High copy number variation of cancer-related microRNA genes and frequent amplification of<i>DICER1</i>and<i>DROSHA</i>in lung cancer

Czubak, Karol; Lewandowska, Marzena Anna; Klonowska, Katarzyna; Roszkowski, Krzysztof; Kowalewski, Janusz; Figlerowicz, Marek; Kozlowski, Piotr

doi:10.18632/oncotarget.4351

Cited by 62 publications

(63 citation statements)

References 94 publications

(100 reference statements)

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“…Karyotype copy number alterations were previously associated with deregulated miRNA expression in some cancers and miRNA coding regions show high frequency of copy number variations in ovarian, breast, melanoma and lung cancer [41,42]. Interestingly, some studies report no correlation between the copy number status and miRNA expression in haematopoetic cancer and acute myeloid leukemia [43,44].…”

Section: Discussionmentioning

confidence: 99%

The deregulated microRNAome contributes to the cellular response to aneuploidy

et al. 2018

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Background: Aneuploidy, or abnormal chromosome numbers, severely alters cell physiology and is widespread in cancers and other pathologies. Using model cell lines engineered to carry one or more extra chromosomes, it has been demonstrated that aneuploidy per se impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes. Results: In this study, we analysed for the first time miRNAs and demonstrate that their expression is altered in response to chromosome gain. The miRNA deregulation is independent of the identity of the extra chromosome and specific to individual cell lines. By cross-omics analysis we demonstrate that although the deregulated miRNAs differ among individual aneuploid cell lines, their known targets are predominantly associated with cell development, growth and proliferation, pathways known to be inhibited in response to chromosome gain. Indeed, we show that up to 72% of these targets are downregulated and the associated miRNAs are overexpressed in aneuploid cells, suggesting that the miRNA changes contribute to the global transcription changes triggered by aneuploidy. We identified hsa-miR-10a-5p to be overexpressed in majority of aneuploid cells. Hsa-miR-10a-5p enhances translation of a subset of mRNAs that contain so called 5'TOP motif and we show that its upregulation in aneuploids provides resistance to starvation-induced shut down of ribosomal protein translation.

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Section: Discussionmentioning

confidence: 99%

The deregulated microRNAome contributes to the cellular response to aneuploidy

et al. 2018

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“…Another pan‐cancer study indicated that the genomic loci harbouring miRNAs genes exhibited high proportion of somatic copy number alterations accounting for about 37.1% in ovarian cancer, 72.8% in breast cancer and 85.9% in melanomas (Zhang et al ., 2006). miRNA genes were also demonstrated to undergo substantial SCNAs in lung cancer, with miR‐30d, miR‐21, miR‐17 and miR‐155 being the most amplified ones (Czubak et al ., 2015). …”

Section: Discussionmentioning

confidence: 99%

Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor

et al. 2017

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Glioblastoma (GBM) is the most frequent and most malignant primary brain tumour in adults. GBMs have a unique landscape of somatic copy number alterations (SCNAs), with the concomitant appearance of numerous driver amplifications and deletions. Here, we examined the genomic regions harbouring SCNAs and their impact on the GBM miRNome. We found that 40% of SCNA events covering 70–88% of the genomically altered regions, as identified by GISTIC and RAE algorithms, carried miRNA genes. Of 1426 annotated mature miRNAs analysed, ~ 14% (n = 198) were mapped to such fragile loci. Further, we identified an intragenic miRNA, miR‐4484 located on chromosome‐10, as a deleted and downregulated miRNA in GBM. miR‐4484 exhibited a strong positive correlation with the expression of its host gene uroporphyrinogen III synthase (UROS), thereby indicating that the loss of miR‐4484 is a codeletion event in GBM. Overexpression of miR‐4484 reduced the colony‐forming ability and suppressed the migratory capacity of glioma cells. Analysis of the RNA‐seq‐derived transcriptome upon exogenous miR‐4484 overexpression in conjunction with an integrative bioinformatics approach revealed several putative targets of miR‐4484. Unbiased functional enrichment of these targets through DAVID identified a cohort of important gene ontology terms, which possibly explain the functional role of miR‐4484 in gliomagenesis. Selected targets were validated and, importantly, were found to be upregulated in GBM. In brief, our study identified a panel of miRNAs that are likely to be regulated by genomic deletions and amplifications. Further, miR‐4484 was found to be deleted and acts as a tumour suppressor miRNA in GBM.

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“…Interestingly, Czubak et al [45] showed several miRNA genes (miR-30d, miR-21, miR-17 and miR-155), as well as two miRNA biogenesis genes, DICER1 and DROSHA, to be frequently amplified in tumour tissue specimens from 254 NSCLC patients. Moreover, the copy number variation of DICER1 and DROSHA correlated well with their expression cell-free miRNA in plasma serial blood collecƟon during treatment Fig.…”

Section: Mirna Biogenesis and Functionmentioning

confidence: 99%

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Florczuk¹,

Szpechcinski²,

Chorostowska‐Wynimko³

2017

Targ Oncol

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Lung cancer is the most common cancer worldwide. Up to 85% of lung cancer cases are diagnosed as nonsmall cell lung cancer (NSCLC). The effectiveness of NSCLC treatment is expected to be improved through the implementation of robust and specific biomarkers. MicroRNAs (miRNAs) are small, non-coding molecules that play a key role in the regulation of basic cellular processes, including differentiation, proliferation and apoptosis, by controlling gene expression at the post-transcriptional level.

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High copy number variation of cancer-related microRNA genes and frequent amplification ofDICER1andDROSHAin lung cancer

Cited by 62 publications

References 94 publications

The deregulated microRNAome contributes to the cellular response to aneuploidy

The deregulated microRNAome contributes to the cellular response to aneuploidy

Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

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