Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer

Luna, Joseph M.; Barajas, Juan M.; Teng, Kun-Yu; Sun, Hui-Lung; Moore, Michael J.; Rice, Charles M.; Darnell, Robert B.; Ghoshal, Kalpana

doi:10.1016/j.molcel.2017.06.025

Cited by 72 publications

(69 citation statements)

References 70 publications

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“…Xing et al demonstrated in Huh7, HepG2, and QSG‐7701 cell lines that the expression of miR‐122 was inhibited by its promoter methylation, and that when miR‐122 promoter methylation was inhibited, it could restore its expression and subsequently induce apoptosis in these three HCC cell lines. Luna et al 33 found that miR‐122 was also significantly downregulated in HCC tissues and negatively correlated with a poor prognosis and metastasis. The upregulation of miR‐122 in HCC cell lines allows it to bind to the 3′‐untranslated region of the DLX4 gene directly and downregulate its expression, thereby inhibiting the proliferation and metastasis in HCC cells and inducing apoptosis by targeting AKT3 33 .…”

Section: Discussionmentioning

confidence: 99%

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma

Lin

Dai

et al. 2020

J of Cellular Biochemistry

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The promoter methylation mode of microribonucleic acid (miRNA) plays a crucial role in the process of hepatocellular carcinoma (HCC). Therefore, the primary purpose of this study was to screen and verify the miRNA methylation sites associated with the overall survival (OS) and clinical characteristics of HCC patients. Methylation-related data were from the Cancer Genome Atlas (TCGA). R software was utilized to screen the methylation sites. The least absolute shrinkage and selection operator algorithm was utilized to develop the miRNA promoter methylation models. Then, methylation-specific polymerase chain reaction was performed with 146 HCC tissues to verify the accuracy of the vascular infiltrationrelated model. Additionally, we verified the functions of vascular infiltration-related miRNA by utilizing cells transfected with miR-199a-3p mimic. The model for predicting OS of HCC patients contained eight methylation sites. The Kaplan-Meier analysis suggested that the model could divide HCC patients into high-and low-risk groups (P < .0001). COX regression analysis suggested that the model (P < .001; 95% CI, 1.264-2.709) and T category (P < .001; 95% CI, 1.472-3.119) were independent risk factors for affecting OS of HCC patients. The model for predicting vascular infiltration, pathological grade, and clinical stage contained 7, 10, and 9 methylation sites respectively, with their area under the receiver operating characteristic curve (AUC) values 0.667, 0.745, and 0.725, respectively. The functional analysis suggested that miRNA methylation is involved in various biological processes such as WNT, MAPK, and mTOR signaling pathways. The accuracy of the vascular infiltration-related model was consistent with our previous bioinformatics assay.And upregulation of miR-199a-3p decreased migration and invasion abilities. The screened miRNA promoter methylation sites can be served as biomarkers for judging OS, vascular infiltration, pathology grade, and clinical stage. It can also provide new targets for improving the treatment and prognosis of HCC patients. K E Y W O R D Sbioinformatics, hepatocellular carcinoma, miRNA, overall survival, promoter methylation, vascular infiltration Xiaofeng Ni, Zhuo Lin, and Shengjie Dai contributed equally to this study. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Ni X, Lin Z, Dai S, et al. Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma.

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Section: Discussionmentioning

confidence: 99%

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma

Lin

Dai

et al. 2020

J of Cellular Biochemistry

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“…Here, we confirmed that increased BCL9 phosphorylation by aberrant CDK1 activation in cancer also contributes to mitotic Wnt signalling deregulation. In addition to phosphorylation, BCL9 gene expression has been shown to be highly enriched in many cancers, predominantly due to gene amplification (TCGA cbioportal, http://www.cbioportal.org/) and/or post‐transcriptional deregulation (Jia et al , ; Luna et al , ). In addition, the deregulation of mitotic progression regulators in cancer, such as spindle regulators (Chen et al , , ), might induce abnormal mitotic distribution and lead to aberrant activation of mitotic Wnt signalling, which eventually leads to cancer progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

CDK 1‐mediated BCL 9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling

et al. 2018

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Uncontrolled cell division is a hallmark of cancer. Deregulation of Wnt components has been linked to aberrant cell division by multiple mechanisms, including Wnt-mediated stabilisation of proteins signalling, which was notably observed in mitosis. Analysis of Wnt components revealed an unexpected role of B-cell CLL/lymphoma 9 (BCL9) in maintaining mitotic Wnt signalling to promote precise cell division and growth of cancer cell. Mitotic interactome analysis revealed a mechanistic role of BCL9 in inhibiting clathrin-mediated degradation of LRP6 signalosome components by interacting with clathrin and the components in Wnt destruction complex; this function was further controlled by CDK1-driven phosphorylation of BCL9 N-terminal, especially T172. Interestingly, T172 phosphorylation was correlated with cancer patient prognosis and enriched in tumours. Thus, our results revealed a novel role of BCL9 in controlling mitotic Wnt signalling to promote cell division and growth.

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“…These studies, and most others in adipose tissue, rely on computational predictions and low-throughput validation to identify miRNA targets. Although high-throughput crosslinking techniques to map the miRNA targetome have been applied to liver, brain, heart and other tissues 11,12,13 , thus far, no comprehensive targetome has been described for adipose tissue.…”

Section: Figmentioning

confidence: 99%

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

O’Connor

Murphy

et al. 2020

Preprint

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MicroRNAs (miRNAs) are short, non-coding RNAs that associate with Argonaute (AGO) to regulate mRNA stability and translation. While individual miRNAs have been shown to play important roles in white and brown adipose tissue in normal physiology and disease 1,2,3 , a comprehensive analysis of miRNA activity in these tissues has not been performed. We used high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) to comprehensively characterize the network of high-confidence, in vivo mRNA:miRNA interactions across white and brown fat, revealing over 100,000 unique miRNA binding sites. Targets for each miRNA were ranked to generate a catalog of miRNA binding activity, and the miR-29 family emerged as a top regulator of adipose tissue gene expression. Among the top targets of miR-29 was leptin, an adipocyte-derived hormone that acts on the brain to regulate food intake and energy expenditure 4 . Two independent miR-29 binding sites in the leptin 3'-UTR were validated using luciferase assays, and miR-29 gain and loss-of-function modulated leptin mRNA and protein secretion in primary adipocytes. In mice, miR-29 abundance inversely correlated with leptin levels in two independent models of obesity. This work represents the only experimentally generated miRNA targetome in adipose tissue and identifies the first known post-transcriptional regulator of leptin. Future work aimed at manipulating miR-29:leptin binding may provide a therapeutic opportunity to treat obesity and its sequelae.Much of the work on adipocyte development and function over the last several decades has focused on transcriptional regulators. These include PPARG2, which is necessary and sufficient for the development and maintenance of white and brown adipocytes 5 , and PRDM16, which regulates brown and beige adipocyte identity 6,7 . More recently, it has become clear that post-transcriptional regulators also play 3 a key role in influencing adipocyte phenotype. Studies with adipose-specific dicer KO mice demonstrate that microRNAs (miRNAs) are essential in regulating adipogenesis, insulin sensitivity and non-shivering thermogenesis 8,9 . Several individual miRNAs have been shown to contribute to these phenotypic effects.miR-133 represses BAT function by directly targeting Prdm16 and inhibiting expression of thermogenic genes 2 . miR-196a induces browning of WAT by targeting Hoxc8 1 , and miR-26 protects mice from dietinduced obesity by blocking adipogenesis 10 . These studies, and most others in adipose tissue, rely on computational predictions and low-throughput validation to identify miRNA targets. Although highthroughput crosslinking techniques to map the miRNA targetome have been applied to liver, brain, heart and other tissues 11,12,13 , thus far, no comprehensive targetome has been described for adipose tissue.To profile the complete network of in vivo, adipose-specific miRNA binding activity across both brown and white fat, we used AGO HITS-CLIP on interscapular brown adipose tissue (iBAT) and epididymal white a...

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Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer

Cited by 72 publications

References 70 publications

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma

CDK 1‐mediated BCL 9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

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