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Journal ArticleDOI

Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma

01 Mar 2013-Carcinogenesis (Oxford University Press)-Vol. 34, Iss: 3, pp 577-586
TL;DR: It is shown that H19 was underexpressed in intratumoral HCC tissues (T), as compared with peritumoral tissues (L), and low T/L ratio of H19 predicted poor prognosis, which could suggest the development of combination therapies that target H19 and the miR-200 family.
Abstract: Although numerous long non-coding RNAs (lncRNAs) have been identified in mammals, many of their biological roles remain to be characterized. Early reports suggest that H19 contributes to carcinogenesis, including hepatocellular carcinoma (HCC). Examination of the Oncomine resource showed that most HCC cases express H19 at a level that is comparable with the liver, with a tendency toward lower expression. This is consistent with our previous microarray data and indicates a more complicated role of H19 in HCC that needs to be characterized. In this study, the expression level of H19 was assessed in different regions of HCC patients' liver samples. Loss- and gain-of-function studies on this lncRNA in the HCC cell lines, SMMC7721 and HCCLM3, were used to characterize its effects on gene expression and to assess its effect on HCC metastasis both in vitro and in vivo. In this study, we show that H19 was underexpressed in intratumoral HCC tissues (T), as compared with peritumoral tissues (L). Additionally, low T/L ratio of H19 predicted poor prognosis. H19 suppressed HCC progression metastasis and the expression of markers of epithelial-to-mesenchymal transition. Furthermore, H19 associated with the protein complex hnRNP U/PCAF/RNAPol II, activating miR-200 family by increasing histone acetylation. The results demonstrate that H19 can alter the miR-200 pathway, thus contributing to mesenchymal-to-epithelial transition and to the suppression of tumor metastasis. These data provide an explanation for the hitherto puzzling literature on the relationship between H19 and cancer, and could suggest the development of combination therapies that target H19 and the miR-200 family.

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Citations
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Journal ArticleDOI
TL;DR: LncBase v2 hosts in silico predicted miRNA targets on lncRNAs, identified with the DIANA-microT algorithm, and caters information regarding cell type specific miRNA:lncRNA regulation and enables users to easily identify interactions in 66 different cell types, spanning 36 tissues for human and mouse.
Abstract: microRNAs (miRNAs) are short non-coding RNAs (ncRNAs) that act as post-transcriptional regulators of coding gene expression. Long non-coding RNAs (lncRNAs) have been recently reported to interact with miRNAs. The sponge-like function of lncRNAs introduces an extra layer of complexity in the miRNA interactome. DIANA-LncBase v1 provided a database of experimentally supported and in silico predicted miRNA Recognition Elements (MREs) on lncRNAs. The second version of LncBase (www.microrna.gr/LncBase) presents an extensive collection of miRNA:lncRNA interactions. The significantly enhanced database includes more than 70 000 low and high-throughput, (in)direct miRNA:lncRNA experimentally supported interactions, derived from manually curated publications and the analysis of 153 AGO CLIP-Seq libraries. The new experimental module presents a 14-fold increase compared to the previous release. LncBase v2 hosts in silico predicted miRNA targets on lncRNAs, identified with the DIANA-microT algorithm. The relevant module provides millions of predicted miRNA binding sites, accompanied with detailed metadata and MRE conservation metrics. LncBase v2 caters information regarding cell type specific miRNA:lncRNA regulation and enables users to easily identify interactions in 66 different cell types, spanning 36 tissues for human and mouse. Database entries are also supported by accurate lncRNA expression information, derived from the analysis of more than 6 billion RNA-Seq reads.

535 citations


Cites background from "Epigenetic activation of the MiR-20..."

  • ...Interactions are also coupled with miRNA binding site details [10]....

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Journal ArticleDOI
TL;DR: Some state-of-the-art computational models are introduced, which could be effectively used to identify disease-related lncRNAs on a large scale and select the most promising disease- related lnc RNAs for experimental validation and discussed the future directions of developing computational models for lncRNA research.
Abstract: 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.

439 citations

Journal ArticleDOI
TL;DR: The growing evidence of H19’s involvement in both proliferation and differentiation processes, together with its involvement in epithelial to mesenchymal transition (EMT), has led to the conclusion that some of the recent disputes and discrepancies arising from current research findings can be resolved from a viewpoint supporting the oncogenic properties of H 19.
Abstract: The imprinted oncofetal long non-coding RNA (lncRNA) H19 is expressed in the embryo, down-regulated at birth and then reappears in tumors. Its role in tumor initiation and progression has long been a subject of controversy, although accumulating data suggest that H19 is one of the major genes in cancer. It is actively involved in all stages of tumorigenesis and is expressed in almost every human cancer. In this review we delineate the various functions of H19 during the different stages in the complex process of tumor progression. H19 up-regulation allows cells to enter a “selfish” survival mode in response to stress conditions, such as destabilization of the genome and hypoxia, by accelerating their proliferation rate and increasing overall cellular resistance to stress. This response is tightly correlated with nullification, dysfunction or significant down-regulation of the master tumor suppressor gene P53. The growing evidence of H19’s involvement in both proliferation and differentiation processes, together with its involvement in epithelial to mesenchymal transition (EMT) and also mesenchymal to epithelial transition (MET), has led us to conclude that some of the recent disputes and discrepancies arising from current research findings can be resolved from a viewpoint supporting the oncogenic properties of H19. According to a holistic approach, the versatile, seemingly contradictory functions of H19 are essential to, and differentially harnessed by, the tumor cell depending on its context within the process of tumor progression.

430 citations


Cites background from "Epigenetic activation of the MiR-20..."

  • ...In addition, it downregulated the EMT key mediator, Twist1 (as opposed to its high positive correlation with H19 in the murine metastasis model of 4 T1 breast cancer cell line in which Twist was initially identified as a metastasis marker [74])....

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  • ...Hernandez JM, Elahi A, Clark CW, Wang J, Humphries LA, Centeno B, et al. miR-675 mediates downregulation of Twist1 and Rb in AFP-secreting hepatocellular carcinoma....

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  • ...Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis....

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  • ...However, in regard to the ZEB1–miR200 loop, H19 rather promotes the MET axis, apparently by interaction with a ribonucleoprotein complex that activates miR200 expression [93]....

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  • ...Subsequently, miR-200 mediates H19 dependent down-regulation of Snail and Twist [93]....

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Journal ArticleDOI
TL;DR: Recent progress on the mechanisms and functions of lncRNAs in cancer are summarized, especially focusing on the oncogenic and tumor suppressive roles of the newly identified lnc RNAs, and the pathways these novel molecules might be involved in.
Abstract: Emerging evidence showed that long non-coding RNAs (lncRNAs) play important roles in a wide range of biological processes and dysregulated lncRNAs are involved in many complex human diseases, including cancer. Although a few lncRNAs’ functions in cancer have been characterized, the detailed regulatory mechanisms of majority of lncRNAs in cancer initiation and progression remain largely unknown. In this review, we summarized recent progress on the mechanisms and functions of lncRNAs in cancer, especially focusing on the oncogenic and tumor suppressive roles of the newly identified lncRNAs, and the pathways these novel molecules might be involved in. Their potentials as biomarkers for diagnosis and prognosis in cancer are also discussed in this paper.

382 citations


Cites background from "Epigenetic activation of the MiR-20..."

  • ...Furthermore high HOTAIR gene expression DD3 (PCA3) Prostate Upregulated Biomarker [43] HOTAIR Breast, hepatocellular, colorectal, gastrointestinal stromal Upregulated Biomarker [16,44-47] Oncogenic [16,48] MALAT1 Lung, hepatocellular Upregulated Biomarker [49-51] Lung, liver, renal cell, breast, cervical, uterine endometrial stromal, colorectal, bladder, osteosarcoma Oncogenic [52] H19 Hepatocellular Downregulated Biomarker [53] Hepatocellular, bladder Upregulated Oncogenic [54] PCAT-1 Prostate Upregulated Oncogenic [27] PCGEM1 Prostate Upregulated Oncogenic [55] TUC338 Hepatocellular Upregulated Oncogenic [56] BANCR Melanoma Upregulated Oncogenic [57] YIYA Hepatocellular, ovary, breast, esophageal Upregulated Oncogenic [58] CRNDE Colorectal, hepatocellular, pancreatic, prostate, ovarian, leukemia, gliomas Upregulated Oncogenic [59] CCAT1 Gastric Upregulated Oncogenic [60] HULC Hepatocellular Upregulated Oncogenic [61] CUDR Bladder Upregulated Oncogenic [62] GAS5 Breast Downregulated Tumor suppressive [63] linc-p21 Mouse models of lung, sarcoma, lymphoma Downregulated Tumor suppressive [29] MEG3 Meningioma, glioma, hepatocellular, leukemia Downregulated Tumor suppressive [64-67] PTENP1 Prostate, colon Downregulated Tumor suppressive [40] PTCSC3 Papillary thyroid Downregulated Tumor suppressive [68] is correlated with metastasis in these four types of cancers, poor survival rate in breast cancer, increasing risk of recurrence after hepatectomy in HCC and high-risk grade in GIST, indicating HOTAIR may be a useful biomarker of poor prognosis and tumor metastasis in these cancers [16,44-47]....

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  • ...H19 Hepatocellular Downregulated Biomarker [53]...

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  • ...More recently, it was reported that lncRNA H19 is underexpressed in intratumoral HCC tissues (T), as compared with peritumoral tissues (L), and low T/L ratio of H19 is associated with shorter disease-free survival and can be used to predict poor prognosis [53]....

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Journal ArticleDOI
TL;DR: The regulation and functional role of lncRNAs in HCC is discussed and the potential of lNCRNAs as prospective novel therapeutic targets in H CC is evaluated.

353 citations

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Journal ArticleDOI
15 Sep 2011-Nature
TL;DR: It is shown that Knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators.
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