Profiling of Small Nucleolar RNAs by Next Generation Sequencing: Potential New Players for Breast Cancer Prognosis

Krishnan, Preethi; Ghosh, Sunita; Wang, Bo; Heyns, Mieke; Graham, Kathryn; Mackey, John R.; Kovalchuk, Olga; Damaraju, Sambasivarao

doi:10.1371/journal.pone.0162622

Cited by 59 publications

(59 citation statements)

References 53 publications

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“…6, the initial analyses performed by Krishnan et al 26 did not identify any significant correlation between snoRNA-93 expression and breast malignancy. While our analyses both observe robust expression of SNORD93, Krishnan et al did not report any significant production of sdRNA-93 in these samples.…”

Section: Discussionmentioning

confidence: 92%

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Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion

et al. 2017

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Genetic searches for tumor suppressors have recently linked small nucleolar RNA misregulations with tumorigenesis. In addition to their classically defined functions, several small nucleolar RNAs are now known to be processed into short microRNA-like fragments called small nucleolar RNA-derived RNAs. To determine if any small nucleolar RNA-derived RNAs contribute to breast malignancy, we recently performed a RNA-seq-based comparison of the small nucleolar RNA-derived RNAs of two breast cancer cell lines (MCF-7 and MDA-MB-231) and identified small nucleolar RNA-derived RNAs derived from 13 small nucleolar RNAs overexpressed in MDA-MB-231s. Importantly, we find that inhibiting the most differentially expressed of these small nucleolar RNA-derived RNAs (sdRNA-93) in MDA-MB-231 cells results primarily in a loss of invasiveness, whereas increased sdRNA-93 expression in either cell line conversely results in strikingly enhanced invasion. Excitingly, we recently determined sdRNA-93 expressions in small RNA-seq data corresponding to 116 patient tumors and normal breast controls, and while we find little sdRNA-93 expression in any of the controls and only sporadic expression in most subtypes, we find robust expression of sdRNA-93 in 92.8% of Luminal B Her2+tumors. Of note, our analyses also indicate that at least one of sdRNA-93’s endogenous roles is to regulate the expression of Pipox, a sarcosine metabolism-related protein whose expression significantly correlates with distinct molecular subtypes of breast cancer. We find sdRNA-93 can regulate the Pipox 3′UTR via standard reporter assays and that manipulating endogenous sdRNA-93 levels inversely correlates with altered Pipox expression. In summary, our results strongly indicate that sdRNA-93 expression actively contributes to the malignant phenotype of breast cancer through participating in microRNA-like regulation.

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Section: Discussionmentioning

confidence: 92%

“…In order to similarly examine the expression of sdRNA-93 in various breast cancer subtypes, we elected to obtain the same SRA data sets utilized by Krishnan et al 26 along with several additional controls. Excitingly, as depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion

et al. 2017

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“…Finally, altered expression of snoRNAs, such as overexpression of SNORA42 in lung cancers and SNORA21 in colorectal cancers, have been associated with oncogenesis (Mei et al 2012;Yoshida et al 2017). In addition, multiple transcriptome-wide surveys have identified snoRNAs as commonly differentially expressed in cancers, although for none of these studies has it been shown that alterations actually involve changes in rRNA modifications (Mannoor et al 2012;Krishnan et al 2016;Gong et al 2017). Whether the divergent ribosome populations arising from rRNA modifications have physiological (as opposed to pathological) roles remains to be seen.…”

Section: Posttranscriptional Modification Of Rrnamentioning

confidence: 99%

Does functional specialization of ribosomes really exist?

Ferretti

Karbstein

2019

RNA

101

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It has recently become clear that ribosomes are much more heterogeneous than previously thought, with diversity arising from rRNA sequence and modifications, ribosomal protein (RP) content and posttranslational modifications (PTMs), as well as bound nonribosomal proteins. In some cases, the existence of these diverse ribosome populations has been verified by biochemical or structural methods. Furthermore, knockout or knockdown of RPs can diversify ribosome populations, while also affecting the translation of some mRNAs (but not others) with biological consequences. However, the effects on translation arising from depletion of diverse proteins can be highly similar, suggesting that there may be a more general defect in ribosome function or stability, perhaps arising from reduced ribosome numbers. Consistently, overall reduced ribosome numbers can differentially affect subclasses of mRNAs, necessitating controls for specificity. Moreover, in order to study the functional consequences of ribosome diversity, perturbations including affinity tags and knockouts are introduced, which can also affect the outcome of the experiment. Here we review the available literature to carefully evaluate whether the published data support functional diversification, defined as diverse ribosome populations differentially affecting translation of distinct mRNA (classes). Based on these observations and the commonly observed cellular responses to perturbations in the system, we suggest a set of important controls to validate functional diversity, which should include gainof-function assays and the demonstration of inducibility under physiological conditions.

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“…Martinez et al attempted to identify the signatures of gastric cancer recurrence by analyzing the transcriptomes of 320 gastric cancer and 38 non-malignant stomach tissues and identified a 6.3-fold overexpression of piR-24000 (FR326119) in gastric adenocarcinoma as compared to the non-cancerous stomach tissues [34]. Furthermore, embedded within the Tumor Protein, Translationally-Controlled (TPT1) gene, which is known to be oncogenic in several cancers [35][36][37], the small nucleolar RNA 31 (SNORA31-001)-piR-24000 (piR_017184) pair was found to be significantly overexpressed in breast cancer tumor tissues as compared to normal breast tissues [38]. Additionally, within CRC there are two reports to date indicating a significantly upregulated expression of piR-24000 in malignant colorectal tissues; however, no clinical correlation was provided for this piRNA by either of the studies [26,39].…”

Section: Discussionmentioning

confidence: 99%

Small RNA Profiling of piRNAs in Colorectal Cancer Identifies Consistent Overexpression of piR-24000 That Correlates Clinically with an Aggressive Disease Phenotype

Iyer¹,

Wan²,

Man³

et al. 2020

Cancers

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Piwi-interacting RNAs (piRNAs) represent a novel class of small non-coding RNAs (ncRNAs) that have been shown to have a deregulated expression in several cancers, although their clinical significance in colorectal cancer (CRC) remains unclear. With an aim of delineating the piRNA distribution in CRC, we conducted a systematic discovery and validation of piRNAs within two clinical cohorts. In the discovery phase, we profiled tumor and adjacent normal tissues from 18 CRC patients by deep sequencing and identified a global piRNA downregulation in CRC. Moreover, we identified piR-24000 as an unexplored piRNA that was significantly overexpressed in CRC. Using qPCR, we validated the overexpression of piR-24000 in 87 CRC patients. Additionally, we identified a significant association between a high expression of piR-24000 and an aggressive CRC phenotype including poor differentiation, presence of distant metastases, and a higher stage. Lastly, ROC analysis demonstrated a strong diagnostic power of piR-24000 in discriminating CRC patients from normal subjects. Taken together, this study provides one of the earliest large-scale reports of the global distribution of piRNAs in CRC. In addition, piR-24000 was identified as a likely oncogene in CRC that can serve as a biomarker or a therapeutic target.

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Profiling of Small Nucleolar RNAs by Next Generation Sequencing: Potential New Players for Breast Cancer Prognosis

Cited by 59 publications

References 53 publications

Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion

Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion

Does functional specialization of ribosomes really exist?

Small RNA Profiling of piRNAs in Colorectal Cancer Identifies Consistent Overexpression of piR-24000 That Correlates Clinically with an Aggressive Disease Phenotype

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