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  • br Author Contributions br Competing Interests br Introducti

    2018-10-23


    Author Contributions
    Competing Interests
    Introduction Colorectal cancer (CRC) is a common malignancy, and remains the second leading cause of cancer-related deaths in the Western countries (Siegel et al., 2015). Although cancer-related mortality associated with CRC have declined over the past 2 decades due to advances in cancer prevention, early detection and treatment (Siegel et al., 2015), the five-year relative survival rates from this disease still remain poor (Maeda et al., 2009; Siegel et al., 2015; Van Cutsem et al., 2006; Yoo et al., 2006). In order to improve overall prognosis of CRC patients, more individualized treatments are necessary, which rely on a further understanding of the complex molecular mechanisms underlying its pathogenesis. Emerging evidence indicates that stepwise accumulation of genetic and epigenetic alterations drives CRC progression (Goel and Boland, 2010; Ogino et al., 2011; Pritchard and Grady, 2011). For instance, mutational activation of genes such as KRAS and BRAF facilitate tumor formation and progression through gain of function events (Ogino et al., 2011; Pritchard and Grady, 2011). Likewise, epigenetic alterations, including DNA methylation, histone modifications, and dysregulated hmg-coa reductase inhibitor of non-coding RNAs (ncRNAs) are frequently being recognized as pathogenic mechanisms in CRC (Goel and Boland, 2010). The current consensus is that epigenetic alterations in CRC occur early in neoplastic cascade, and perhaps manifest more frequently than genetic alterations – making them attractive candidates for exploitation as cancer biomarkers (Eddy, 2001; Goel and Boland, 2010). Over the past two decades, ncRNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been recognized as key molecular regulators in oncogenesis. In this very context, more recent evidence indicates that another class of ncRNAs, called ‘small nucleolar RNAs or snoRNAs’, sized 60–300bp, may play a critical role in multiple human cancers. Traditionally, snoRNAs have been considered to act as “housekeeping genes” because they are known to facilitate the modification, maturation, and stabilization of pre-ribosomal RNAs (rRNAs) by inducing 2′-O-methylation or pseudouridylation of specific rRNA sites by utilizing help from small nucleolar ribosonucleoproteins (snoRNPs) (Mannoor et al., 2012). In 2002, the first report for dysregulated expression of snoRNAs in cancer revealed H5sn2 expression to be significantly downregulated in meningiomas (Chang et al., 2002; Esteller, 2011). More recently, work from our laboratory and others demonstrated that SNORA42 acts as an oncogene in lung cancer and CRC (Mannoor et al., 2014; Mei et al., 2012; Okugawa et al., 2017). On similar lines, SNORD50 appears to play a tumor suppressive role in prostate and breast cancer (Dong et al., 2009, 2008) through modulation of Ras-ERK1/ERK2 signaling via direct biding to the KRAS protein (Siprashvili et al., 2016). In addition, several high-throughput RNA-sequencing and microarray-based analyses have identified several snoRNAs to be deregulated in a number of cancers, suggesting their potential role in oncogenesis. However, considering their small size and stability, snoRNAs are also gaining momentum as plausible disease biomarkers and therapeutic targets (Gao et al., 2015; Liao et al., 2010; Mannoor et al., 2014; Muller et al., 2015; Ravo et al., 2015; Xu et al., 2016). Herein, we performed a systematic and comprehensive analysis for snoRNAs expression profiles across multiple CRC datasets, and using a series of bioinformatics analysis, identified key snoRNAs involved in oncogenesis. Among these, we identified SNORA21 as a potential oncogenic snoRNA in CRC. We further evaluated its clinical significance in CRC by analyzing clinical specimens from multiple independent patient cohorts, followed by interrogation and confirmation of its oncogenic potential in a series of in vitro and in vivo experiments. Based on the clinical validation and functional analysis of oncogenic roles, our data suggest SNORA21 to be an oncogenic snoRNA in CRC pathogenesis, could provide potential biomarkers for prognostication of CRC and prediction of metastasis, which has important clinical significance in terms of better management for the patients suffering from CRC.