A Genetic Screen Implicates miRNA-372 and miRNA-373 as Oncogenes in Testicular Germ Cell Tumors

Voorhoeve, P. Mathijs; Sage, Carlos le; Schrier, Mariëtte; Gillis, Ad J. M.; Stoop, Hans; Nagel, Remco; Liu, Ying Poi; Duijse, Josyanne van; Drost, Jarno; Griekspoor, Alexander; Zlotorynski, Eitan; Yabuta, Norikazu; Vita, Gabriella De; Nishimura, Hiroshi; Looijenga, Leendert; Agami, Reuven

doi:10.1007/978-0-387-69116-9_2

Cited by 148 publications

(133 citation statements)

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“…On the contrary, isomiRs of miR-10a-5p and the mir-200 family are largely absent from LGG and present in 71–93% of the other cancers (Figure 1B). Another example can be seen in Supplementary Table S3: the mir-302 family and the mir-371/372/373 cluster express several isomiRs that are nearly exclusive to testicular germ cell tumors (TGCT) (71). …”

Section: Resultsmentioning

confidence: 99%

Knowledge about the presence or absence of miRNA isoforms (isomiRs) can successfully discriminate amongst 32 TCGA cancer types

Telonis

Magee

Loher

et al. 2017

Nucleic Acids Research

171

182

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Isoforms of human miRNAs (isomiRs) are constitutively expressed with tissue- and disease-subtype-dependencies. We studied 10 271 tumor datasets from The Cancer Genome Atlas (TCGA) to evaluate whether isomiRs can distinguish amongst 32 TCGA cancers. Unlike previous approaches, we built a classifier that relied solely on ‘binarized’ isomiR profiles: each isomiR is simply labeled as ‘present’ or ‘absent’. The resulting classifier successfully labeled tumor datasets with an average sensitivity of 90% and a false discovery rate (FDR) of 3%, surpassing the performance of expression-based classification. The classifier maintained its power even after a 15× reduction in the number of isomiRs that were used for training. Notably, the classifier could correctly predict the cancer type in non-TCGA datasets from diverse platforms. Our analysis revealed that the most discriminatory isomiRs happen to also be differentially expressed between normal tissue and cancer. Even so, we find that these highly discriminating isomiRs have not been attracting the most research attention in the literature. Given their ability to successfully classify datasets from 32 cancers, isomiRs and our resulting ‘Pan-cancer Atlas’ of isomiR expression could serve as a suitable framework to explore novel cancer biomarkers.

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Section: Resultsmentioning

confidence: 99%

Knowledge about the presence or absence of miRNA isoforms (isomiRs) can successfully discriminate amongst 32 TCGA cancer types

Telonis

Magee

Loher

et al. 2017

Nucleic Acids Research

171

182

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show abstract

“…24 While gain-of-function approaches (and loss-of-function studies, in the case of miR-335) in xenograft models have demonstrated that each of the aforementioned miRNAs was capable of altering metastatic capacity, it has remained unclear whether these in vivo effects could be attributed specifically to influences on one or more steps of the invasion-metastasis cascade; resolution of this question has been obscured by the potentially confounding reported influences of these miRNAs on primary tumor development, cell proliferation and/or apoptosis. 19,[23][24][25][26][27][28] Hence, the extent to which miRNAs were capable of specifically regulating metastasis has remained unresolved.…”

Section: Micrornas As Critical Regulators Of Tumor Metastasismentioning

confidence: 99%

MicroRNAs: Crucial multi-tasking components in the complex circuitry of tumor metastasis

Valastyan¹,

Weinberg²

2009

Cell Cycle

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Distant metastases are the underlying cause of patient mortality in an overwhelming majority of human carcinomas. Certain microRNAs have recently been found capable of regulating the process of tumor metastasis. In this review, we highlight advances within this rapidly emerging field, endeavor to connect known microRNA pathways with recent conceptual advances in the larger field of metastasis research, and speculate regarding the future utility of microRNAs in the diagnosis and treatment of human cancers. Assessed collectively, current evidence suggests that the pleiotropic activities of microRNAs endow them with the capacity to function as crucial, yet previously unappreciated, nodes within already-identified metastasis regulatory circuitry. This has important implications for our understanding of the pathogenesis of high-grade malignancies.

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“…The first three nucleotides of the miRNA binding site in the 3’UTR were mutated by site directed mutagenesis, creating the 3’UTR-mut-pGL3 vector. The miR-6715 miRNA expression vector was created by cloning the genomic polycistronic miR-6715-3p and miR-6715-5p into the miRvec expression vector (obtained as a gift from Reuven Agami) [43]. HEK293T cells were transiently transfected with either 3’UTR-wt-pGL3 or with 3’UTR-mut-pGL3, for each of the tested targets, together with the corresponding miRNA expression vector and Renilla expressing vector.…”

Section: Methodsmentioning

confidence: 99%

Next-generation sequencing of small RNAs from inner ear sensory epithelium identifies microRNAs and defines regulatory pathways

et al. 2014

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BackgroundThe mammalian inner ear contains sensory organs, the organ of Corti in the cochlea and cristae and maculae in the vestibule, with each comprised of patterned sensory epithelia that are responsible for hearing and balance. The development, cell fate, patterning, and innervation of both the sensory and nonsensory regions of the inner ear are governed by tight regulation involving, among others, transcription factors and microRNAs (miRNAs). In humans, mutations in specific miRNA genes are associated with hearing loss. In mice, experimental reduction or mutations of miRNAs in the inner ear leads to severe developmental and structural abnormalities. A comprehensive identification of miRNAs in the sensory epithelia and their gene targets will enable pathways of auditory and vestibular function to be defined.ResultsIn this study, we used Next-Generation Sequencing (NGS) to identify the most prominent miRNAs in the inner ear and to define miRNA-target pairs that form pathways crucial for the function of the sensory epithelial cells. NGS of RNA from inner ear sensory epithelial cells led to the identification of 455 miRNAs in both cochlear and vestibular sensory epithelium, with 30 and 44 miRNAs found in only cochlea or vestibule, respectively. miR-6715-3p and miR-6715-5p were defined for the first time in the inner ear. Gene targets were identified for each of these miRNAs, including Arhgap12, a GTPase activating protein, for miR-6715-3p, implicating this miRNA in sensory hair cell bundle development, actin reorganization, cell adhesion and inner ear morphogenesis.ConclusionsThis study provides a comprehensive atlas of miRNAs in the inner ear sensory epithelia. The results provide further support of the essential regulatory role of miRNAs in inner ear sensory epithelia and in regulating pathways that define development and growth of these cells.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-484) contains supplementary material, which is available to authorized users.

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A Genetic Screen Implicates miRNA-372 and miRNA-373 as Oncogenes in Testicular Germ Cell Tumors

Cited by 148 publications

References 0 publications

Knowledge about the presence or absence of miRNA isoforms (isomiRs) can successfully discriminate amongst 32 TCGA cancer types

Knowledge about the presence or absence of miRNA isoforms (isomiRs) can successfully discriminate amongst 32 TCGA cancer types

MicroRNAs: Crucial multi-tasking components in the complex circuitry of tumor metastasis

Next-generation sequencing of small RNAs from inner ear sensory epithelium identifies microRNAs and defines regulatory pathways

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