Relevant microRNAs Research Articles

EnrichMiR predicts functionally relevant microRNAs based on target collections.

MicroRNAs (miRNAs) are small non-coding RNAs that are among the main post-transcriptional regulators of gene expression. A number of data collections and prediction tools have gathered putative or confirmed targets of these regulators. It is often useful, for discovery and validation, to harness such collections to perform target enrichment analysis in given transcriptional signatures or gene-sets in order to predict involved miRNAs. While several methods have been proposed to this end, a flexible and user-friendly interface for such analyses using various approaches and collections is lacking. enrichMiR (https://ethz-ins.org/enrichMiR/) addresses this gap by enabling users to perform a series of enrichment tests, based on several target collections, to rank miRNAs according to their likely involvement in the control of a given transcriptional signature or gene-set. enrichMiR results can furthermore be visualised through interactive and publication-ready plots. To guide the choice of the appropriate analysis method, we benchmarked various tests across a panel of experiments involving the perturbation of known miRNAs. Finally, we showcase enrichMiR functionalities in a pair of use cases.

The Connection between MicroRNAs and Oral Cancer Pathogenesis: Emerging Biomarkers in Oral Cancer Management.

Oral cancer is a common human malignancy that still maintains an elevated mortality rate despite scientific progress. Tumorigenesis is driven by altered gene expression patterns of proto-oncogenes and tumor-suppressor genes. MicroRNAs, a class of short non-coding RNAs involved in gene regulation, seem to play important roles in oral cancer development, progression, and tumor microenvironment modulation. As properties of microRNAs render them stable in diverse liquid biopsies, together with their differential expression signature in cancer cells, these features place microRNAs at the top of promising biomarkers for diagnostic and prognostic values. In this review, we highlight eight expression levels and functions of the most relevant microRNAs involved in oral cancer development, progression, and microenvironment sustainability. Furthermore, we emphasize the potential of using these small RNA species as non-invasive biomarkers for the early detection of oral cancerous lesions. Conclusively, we highlight the perspectives and limitations of microRNAs as novel diagnostic tools, as well as therapeutic models.

Prognostic value of microRNAs in heart failure: A meta-analysis.

Background:Reported studies have shown that expression levels of microRNAs (miRNAs) are related to survival time of patients with heart failure (HF). A systematic review and meta-analysis were conducted to study circulating miRNAs expression and patient outcome.Methods:Meta-analysis estimating expression levels of circulating miRNAs in HF patients from January 2010 until June 30, 2018, through conducting online searches in Pub Med, Cochrane Database of Systematic, EMBASE and Web of Science and reviewed by 2 independent researchers. Using pooled hazard ratio with a 95% confidence interval to assess the correlation between miRNAs expression levels and overall survival.Results:Four relevant articles assessing 19 circulating miRNAs in 867 patients were included. In conclusion, the meta-analysis results suggest that HF patients with low expression of serum miR-1, miR-423-5p, miR-126, miR-21, miR-23, miR-30d, miR-18a-5p, miR-16-5p, miR-18b-5p, miR-27a-3p, miR-26b-5p, miR-30e-5p, miR-106a-5p, miR-233-3P, miR-301a-3p, miR-423-3P, and miR-128 have significantly worse overall survival (P < .05). Among them, miR-18a-5p, miR-18b-5p, miR-30d, miR-30e-5p, and miR-423-5p are strong biomarkers of prognosis in HF.

The Molecular Networks of microRNAs and Their Targets in the Drug Resistance of Colon Carcinoma.

Simple SummaryWe systematically reviewed the recent scientific publications describing the role of microRNAs in the regulation of drug resistance in colon cancer. To clarify the intricate web of resulting genetic and biochemical interactions, we used a machine learning approach aimed at creating: (i) networks of validated miRNA/target interactions involved in drug resistances and (ii) drug-centric networks, from which we identified the major clusters of proteins affected by drugs used in the treatment of colon cancer. Finally, to facilitate a high-level interpretation of these molecular interactions, we determined the cellular pathways related with drug resistance and regulated by the miRNAs in colon cancer.Drug resistance is one of the major forces driving a poor prognosis during the treatment and progression of human colon carcinomas. The molecular mechanisms that regulate the diverse processes underlying drug resistance are still under debate. MicroRNAs (miRNAs) are a subgroup of non-coding RNAs increasingly found to be associated with the regulation of tumorigenesis and drug resistance. We performed a systematic review of the articles concerning miRNAs and drug resistance in human colon cancer published from 2013 onwards in journals with an impact factor of 5 or higher. First, we built a network with the most studied miRNAs and targets (as nodes) while the drug resistance/s are indicated by the connections (edges); then, we discussed the most relevant miRNA/targets interactions regulated by drugs according to the network topology and statistics. Finally, we considered the drugs as nodes in the network, to allow an alternative point of view that could flow through the treatment options and the associated molecular pathways. A small number of microRNAs and proteins appeared as critically involved in the most common drugs used for the treatment of patients with colon cancer. In particular, the family of miR-200, miR34a, miR-155 and miR-17 appear as the most relevant microRNAs. Thus, regulating these miRNAs could be useful for interfering with some drug resistance mechanisms in colorectal carcinoma.

Engineering DNA‐Grafted Quatsomes as Stable Nucleic Acid‐Responsive Fluorescent Nanovesicles

AbstractThe development of artificial vesicles into responsive architectures capable of sensing the biological environment and simultaneously signaling the presence of a specific target molecule is a key challenge in a range of biomedical applications from drug delivery to diagnostic tools. Herein, the rational design of biomimetic DNA‐grafted quatsome (QS) nanovesicles capable of translating the binding of a target molecule to amphiphilic DNA probes into an optical output is presented. QSs are synthetic lipid‐based nanovesicles able to confine multiple organic dyes at the nanoscale, resulting in ultra‐bright soft materials with attractiveness for sensing applications. Dye‐loaded QS nanovesicles of different composition and surface charge are grafted with fluorescent amphiphilic nucleic acid‐based probes to produce programmable FRET‐active nanovesicles that operate as highly sensitive signal transducers. The photophysical properties of the DNA‐grafted nanovesicles are characterized and the highly selective, ratiometric detection of clinically relevant microRNAs with sensitivity in the low nanomolar range are demonstrated. The potential applications of responsive QS nanovesicles for biosensing applications but also as functional nanodevices for targeted biomedical applications is envisaged.

The Landscape of Regulatory Noncoding RNAs in Ewing's Sarcoma.

Ewing’s sarcoma (ES) is a pediatric sarcoma caused by a chromosomal translocation. Unlike in most cancers, the genomes of ES patients are very stable. The translocation product of the EWS-FLI1 fusion is most often the predominant genetic driver of oncogenesis, and it is pertinent to explore the role of epigenetic alterations in the onset and progression of ES. Several types of noncoding RNAs, primarily microRNAs and long noncoding RNAs, are key epigenetic regulators that have been shown to play critical roles in various cancers. The functions of these epigenetic regulators are just beginning to be appreciated in ES. Here, we performed a comprehensive literature review to identify these noncoding RNAs. We identified clinically relevant tumor suppressor microRNAs, tumor promoter microRNAs and long noncoding RNAs. We then explored the known interplay between different classes of noncoding RNAs and described the currently unmet need for expanding the noncoding RNA repertoire of ES. We concluded the review with a discussion of epigenetic regulation of ES via regulatory noncoding RNAs. These noncoding RNAs provide new avenues of exploration to develop better therapeutics and identify novel biomarkers.

Abstract 2359: MicroRNA 494-5p acts as tumor suppressor in colorectal cancer by targeting JAK1

Abstract Recently, we have characterized the metastatically relevant microRNA landscape by comparing microRNA (miR) expression between human colorectal metastasis and matched primary tumors and normal tissues (Mudduluru et. al. Cancer Res. 2015; PMID: 26069251). One of these, miR-494-5p, was deregulated already in primary tumors. In vitro invasion and migration (Boyden chamber and Matrigel) assays of cultured colorectal cancer cells were significantly reduced after miR-494-5p overexpression (mimic). Conversely, this was abolished by anti-miR-494-5p as an inhibitor. Overexpression of miR-494-5p in cell lines showed a significant reduction in cellular proliferation, which was reversed upon inhibitor co-transfection in a time dependent manner. In silico analysis suggested an interaction of miR-494-5p with the 3´UTR of JAK1. Accordingly, an overexpression of miR-494-5p in cultured colon cancer significantly reduced luciferase activity of a reporter plasmid containing the wild type JAK1-3'UTR, which was abolished when the miR-494-5p seed sequence was mutated to prevent miR-494-5p binding, suggesting a physical interaction and translational repression of JAK1 by miR-494-5p. Furthermore, overexpression of miR-494-5p led to a significant reduction of JAK1 expression in colorectal cancer cell lines in a time dependent manner, which was abolished by co-transfecting a specific anti-miR-494-5p as an inhibitor. Taken together, our preliminary data suggests that miR-494-5p inhibits the expression of JAK1 as a direct molecular target via specific interaction at the JAK1-3'UTR. Additionally, miR-494-5p is capable of reducing proliferation, migration, and invasion, suggesting miR-494-5p as an early tumor suppressor molecule in colorectal cancer. Citation Format: Heike Allgayer, Nitin Patil, Omar Abdelrahim, Joerg H. Leupold. MicroRNA 494-5p acts as tumor suppressor in colorectal cancer by targeting JAK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2359.

MiR-205 is up-regulated in islets of diabetes-susceptible mice and targets the diabetes gene Tcf7l2.

MicroRNAs play an important role in the maintenance of cellular functions by fine-tuning gene expression levels. The aim of the current study was to identify genetically caused changes in microRNA expression which associate with islet dysfunction in diabetic mice. To identify novel microRNAs involved in islet dysfunction, transcriptome and miRNome analyses were performed in islets of obese, diabetes-susceptible NZO and diabetes-resistant B6-ob/ob mice and results combined with quantitative trait loci (QTL) and functional in vitro analysis. In islets of NZO and B6-ob/ob mice, 94 differentially expressed microRNAs were detected, of which 11 are located in diabetes QTL. Focusing on conserved microRNAs exhibiting the strongest expression difference and which have not been linked to islet function, miR-205-5p was selected for further analysis. According to transcriptome data and target prediction analyses, miR-205-5p affects genes involved in Wnt and calcium signalling as well as insulin secretion. Over-expression of miR-205-5p in the insulinoma cell line INS-1 increased insulin expression, left-shifted the glucose-dependence of insulin secretion and supressed the expression of the diabetes gene TCF7L2. The interaction between miR-205-5p and TCF7L2 was confirmed by luciferase reporter assay. MiR-205-5p was identified as relevant microRNA involved in islet dysfunction by interacting with TCF7L2.

MicroRNA biomarkers of type 2 diabetes: A protocol for corroborating evidence by computational genomics and meta-analyses.

BackgroundFew microRNAs were found consistently dysregulated in type 2 diabetes (T2D) that would gain confidence from Big Pharma to develop diagnostic or therapeutic biomarkers. This study aimed to corroborate evidence from eligible microRNAs-T2D association studies according to stringent quality criteria covering both biological and statistical significance in T2D for biomarker development.Methods and analysesControlled microRNA expression profiling studies on human with T2D will be retrieved from PubMed, ScienceDirect, and Embase for selecting the statistically significant microRNAs according to pre-specified search strategies and inclusion criteria. Multiple meta-analyses with restricted maximum-likelihood estimation and empirical Bayes estimation under the random-effects model will be conducted by metafor package in R. Subgroup and sensitivity analyses further examine the microRNA candidates for their disease specificity, tissue specificity, blood fraction specificity, and statistical robustness of evidence. Biologically relevant microRNAs will then be selected through genomic database corroboration. Their association with T2D is further measured by area under the curve (AUC) of receive operating characteristic (ROC). Meta-analysis of AUC of potential biomarkers will also be conducted. Enrichment analysis on potential microRNA biomarkers and their target genes will be performed by iPathwayGuide and clusterProfiler, respectively. The corresponding reporting guidelines will be used to assess the quality of included studies according to their profiling methods (microarray, RT-PCR, and RNA-Seq).Ethics and disseminationNo ethics approval is required since this study does not include identifiable personal patient data.Protocol registration numberCRD42017081659.

MicroRNAs as Novel Therapeutics in Cancer.

Simple SummaryOver the last few years, we have witnessed incredible advancements in anti-tumor drug development. microRNAs, a class of small non-coding RNAs dysregulated in all cancers, have been recently elected as candidate therapeutics for treating a variety of diseases, including cancer. The scope of this review is to give some insight into the role of the most relevant microRNAs in cancer. We will focus on examining their biological role in tumor development while also providing a broad overview of microRNAs as therapeutics. There is a dedicated focus on the different methods available for microRNA delivery in addition to the efforts being made to increase the specificity of these delivery methods. Finally, we discuss the ongoing clinical trials that are using microRNAs for cancer treatment.In the last 20 years, the functional roles for miRNAs in gene regulation have been well established. MiRNAs act as regulators in virtually all biological pathways and thus have been implicated in numerous diseases, including cancer. They are particularly relevant in regulating the basic hallmarks of cancer, including apoptosis, proliferation, migration, and invasion. Despite the substantial progress made in identifying the molecular mechanisms driving the deregulation of miRNAs in cancer, the clinical translation of these important molecules to therapy remains in its infancy. The paucity of vehicles available for the safe and efficient delivery of miRNAs and ongoing concerns for toxicity remain major obstacles to clinical application. Novel formulations and the development of new vectors have significantly improved the stability of oligonucleotides, increasing the effectiveness of therapy. Furthermore, the use of specific moieties for delivery in target tissues or cells has increased the specificity of treatment. The use of new technologies has allowed small but important steps toward more specific therapeutic delivery in tumor tissues and cells. Although a long road remains, the path ahead holds great potential. Currently, a few miRNA drugs are under investigation in human clinical trials with promising results ahead.

MicroRNA-1911-3p targets mEAK-7 to suppress mTOR signaling in human lung cancer cells

Regulation of mTOR signaling depends on an intricate interplay of post-translational protein modification. Recently, mEAK-7 (mTOR associated protein, eak-7 homolog) was identified as a positive activator of mTOR signaling via an alternative mTOR complex. However, the upstream regulation of mEAK-7 in human cells is not known. Because microRNAs are capable of modulating protein translation of RNA in eukaryotes, we conducted a bioinformatic search for relevant mEAK-7 targeting microRNAs using the Exiqon miRSearch V3.0 algorithm. Based on the score obtained through miRSearch V3.0, the top predicted miRNA (miR-1911-3p) was studied. miR-1911-3p mimics decreased protein levels of both mEAK-7 and mTORC1 downstream effectors p-S6 and p-4E-BP1 in non-small cell lung carcinoma (NSCLC) cell lines H1975 and H1299. miR-1911-3p levels and MEAK7 mRNA/mEAK-7/mTOR signaling levels were negatively correlated between normal lung and NSCLC cells. miR-1911-3p directly interacted with MEAK7 mRNA at the 3′-UTR to negatively regulate mEAK-7 and significantly decreased mTOR localization to the lysosome. Furthermore, miR-1911-3p significantly decreased cell proliferation and migration in both H1975 and H1299 cells. Thus, miR-1911-3p functions as a suppressor of mTOR signaling through the regulation of MEAK7 mRNA translation in human cancer cells.

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition.

Network analysis of MicroRNA transcripts revealed relevant MicroRNAs and gene candidates for angiogenesis in gastric cancer

BackgroundAngiogenesis is considered as one of the hallmarks of cancer progression. ObjectiveThis study aimed to identify the microRNAs(miRNAs) and their target genes and pathways responsible for angiogenesis in gastric cancer. MethodsFrom the public miRNA transcriptomic profiles of gastric cancer in three conditions (normal, adjacent to tumor, and tumor), we identified differentially expressed miRNAs that were commonlypresent in all the three conditions i.e. adjacent to tumor-normal [adj-nor],tumor-adjacent to tumor [tum-adj], and tumor-normal [tum-nor].The target genes of those miRNAs were predicted and subjected to network analysis. The resultant sub-network clusters were annotated with functional enrichment analysis and pathway analysis to identify potential genes and pathways related to angiogenesis in gastric cancer. ResultThis study identified two miRNAs (miR-196a-5p and miR-223-3p), 12 genes (IL6, SP1, STAT3, FBXW7, STAT1, STAT5A, ZEB1, HMOX1, CCND1, CDKN1B, GLMN, and PRDM1) and one pathway (FoxO signaling pathway) related to angiogenesis in gastric cancer. Among these 12 genes, five genes (HMOX1, CCND1, CDKN1B, GLMN, and PRDM1) were first reported in our study for their role in tumor angiogenesis in gastric cancer. ConclusionAs angiogenesis is the crucial step in tumor progression, further studies on these two miRNAs, five target genes,and reported pathway will shed light on the early detection, diagnosis, and treatment of gastric cancer.

EPHA2 antisense RNA modulates EPHA2 mRNA levels in basal-like/triple-negative breast cancer cells

Ephrin type-A receptor 2 (EPHA2) is a receptor tyrosine kinase (RTK), whose over-expression has been observed in a variety of cancers, including breast cancer. EPHA2 expression may be causally related to tumorigenesis; therefore, it is important to understand how EPHA2 gene (EPHA2) expression is regulated. Here, we report that EPHA2 antisense RNA (EPHA2-AS), a natural antisense transcript, is an important modulator of EPHA2 mRNA levels. EPHA2-AS is a ∼1.8 kb long non-coding RNA (lncRNA) with a poly(A) tail that encodes two splice variants, EPHA2-AS1/2. They are constitutively expressed in a concordant manner with EPHA2 mRNA in human breast adenocarcinoma cell lines and in patient samples, with the highest levels detected in the triple-negative breast cancer (TNBC) subtype. The silencing of EPHA2-AS1/2 by a sense oligonucleotide or over-expression of an antisense oligoribonucleotide, which were both designed from the EPHA2 mRNA region (nt 2955–2974) targeted by AS1/2, showed that EPHA2-AS1/2 modulated EPHA2 mRNA levels by interacting with the specific AS1/2-complementary region in the mRNA. The EPHA2-AS1/2 did not prevent microRNAs from acting on the relevant microRNA response elements shared by EPHA2-AS1/2 and EPHA2 mRNA. Our studies demonstrate a crucial role played by EPHA2-AS1/2 in modulating EPHA2 mRNA levels, and hence production of EPHA2 protein, a key oncogenic RTK that contributes to the tumorigenesis of TNBC cells.

MiRNA Modulation and Antitumor Activity by the Extra-Virgin Olive Oil Polyphenol Oleacein in Human Melanoma Cells.

Extra-virgin olive oil (EVOO) polyphenols contribute to Mediterranean diet health-promoting properties. One of the most abundant secoiridoid present in EVOO, Oleacein (OA), demonstrated anticancer activity against several tumors. Nevertheless, its role against melanoma has not still investigated. This study aimed at determining in vitro the antimelanoma activity of OA and the relative mechanism of action. OA induced cell growth inhibition in 501Mel melanoma cells with an IC50 in the low micromolar range of concentrations. Moreover, an OA concentration approximating the IC50 induced G1/S phase arrest, DNA fragmentation, and downregulation of genes encoding antiapoptotic (BCL2 and MCL1) and proproliferative (c-KIT, K-RAS, PIK3R3, mTOR) proteins, while increased transcription levels of the proapoptotic protein BAX. Concordantly, OA increased the levels of miR-193a-3p (targeting MCL1, c-KIT and K-RAS), miR-193a-5p (targeting PIK3R3 and mTOR), miR-34a-5p (targeting BCL2 and c-KIT) and miR-16-5p (miR-16-5p targeting BCL2, K-RAS and mTOR), while decreased miR-214-3p (targeting BAX). These modulatory effects might contribute to the inhibition of 501Mel melanoma cell growth observed after treatment with an olive leaves-derived formulation rich in OA, with potential application against in situ cutaneous melanoma. Altogether, these results demonstrate the ability of OA to contrast the proliferation of cutaneous melanoma cells through the transcriptional modulation of relevant genes and microRNAs, confirming the anticancer potential of EVOO and suggesting OA as a chemopreventive agent for cancer disease therapy.

Recent Progress on Relevant microRNAs in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathogenesis is unclear and is affected by both genetic and environmental factors. The microRNAs (miRNAs) are a kind of single-stranded non-coding RNA with 20-22 nucleotides, which normally inhibit their target mRNAs at a post-transcriptional level. miRNAs are involved in almost all biological processes and are closely related to ASD and many other diseases. In this review, we summarize relevant miRNAs in ASD, and analyze dysregulated miRNAs in brain tissues and body fluids of ASD patients, which may contribute to the pathogenesis and diagnosis of ASD.

Abstract 5717: LncRNA RP11-291B21.2 is associated with Durvalumab response in NSCLC and BLCA cancers

Abstract Introduction Long noncoding RNAs (lncRNAs) are interacting with oncogenes, tumor suppressors and immune genes by regulating their expression and activity of relevant transcription factors, RNA-binding proteins, and microRNAs. Dysregulated lncRNAs in immune cells are associated with excessive or uncontrolled inflammation, and play vital roles in innate immune responses, carcinogenesis and tumor microenvironment (TME). Understanding potential associations of lncRNAs with bladder cancer (BLCA) and non-small cell lung cancer (NSCLC) patients treated by ICB agents, such as durvalumab, is emerging. Methods RNAseq data from CP1108 (NCT01693562) clinical trial samples (97 NSCLC samples and 66 BLCA samples treated by durvalumab monotherapy) were processed using a comprehensive annotated genome (GRCh38.p12, release 28). The normalized lncRNA expression was reported, significantly differentially expressed lncRNAs between RECIST responders and non-responders in both BLCA and NSCLC patients were then identified using R limma package. Single-cell RNAseq data analysis was done with R Seurat package. Correlation analysis between interested lncRNAs and known oncogenic or immune genes was carried out using Spearman's rho metric in both CP1108 and TCGA RNAseq datasets. Kaplan-Meier survival analysis (OS and PFS) was performed and log-rank p-value was reported. Results Eight lncRNAs (RP4-740C4.7, AL1333245.1, RP11-284F21.10, RP5-1139B12.4, RP11-291B21.2, CTD-3064M3.7, TRG-AS1, and RP11-291B21.2) were identified to be differentially expressed between durvalumab responders and non-responders in both CP1108 BLCA and NSCLC tumors. RP11-291B21.2 is the most interested lncRNAs since 6 of 7 its upstream proximity genes (up to 300kb) are killer cell lectin like receptors (KLRs): KLRC1, KLRC2, KLRC3, KLRC4, KLRK1, GABARAPL1, and KLRD1 and they are all significantly correlated with the expression of RP11-291B21.2. Co-expression analysis has shown that lncRNA RP11-291B21.2 is highly correlated with multiple key immune genes, including NK / T cells markers and IFNg induced genes, suggesting its important role in regulating tumor microenvironment. The analysis of scRNAseq data of NSCLC tumors suggests RP11-291B21.2 is dominantly expressed in CD8+ T cells, especially in exhaustive T cells. RP11-291B21.2 is also confirmed to be highly expressed (FC&amp;gt;1.8, p&amp;lt;0.03) in exhausted CD8+ T cells both 40h and day 6 after stimulation in the in vitro experiments. Survival analysis has revealed high expression of RP11-291B21.2 is associated with better survival for patients treated by durvalumab in NSCLC and BLCA (HR=~0.3), but not for patients treated with chemotherapy in TCGA datasets. In conclusion, high expression of RP11-291B21.2 predicts better survival to NSCLC and BLCA patients treated by durvalumab which may suggest that RP11-291B21.2 is a potential lncRNA biomarker to PD1/PDL1 blockage. Citation Format: Song Wu, Sarah Hsu, Qu Zhang, Lydia Greenlees, Mike Xiao, Ashok Gupta. LncRNA RP11-291B21.2 is associated with Durvalumab response in NSCLC and BLCA cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5717.

CircEPSTI1 Promotes the Progression of Non-Small Cell Lung Cancer Through miR-145/HMGB3 Axis.

BackgroundThe high expression of circular RNA circEPSTI1 (hsa_circRNA_000479) has been reported to be associated with the malignant potential of ovarian cancer cells and triple-negative breast cancer cells. However, the expression profile and function of circEPSTI1 in non-small cell lung cancer (NSCLC) are not fully addressed.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) was applied to measure the RNA expression of circEPSTI1, relevant microRNAs (miRNAs) and high mobility group box 3 (HMGB3) in NSCLC tissues and cells. Cell counting kit 8 (CCK8) assay, colony formation and transwell assays were conducted to detect the capacities of proliferation, colony formation and metastasis in NSCLC cells. Western blot assay was performed to detect the expression of metastasis-associated proteins and HMGB3. Animal experiment was carried out to confirm the function of circEPSTI1 in vivo. The combination between miR-145 and circEPSTI1 or HMGB3 was verified by dual-luciferase reporter assay, RNA pull-down and RIP assays.ResultsCircEPSTI1 was abnormally up-regulated in NSCLC tissues and cells in comparison with that in normal tissues and cells. The high expression of circEPSTI1 was associated with the low survival rate of NSCLC patients. CircEPSTI1 accelerated the proliferation, colony formation and motility of NSCLC cells in vitro. CircEPSTI1 silencing restrained the NSCLC tumor growth in vivo. miR-145 was validated as a target of circEPSTI1 in NSCLC cells. HMGB3 was a direct downstream target of miR-145 in NSCLC cells. The decreased abilities of proliferation, colony formation and metastasis caused by the silencing of circEPSTI1 were reversed by the depletion of miR-145 or the accumulation of HMGB3 in NSCLC cells.ConclusionCircEPSTI1 aggravated the progression of NSCLC through elevating the expression of HMGB3 via sponging miR-145.

MiR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

MicroRNA Signatures in Blood or Bone Marrow Distinguish Subtypes of Pediatric Acute Lymphoblastic Leukemia

OncomiRs are microRNAs that are associated with early onset of specific cancers. To identify microRNAs involved in pediatric acute lymphoblastic leukemia (ALL) subtypes T-ALL and B-ALL, peripheral blood and bone marrow samples were independently subjected to microarray analysis using two different high-fidelity array platforms. The unique and common gene signatures from both arrays were validated by TaqMan individual assays in 100 pediatric ALL samples. Survival studies were carried out in the test set and validation set with 50 randomly selected samples in each set. MicroRNA expression profile revealed characteristic signatures for distinguishing T and B lineages and identified 51 novel microRNAs in pediatric ALL. Interestingly, the present study also revealed endogenous similarities and differences between blood and bone marrow within each ALL subtype. When Cox regression analysis was carried out with these identified microRNAs, 11 of them exhibited expression levels significantly correlated with survival. Validation of some of the common and relevant microRNAs from both arrays showed that their targets are involved in key oncogenic signaling pathways. Thus, this study suggests that microRNAs have the potential to become important diagnostic tools for identification and monitoring clinical outcomes in ALL patients.