Functional Roles Of lncRNAs Research Articles

The research progression of correlation between long non-coding RNA and breast cancer

Long non-coding RNA (lncRNA) is a group of length more than 200 nucleotides, the lack of complete open reading frame and no protein-coding function RNAs, which play an important role during the development of breast cancer and other malignant tumors. With the evolution of molecular biology, gene therapy of tumor has been the most intensively studied recent years. Compared with microRNA, the functional roles of lncRNAs are still being elucidated. Therefore, it is hopeful to provide new thoughts for diagnosis and treatment of tumor gene level by deepening the study of lncRNAs.

Abstract 18412: Long Non-coding RNA Meg3 Regulates Senescence-associated Genes and Controls Endothelial Cell Function

The majority of transcribed RNAs does not encode proteins, but function as regulatory RNAs. Non-protein-coding RNA are classified in short (<200 nt) and long (>200 nt) non-coding RNAs (lncRNAs). lncRNAs have been described to play an important role in many biological processes, including epigenetic regulation of gene expression. To determine the expression and functional role of lncRNAs in endothelial cells, we performed RNA deep sequencing of human umbilical venous endothelial cells (ECs). Among the highest expressed lncRNAs, we identified Maternally Expressed 3 (Meg3, 35.3±0.6 RPKM), which has been correlated to VEGF expression. In HUVECs, Meg3 localizes to the nucleus and is induced by hypoxia (4.08±0.78-fold, p<0.05). Interestingly, Meg3 was also found to be induced in the intima of aged mice and correlates with age in human hearts (p=0.016). Meg3 levels are also induced in replicative senescent HUVECs in vitro (passage 16/17 vs 2/3, 2.9±0.99-fold).Conversely, silencing of Meg3 using LNA-GapmeRs induced angiogenic sprouting of endothelial cells in vitro (1.4±0.14-fold, P<0.05) but did not affect caspase-3 activation. Mechanistically, RNA immunoprecipations showed that Meg3 associates specifically to H3K27me3, a silencing chromatin mark. Silencing of Meg3 in HUVECs induces a robust repression of global gene expression, as measured by exon array analysis, with a highly significant repression of the anti-senescent HMGA2. In summary these results demonstrate, that the lncRNA Meg3 is highly expressed in endothelial cells and is up-regulated by hypoxia and aging. Functionally, Meg3 inhibits sprouting angiogenesis in vitro. Meg3 depletion leads to a general repression of gene expression and the senescence marker HMGA2 likely by inducing the recruitment of silencing H3K27me3 marks to the promoters Therefore, modulating Meg3 may be a potential strategy to reduce endothelial senescence or increase regenerative angiogenesis.

Long noncoding RNAs: Novel insights into gastric cancer

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides. Recent advances in the non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack coding protein function, termed non-coding RNA (ncRNA). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNA world. Moreover, accumulating evidence has demonstrated that many lncRNAs are dysregulated in gastric cancer (GC) and closely related to tumorigenesis, metastasis, and prognosis or diagnosis. In this review, we will briefly outline the regulation and functional role of lncRNAs in GC. Finally, we discussed the potential of lncRNAs as prospective novel targets in GC treatment and biomarkers for GC diagnosis.

Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy.

Hepatocellular cancer (HCC) is a highly treatment-refractory cancer and is also highly resistant to adverse cellular stress. Although cell behavior can be modulated by noncoding RNAs (ncRNA) within extracellular vesicles (EV), the contributions of long noncoding RNAs (lncRNAs) are largely unknown. To this end, the involvement and functional roles of lncRNAs contained within EVs during chemotherapeutic stress in human HCC were determined. Expression profiling identified a subset of lncRNAs that were enriched in tumor cell-derived vesicles released from two different cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was significantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell-cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, subfamily G member 2), whereas overexpression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an EV-enriched lncRNA that contributes to cellular stress responses. These findings provide new insight into the role of EVs and demonstrate the capacity of lncRNAs to mediate chemotherapeutic stress response in HCC.

The functional role of long non-coding RNAs and epigenetics.

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. The post-transcriptional regulation is influenced by these lncRNAs by interfering with the microRNA pathways, involving in diverse cellular processes. The regulation of gene expression by lncRNAs at the epigenetic level, transcriptional and post-transcriptional level have been well known and widely studied. Recent recognition that lncRNAs make effects in many biological and pathological processes such as stem cell pluripotency, neurogenesis, oncogenesis and etc. This review will focus on the functional roles of lncRNAs in epigenetics and related research progress will be summarized.

LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity.

Long noncoding RNAs (lncRNAs) have recently been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. We identified lincRNA-p21 as a key regulator of cell proliferation and apoptosis during atherosclerosis. The expression of lincRNA-p21 was dramatically downregulated in atherosclerotic plaques of ApoE(-/-) mice, an animal model for atherosclerosis. Through loss- and gain-of-function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in vascular smooth muscle cells and mouse mononuclear macrophage cells in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Genome-wide analysis revealed that lincRNA-p21 inhibition dysregulated many p53 targets. Furthermore, lincRNA-p21, a transcriptional target of p53, feeds back to enhance p53 transcriptional activity, at least in part, via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and to bind to the promoters/enhancers of its target genes. Finally, we show that lincRNA-p21 expression is decreased in patients with coronary artery disease. Our studies identify lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis and related cardiovascular disorders.

Up-regulation of 91H promotes tumor metastasis and predicts poor prognosis for patients with colorectal cancer.

BackgroundLong noncoding RNAs (lncRNAs) play widespread roles in gene regulation and cellular processes. However, the functional roles of lncRNAs in colorectal cancer (CRC) are not yet well elucidated. The aim of the present study was to measure the levels of lncRNA 91H expression in CRC and evaluate its clinical significance and biological roles in the development and progression of CRC.Methods91H expression and copy number variation (CNV) were measured in 72 CRC tumor tissues and adjacent normal tissues by real-time PCR. The biological roles of 91H were evaluated by MTT, scratch wound assay, migration and invasion assays, and flow cytometry.Results91H was significantly overexpressed in cancerous tissue and CRC cell lines compared with adjacent normal tissue and a normal human intestinal epithelial cell line. Moreover, 91H overexpression was closely associated with distant metastasis and poor prognosis in patients with CRC, except for CNV of 91H. Multivariate analysis indicated that 91H expression was an independent prognostic indicator, as well as distant metastasis. Our in vitro data indicated that knockdown of 91H inhibited the proliferation, migration, and invasiveness of CRC cells.Conclusions91H played an important role in the molecular etiology of CRC and might be regarded as a novel prognosis indicator in patients with CRC.

Abstract 32: LincRNA-p21 Regulates Neointima Formation and Atherosclerosis by Enhancing p53 Activity

Background: Long non-coding RNAs (lncRNAs) recently have been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. Methods and Results: The downstream targets of p53 also been detected by un-bias mRNA array and specific qPCR. Furthermore, bioinformatics prediction, RNA-Immunoprecipitation, biotin-labeled RNA-pulldown and deletion mapping were performed to test the potential interaction between lincRNA-p21 and MDM2. Co-IP, genome-wide ChIP-seq and ChIP-qPCR were preformed to verify the possible influence on p53 transcriptional activity. We further investigated the function of lincRNA-p21 in vivo, therefore recombinant lincRNA-p21 knockdown lentivirus were injected into the injured area of carotid arteries injury mouse model. Then the expression of lincRNA-p21 in vascular samples of clinical coronary disease patients were also detected. We identified lincRNA-p21 as a key regulator of atherosclerosis. Expression of lincRNA-p21 was dramatically down-regulated in atherosclerotic plaques of ApoE-/- mice, an animal model for AS. Through loss- and gain-of function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in VSMCs in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Mechanistically, we revealed that lincRNA-p21, which is a transcriptional target of p53, feeds back to enhance p53 transcriptional activity via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 to regulate apoptosis, cell proliferation and suppress neointima formation. Conclusions: Our studies identified lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis.

A critical role for the long non‐coding RNA GAS5 in proliferation and apoptosis in non‐small‐cell lung cancer

In more recent years, long non-coding RNAs (lncRNAs) have been investigated as a new class of regulators of cellular processes, such as cell growth, apoptosis, and carcinogenesis. Although lncRNAs are dysregulated in numerous cancer types, limited data are available on the expression profile and functional role of lncRNAs in non-small cell lung cancer (NSCLC). In the present study, we determined the expression pattern of the growth arrest-specific transcript 5 (GAS5) in 72 NSCLC specimens by qRT-PCR and assess its biological functions in the development and progression of NSCLC. The results revealed that GAS5 expression was down-regulated in cancerous tissues compared to adjacent noncancerous tissues (P < 0.05) and was highly related to tumor size and TNM stage (P < 0.05). This correlation between GAS5 and clinicopathological parameters indicates that GAS5 might function as a tumor suppressor. Furthermore, GAS5 overexpression increased tumor cell growth arrest and induced apoptosis in vitro and in vivo. Meanwhile, siRNA-mediated knockdown of GAS5 promoted tumor cell growth. Importantly, through western blot analysis, we found that ectopic expression of GAS5 significantly up-regulated p53 expression and down-regulated transcription factor E2F1 expression. Taken together, these findings suggest that GAS5 is a tumor suppressor in NSCLC, and the action of GAS5 is mediated by p53-dependent and p53-independent pathways. GAS5 could serve as a potential diagnostic marker for NSCLC and may be a novel therapeutic target in patients with NSCLC.

Long noncoding RNAs: Novel insights into hepatocelluar carcinoma

Recent advances in non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack of coding protein function, termed long noncoding RNAs (lncRNAs). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNAs world. Moreover, accumulating studies have demonstrated that a class of lncRNAs are dysregulated in hepatocellular carcinoma(HCC) and closely related with tumorigenesis, metastasis, prognosis or diagnosis. In this review, we will briefly discuss the regulation and functional role of lncRNAs in HCC, therefore evaluating the potential of lncRNAs as prospective novel therapeutic targets in HCC.

The novel long non-coding RNA CRG regulates Drosophila locomotor behavior

Long non-coding RNAs (lncRNAs) that have no protein-coding capacity make up a large proportion of the transcriptome of various species. Many lncRNAs are expressed within the animal central nervous system in spatial- and temporal-specific patterns, indicating that lncRNAs play important roles in cellular processes, neural development, and even in cognitive and behavioral processes. However, relatively little is known about their in vivo functions and underlying molecular mechanisms in the nervous system. Here, we report a neural-specific Drosophila lncRNA, CASK regulatory gene (CRG), which participates in locomotor activity and climbing ability by positively regulating its neighboring gene CASK (Ca2+/calmodulin-dependent protein kinase). CRG deficiency led to reduced locomotor activity and a defective climbing ability—phenotypes that are often seen in CASK mutant. CRG mutant also showed reduced CASK expression level while CASK over-expression could rescue the CRG mutant phenotypes in reciprocal. At the molecular level, CRG was required for the recruitment of RNA polymerase II to the CASK promoter regions, which in turn enhanced CASK expression. Our work has revealed new functional roles of lncRNAs and has provided insights to explore the pathogenesis of neurological diseases associated with movement disorders.