recent decades. With the rapid advances in both experimental technology and computational prediction algorithm, thousands of lncRNA have been identified in eukaryotic organisms ranging from nematodes to humans in the past few years. More and more research evidences have indicated that lncRNAs are involved in almost the whole life cycle of cells through different mechanisms and play important roles in many critical biological processes. Therefore, it is not surprising that the mutations and dysregulations of lncRNAs would contribute to the development of various human complex diseases. In this review, we first made a brief introduction about the functions of lncRNAs, five important lncRNA-related diseases, five critical disease-related lncRNAs and some important publicly available lncRNA-related databases about sequence, expression, function, etc. Nowadays, only a limited number of lncRNAs have been experimentally reported to be related to human diseases. Therefore, analyzing available lncRNA-disease associations and predicting potential human lncRNA-disease associations have become important tasks of bioinformatics, which would benefit human complex diseases mechanism understanding at lncRNA level, disease biomarker detection and disease diagnosis, treatment, prognosis and prevention. Furthermore, we introduced some state-of-the-art computational models, which could be effectively used to identify disease-related lncRNAs on a large scale and select the most promising disease-related lncRNAs for experimental validation. We also analyzed the limitations of these models and discussed the future directions of developing computational models for lncRNA research.

Long non-coding RNAs and complex diseases: from experimental results to computational models

http://diposit.ub.edu/dspace/bitstream/2445/113000/1/662712.pdf

lncRNAs and microRNAs with a role in cancer development.

Accumulating evidence indicates that the long non-coding RNA HOTAIR plays a critical role in cancer progression and metastasis However, the overall biological role and clinical significance of HOTAIR in gastric carcinogenesis remains largely unknown HOTAIR expression was measured in 78 paired cancerous and noncancerous tissue samples by real-time PCR The effects of HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches in vitro and in vivo Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation (RIP) The positive HOTAIR/HER2 interaction was identified and verified by immunohistochemistry assay and bivariate correlation analysis HOTAIR upregulation was associated with larger tumor size, advanced pathological stage and extensive metastasis, and also correlated with shorter overall survival of gastric cancer patients Furthermore, HOTAIR overexpression promoted the proliferation, migration and invasion of gastric carcinoma cells, while HOTAIR depletion inhibited both cell invasion and cell viability, and induced growth arrest in vitro and in vivo In particular, HOTAIR may act as a ceRNA, effectively becoming a sink for miR-331-3p, thereby modulating the derepression of HER2 and imposing an additional level of post-transcriptional regulation Finally, the positive HOTAIR/HER2 correlation was significantly associated with advanced gastric cancers HOTAIR overexpression represents a biomarker of poor prognosis in gastric cancer, and may confer malignant phenotype to tumor cells The ceRNA regulatory network involving HOTAIR and the positive interaction between HOTAIR and HER2 may contribute to a better understanding of gastric cancer pathogenesis and facilitate the development of lncRNA-directed diagnostics and therapeutics against this disease

/pdf/lnc-rna-hotair-functions-as-a-competing-endogenous-rna-to-w80rusxr4g.pdf

Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer

Recent evidence highlights long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In non-small cell lung cancer (NSCLC), several lncRNAs' expressions are misregulated and have been nominated as critical actors in NSCLC tumorigenesis. LncRNA ANRIL was first found to be required for the PRC2 recruitment to and silencing of p15(INK4B), the expression of which is induced by the ATM-E2F1 signaling pathway. Our previous study showed that ANRIL was significantly upregulated in gastric cancer, and it could promote cell proliferation and inhibit cell apoptosis by silencing of miR99a and miR449a transcription. However, its clinical significance and potential role in NSCLC is still not documented. In this study, we reported that ANRIL expression was increased in NSCLC tissues, and its expression level was significantly correlated with tumor-node-metastasis stages and tumor size. Moreover, patients with high levels of ANRIL expression had a relatively poor prognosis. In addition, taking advantage of loss-of-function experiments in NSCLC cells, we found that knockdown of ANRIL expression could impair cell proliferation and induce cell apoptosis both in vitro and vivo. Furthermore, we uncover that ANRIL could not repress p15 expression in PC9 cells, but through silencing of KLF2 and P21 transcription. Thus, we conclusively demonstrate that lncRNA ANRIL plays a key role in NSCLC development by associating its expression with survival in patients with NSCLC, providing novel insights on the function of lncRNA-driven tumorigenesis.

https://mct.aacrjournals.org/content/molcanther/14/1/268.full.pdf

Xiang hua Liu

Papers

Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression