Non-coding RNAs In Human Cancer Research Articles

Non-Coding RNAs in Human Cancer and Other Diseases: Overview of the Diagnostic Potential.

Non-coding RNAs (ncRNAs) are abundant single-stranded RNA molecules in human cells, involved in various cellular processes ranging from DNA replication and mRNA translation regulation to genome stability defense. MicroRNAs are multifunctional ncRNA molecules of 18-24 nt in length, involved in gene silencing through base-pair complementary binding to target mRNA transcripts. piwi-interacting RNAs are an animal-specific class of small ncRNAs sized 26-31 nt, responsible for the defense of genome stability via the epigenetic and post-transcriptional silencing of transposable elements. Long non-coding RNAs are ncRNA molecules defined as transcripts of more than 200 nucleotides, their function depending on localization, and varying from the regulation of cell differentiation and development to the regulation of telomere-specific heterochromatin modifications. The current review provides recent data on the several forms of small and long non-coding RNA's potential to act as diagnostic, prognostic or therapeutic target for various human diseases.

Small Non-Coding RNAs in Human Cancer.

Small non-coding RNAs are widespread in the biological world and have been extensively explored over the past decades. Their fundamental roles in human health and disease are increasingly appreciated. Furthermore, a growing number of studies have investigated the functions of small non-coding RNAs in cancer initiation and progression. In this review, we provide an overview of the biogenesis of small non-coding RNAs with a focus on microRNAs, PIWI-interacting RNAs, and a new class of tRNA-derived small RNAs. We discuss their biological functions in human cancer and highlight their clinical application as molecular biomarkers or therapeutic targets.

Small non-coding RNAs in human cancer: function, clinical utility, and characterization.

Small non-coding RNAs (sncRNAs) play critical roles in multiple regulatory processes, including transcription, post-transcription, and translation. Emerging evidence reveals the critical roles of sncRNAs in cancer development and their potential role as biomarkers and/or therapeutic targets. In this paper, we review recent research on four sncRNA species with functional significance in cancer: small nucleolar RNAs, transfer RNA, small nuclear RNAs, and piwi-interacting RNAs. We introduce their functional roles in tumorigenesis and discuss the potential utility of sncRNAs as prognostic and diagnostic biomarkers and therapeutic targets. We further summarize approaches to characterize sncRNAs in a high-throughput manner, including the specific library construction and computational framework. Our review provides a perspective of the functions, clinical utility, and characterization of sncRNAs in cancer.

The emerging role of super enhancer-derived noncoding RNAs in human cancer.

Super enhancers (SEs) are large clusters of adjacent enhancers that drive the expression of genes which regulate cellular identity; SE regions can be enriched with a high density of transcription factors, co-factors, and enhancer-associated epigenetic modifications. Through enhanced activation of their target genes, SEs play an important role in various diseases and conditions, including cancer. Recent studies have shown that SEs not only activate the transcriptional expression of coding genes to directly regulate biological functions, but also drive the transcriptional expression of non-coding RNAs (ncRNAs) to indirectly regulate biological functions. SE-derived ncRNAs play critical roles in tumorigenesis, including malignant proliferation, metastasis, drug resistance, and inflammatory response. Moreover, the abnormal expression of SE-derived ncRNAs is closely related to the clinical and pathological characterization of tumors. In this review, we summarize the functions and roles of SE-derived ncRNAs in tumorigenesis and discuss their prospective applications in tumor therapy. A deeper understanding of the potential mechanism underlying the action of SE-derived ncRNAs in tumorigenesis may provide new strategies for the early diagnosis of tumors and targeted therapy.

Upregulation of DLEU1 expression by epigenetic modification promotes tumorigenesis in human cancer.

The function of DLEU1 in human cancer is largely unknown. The Cancer Genome Atlas data were applied to identify the landscape of differential genes between tumor tissues and normal tissues, which was further validated by our cohort data and pan-cancer data including 33 cancer types with 11,060 patients. Next, DLEU1 was selected to validate the novel finding and result showed that it promoted tumorigenesis in vitro and in vivo. Mechanistically, DLEU1 promotes SRP4 expression via increasing H3K27ac enrichment to SRP4 locus epigenetically. Moreover, epigenetic modification leads to upregulation of DLEU1 expression via decreased DNA methylation and increased H3K27ac and H3K4me3 histone modification in its locus. Finally, high expression of DLEU1 correlates with worse prognosis not only in specific cancer type patients but also in patients in the pan-cancer cohort. In summary, the work broadens the function landscape of known long noncoding RNAs in human cancer and provides novel insights into their roles in tumorigenesis.

Landscape of tumor suppressor long noncoding RNAs in breast cancer

BackgroundThe landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown.MethodsData from whole transcriptome sequencing of 33 breast specimens in the Harbin Medical University Cancer Center cohort and The Cancer Genome Atlas was applied to identify and validate the landscape of tumor suppressor long noncoding RNAs, which was further validated by The Cancer Genome Atlas pancancer data including 33 cancer types and 12,839 patients. Next, the expression model, prognostic roles, potential biological functions and epigenetic regulation of tumor suppressor long noncoding RNAs were investigated and validated in the breast cancer and pancancer cohorts. Finally, EPB41L4A-AS2 was selected to validate our novel finding, and the tumor suppressive roles of EPB41L4A-AS2 in breast cancer were examined.ResultsWe identified and validated the landscape of tumor suppressor long noncoding RNAs in breast cancer. The expression of the identified long noncoding RNAs was downregulated in cancer tissue samples compared with normal tissue samples, and these long noncoding RNAs correlated with a favorable prognosis in breast cancer patients and the patients in the pancancer cohort. Multiple carcinogenesis-associated biological functions were predicted to be regulated negatively by these long noncoding RNAs. Moreover, these long noncoding RNAs were transcriptionally regulated by epigenetic modification, including DNA methylation and histone methylation modification. Finally, EPB41L4A-AS2 inhibited breast cancer cell proliferation, migration and invasion and induced cell apoptosis in vitro. Mechanistically, EPB41L4A-AS2, acting at least in part as a tumor suppressor, upregulated tumor suppressor gene expression. Moreover, ZNF217 recruited EZH2 to the EPB41L4A-AS2 locus and suppressed the expression of EPB41L4A-AS2 by epigenetically increasing H3K27me3 enrichment.ConclusionsThis work enlarges the functional landscape of known long noncoding RNAs in human cancer and provides novel insights into the suppressive roles of these long noncoding RNAs.

Abstract 3495: The DNA methylation landscape of long noncoding RNAs in human cancer

Abstract Integrating multi-dimensional genomic and epigenetic data from the TCGA, ENCODE and CCLE projects, we comprehensively characterized the epigenetic landscape for lncRNA genes in 9837 tumor samples across 33 cancer types. This analysis revealed that lncRNAs can be both epigenetically silenced and activated by DNA methylation alteration in the promoter region, which is in striking contrast to the well-documented hypermethylation of protein-coding gene promoters in tumor. To determine the corresponding transcriptional changes of lncRNAs with epigenetic alterations in tumors, we applied a heuristic strategy to identify the epigenetic silenced and activated lncRNA by integrating the transcriptome of 58,648 lncRNAs from 6475 TCGA RNA-seq files. This analysis characterized a patient-centric matrix with DNA methylation status of 3380 epigenetically regulated lncRNAs across 6475 tumor samples. Some epigenetically-activated lncRNAs exhibited an “on or off” pattern with completely no expression in normal tissues, which potentiated them as promising diagnostic biomarkers. To rule out the interference of tumor associated stromal and immune cells in lncRNA analysis, we investigated the RNA-seq and DNA methylation profiles of 784 cell lines from breast, lung, and bladder cancer. Most of epigenetically regulated lncRNAs identified in tumor samples showed prominently negative correlation between their expression and promoter methylation in cancer cell lines. We then validated the epigenetically activated lncRNAs by performing decitabine treatment on cell lines. The decitabine treatment led to a dosage and time-dependent induction of lncRNA expression and loss of DNA methylation at lncRNA promoter. Further survival analysis indicated that epigenetically activated lncRNAs were generally correlated with poor survival while the epigenetically silenced lncRNAs were generally correlated with good survival. Among the epigenetically silenced lncRNAs are well-documented tumor suppressor lncRNAs such as MEG3. And lncRNA oncogenes, such as MINCR, are epigenetically activated in multiple cancer types. To delineate the relationship between lncRNAs and known cancer pathways, we performed mutual exclusive analysis by combining the lncRNA epigenetic landscape with known protein-coding tumor genes alterations in same tumors. This analysis nominated several lncRNAs as novel members in cancer pathways, including TP53, PI3K, and EGFR cascades. Indeed, functional experiment validation focus on the top epigenetically activated lncRNA (EPIC1) demonstrated that EPIC1 is a potential oncogene. In breast and ovarian cancer cell lines, EPIC1 promotes cancer cell colony formation and increases cell viability by promoting cell cycle pathway. Collectively, our integrative study provides a resource for investigating lncRNAs in cancer and lays the groundwork for the development of novel diagnostics biomarkers and treatments. Citation Format: Da Yang, Zehua Wang, Bo Yang, Min Zhang, Zhiyuan Wu. The DNA methylation landscape of long noncoding RNAs in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3495. doi:10.1158/1538-7445.AM2017-3495

Current status of long non-coding RNAs in human cancer with specific focus on colorectal cancer.

The latest investigations of long non-coding RNAs (lncRNAs) have revealed their important role in human cancers. LncRNAs are larger than 200 nucleotides in length and fulfill their cellular purpose without being translated into proteins. Though the molecular functions of some lncRNAs have been elucidated, there is still a high number of lncRNAs with unknown or controversial functions. In this review, we provide an overview of different lncRNAs and their role in human cancers. In particular, we emphasize their importance in tumorigenesis of colorectal cancer, the third most common cancer worldwide.

Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer

Despite growing appreciations of the importance of long non-coding RNA (lncRNA) in normal physiology and disease, our knowledge of cancer-related lncRNA remains limited. By repurposing microarray probes, we constructed the expression profile of 10,207 lncRNA genes in approximately 1,300 tumors over four different cancer types. Through integrative analysis of the lncRNA expression profiles with clinical outcome and somatic copy number alteration (SCNA), we identified lncRNA that are associated with cancer subtypes and clinical prognosis, and predicted those that are potential drivers of cancer progression. We validated our predictions by experimentally confirming prostate cancer cell growth dependence on two novel lncRNA. Our analysis provided a resource of clinically relevant lncRNA for development of lncRNA biomarkers and identification of lncRNA therapeutic targets. It also demonstrated the power of integrating publically available genomic datasets and clinical information for discovering disease associated lncRNA.

Upregulation of miR-196a andHOTAIRDrive Malignant Character in Gastrointestinal Stromal Tumors

Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXC and HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference-mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs.

MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer.

Early-stage non-small cell lung cancer (NSCLC) can be cured by surgical resection, but a substantial fraction of patients ultimately dies due to distant metastasis. In this study, we used subtractive hybridization to identify gene expression differences in stage I NSCLC tumors that either did or did not metastasize in the course of disease. Individual clones (n=225) were sequenced and quantitative RT-PCR verified overexpression in metastasizing samples. Several of the identified genes (eIF4A1, thymosin beta4 and a novel transcript named MALAT-1) were demonstrated to be significantly associated with metastasis in NSCLC patients (n=70). The genes' association with metastasis was stage- and histology specific. The Kaplan-Meier analyses identified MALAT-1 and thymosin beta4 as prognostic parameters for patient survival in stage I NSCLC. The novel MALAT-1 transcript is a noncoding RNA of more than 8000 nt expressed from chromosome 11q13. It is highly expressed in lung, pancreas and other healthy organs as well as in NSCLC. MALAT-1 expressed sequences are conserved across several species indicating its potentially important function. Taken together, these data contribute to the identification of early-stage NSCLC patients that are at high risk to develop metastasis. The identification of MALAT-1 emphasizes the potential role of noncoding RNAs in human cancer.