Integrated analysis of the prostate cancer small‐nucleolar transcriptome reveals SNORA55 as a driver of prostate cancer progression

Abstract

Metastasis is the primary cause of death in prostate cancer (PCa) patients. Small nucleolar RNAs (snoRNAs) have long been considered “housekeeping” genes with no relevance for cancer biology. Emerging evidence has challenged this assumption, suggesting that snoRNA expression is frequently modulated during cancer progression. Despite this, no study has systematically addressed the prognostic and functional significance of snoRNAs in PCa.We performed RNA Sequencing on paired metastatic/non‐metastatic PCa xenografts derived from clinical specimens. The clinical significance of differentially expressed snoRNAs was further investigated in two independent primary PCa cohorts (131 and 43 patients, respectively). The snoRNA demonstrating the strongest association with clinical outcome was quantified in PCa patient‐derived serum samples and its functional relevance was investigated in PCa cells via gene expression profiling, pathway analysis and gene silencing.Our comparison revealed 21 differentially expressed snoRNAs in the metastatic vs. non‐metastatic xenografts. Of those, 12 were represented in clinical databases and were further analyzed. SNORA55 emerged as a predictor of shorter relapse‐free survival (results confirmed in two independent databases). SNORA55 was reproducibly detectable in serum samples from PCa patients. SNORA55 silencing in PCa cell lines significantly inhibited cell proliferation and migration. Pathway analysis revealed that SNORA55 expression is significantly associated with growth factor signaling and pro‐inflammatory cytokine expression in PCa.Our results demonstrate that SNORA55 up‐regulation predicts PCa progression and that silencing this non‐coding gene affects PCa cell proliferation and metastatic potential, thus positioning it as both a novel biomarker and therapeutic target.

Box C/D snoRNP Autoregulation by a cis-Acting snoRNA in the NOP56 Pre-mRNA

“…Dysregulation of snoRNAs is a signature for many cancers (Gong et al, 2017;Jorjani et al, 2016;Williams and Farzaneh, 2012), and in some cases, it has even been suggested to be a requirement for oncogenesis (Crea et al, 2016;Su et al, 2014;Zheng et al, 2015;Zhou et al, 2017), underscoring a critical need for cells to control snoRNA levels. Human cells express several hundred different variants of each of the two snoRNA types, many of which are known, or predicted, to guide the modification of specific nucleotides in pre-rRNA.…”

Los RNAs pequeños nucleolares y su participación en el cáncer

“…En tumores metastásicos, del SNORD78 está expresado a la alta y el SNORA55 circulante (en suero sanguíneo) fue un predictor de supervivencia libre de recaída de los pacientes. La disminución forzada de la expresión del SNORD78 inhibió la proliferación y migración celular, al regular vías de señalización asociadas con factores de crecimiento y la expresión de citocinas proinflamatorias 65 . Entonces, el snoRD78 y el snoRA55 parecen ser respectivamente indicadores de un peor y mejor pronóstico de los pacientes con cáncer de próstata.…”

“…Por su parte, el carcinoma adrenocortical mostró la expresión diferencial de 19 snoRNAs, los cuales podrían ser usados como molécula biomarcadoras 65 .…”

The nucleolus, an ally, and an enemy of cancer cells

“…Locus deletions of these snoRNAs enhance tumorigenesis, so they are observed in many human cancers (Siprashvili et al 2016). SNORA55 overexpression is associated with activation of oncogenic pathways in prostate tissue which is a driving force in the development of prostate cancer (PtC), while SNORA55 silencing stops proliferation and metastatic potential of PtC cells (Crea et al 2016). On the other hand, the lowered expression of SNORD47 is associated with tumorigenesis in glioblastoma, while its upregulated expression suppresses invasion of glioma cells and extends patient’s survival (Xu et al 2017).…”