Circulating U2 small nuclear RNA fragments as a diagnostic and prognostic biomarker in lung cancer patients

Köhler, Jens; Schüler, Martin; Gauler, Thomas; Nöpel-Dünnebacke, Stefanie; Ahrens, Maike; Hoffmann, Andreas-Claudius; Kasper, Stefan; Nensa, Felix; Gomez, Benedikt; Hahnemann, Maria L.; Breitenbuecher, Frank; Cheufou, Danjouma; Özkan, Filiz; Darwiche, Kaid; Hoiczyk, Mathias; Reis, Henning; Welter, Stefan; Eberhardt, Wilfried; Eisenacher, Martin; Teschler, Helmut; Stamatis, Georgios; Schmiegel, Wolff; Hahn, Stephan A.; Baraniskin, Alexander

doi:10.1007/s00432-015-2095-y

Cited by 40 publications

(36 citation statements)

References 37 publications

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“…Multiple prior studies have identified tantalizing connections between snRNAs and cancer. For example, overexpression of U1 snRNA may promote pro-cancer gene expression (Cheng et al 2017), and U2 snRNA fragments are potential blood-based biomarkers for multiple cancers (Baraniskin et al 2016;Kuhlmann et al 2014;Köhler et al 2016;Kuhlmann et al 2015). Intriguingly, we observed a clear association between snRNA levels and the intrinsic breast cancer subtypes (Sorlie et al 2001).…”

Section: Discussionmentioning

confidence: 64%

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

Dvinge

Guenthoer

Porter

et al. 2018

Preprint

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Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans-acting regulatory proteins that control alternative splicing in both healthy and malignant cells has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here demonstrate that the RNA components of the spliceosome likewise influence alternative splicing decisions and contribute to the establishment of global splicing programs. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and between normal and malignant cells. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing, but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially mis-spliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many solid and liquid tumors, we propose that a full understanding of dysregulated pre-mRNA processing in cancers requires study of the RNA as well as protein components of the splicing machinery.

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Section: Discussionmentioning

confidence: 64%

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

Dvinge

Guenthoer

Porter

et al. 2018

Preprint

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“…RNU11 plays a role in splicing the U12-dependent class of eukaryotic nuclear introns and was found to be downregulated in TNBC samples. Although previous studies have shown the RNU family of snRNAs are expressed in pancreatic, colorectal and lung cancers, no concrete evidence is available to define the function of RNU2 snRNAs 72.…”

Section: Resultsmentioning

confidence: 99%

A Comprehensive NGS Data Analysis of Differentially Regulated miRNAs, piRNAs, lncRNAs and sn/snoRNAs in Triple Negative Breast Cancer

Koduru¹,

Tiwari²,

Leberfinger³

et al. 2017

J. Cancer

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Cancer is the second leading cause of death in the United States and is a major public health concern worldwide. Basic, clinical and epidemiological research is leading to improved cancer detection, prevention, and outcomes. Recent technological advances have allowed unbiased and comprehensive screening of genome-wide gene expression. Small non-coding RNAs (sncRNAs) have been shown to play an important role in biological processes and could serve as a diagnostic, prognostic and therapeutic biomarker for specific diseases. Recent findings have begun to reveal and enhance our understanding of the complex architecture of sncRNA expression including miRNAs, piRNAs, lncRNAs, sn/snoRNAs and their relationships with biological systems. We used publicly available small RNA sequencing data that was derived from 24 triple negative breast cancers (TNBC) and 14 adjacent normal tissue samples to remap various types of sncRNAs. We found a total of 55 miRNAs were aberrantly expressed (p<0.005) in TNBC samples (8 miRNAs upregulated; 47 downregulated) compared to adjacent normal tissues whereas the original study reported only 25 novel miRs. In this study, we used pathway analysis of differentially expressed miRNAs which revealed TGF-beta signaling pathways to be profoundly affected in the TNBC samples. Furthermore, our comprehensive re-mapping strategy allowed us to discover a number of other differentially expressed sncRNAs including piRNAs, lncRNAs, sn/snoRNAs, rRNAs, miscRNAs and nonsense-mediated decay RNAs. We believe that our sncRNA analysis workflow is extremely comprehensive and suitable for discovery of novel sncRNAs changes, which may lead to the development of innovative diagnostic and therapeutic tools for TNBC.

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“…Several studies have shown that transcriptional regulation of snRNA genes is involved in the carcinogenesis of several types of leukemia, lung cancer and germ cell tumors [19][20][21]. Our results raise the possibility that p53 inhibits transcription of snRNA genes through inhibiting the recruitment of LEC to MED26 and functions as an oncosuppressor.…”

Section: Discussionmentioning

confidence: 52%

“…It has been reported that p53 represses the transcription of snRNA genes [18]. In addition, accumulating evidence indicates that snRNA plays a role in the carcinogenesis in lung cancer, germ cell tumors and several types of leukemia [19][20][21] and in the progression of human diseases including Alzheimer's disease [22][23][24].…”

Section: Transcription Elongation Factors Including Eleven Lysine-ricmentioning

confidence: 99%

p53 represses the transcription of snRNA genes by preventing the formation of little elongation complex

Anwar

Takahashi

Watanabe

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Circulating U2 small nuclear RNA fragments as a diagnostic and prognostic biomarker in lung cancer patients

Abstract: Serum RNU2-1f may serve as a biomarker for lung cancer detection, prognosis prediction and treatment monitoring.

Cited by 40 publications

References 37 publications

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

A Comprehensive NGS Data Analysis of Differentially Regulated miRNAs, piRNAs, lncRNAs and sn/snoRNAs in Triple Negative Breast Cancer

p53 represses the transcription of snRNA genes by preventing the formation of little elongation complex

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