Abstract
BackgroundThousands of long noncoding RNAs (lncRNAs) are aberrantly expressed in various types of cancers, however our understanding of their role in the disease is still very limited.MethodsWe applied RNAseq analysis from patient-derived data with validation in independent cohort of patients. We followed these studies with gene regulation analysis as well as experimental dissection of the role of the identified lncRNA by multiple in vitro and in vivo methods.ResultsWe analyzed RNA-seq data from tumors of 456 CRC patients compared to normal samples, and identified SNHG15 as a potentially oncogenic lncRNA that encodes a snoRNA in one of its introns. The processed SNHG15 is overexpressed in CRC tumors and its expression is highly correlated with poor survival of patients. Interestingly, SNHG15 is more highly expressed in tumors with high levels of MYC expression, while MYC protein binds to two E-box motifs on SNHG15 sequence, indicating that SNHG15 transcription is directly regulated by the oncogene MYC.The depletion of SNHG15 by siRNA or CRISPR-Cas9 inhibits cell proliferation and invasion, decreases colony formation as well as the tumorigenic capacity of CRC cells, whereas its overexpression leads to opposite effects. Gene expression analysis performed upon SNHG15 inhibition showed changes in multiple relevant genes implicated in cancer progression, including MYC, NRAS, BAG3 or ERBB3. Several of these genes are functionally related to AIF, a protein that we found to specifically interact with SNHG15, suggesting that the SNHG15 acts, at least in part, by regulating the activity of AIF. Interestingly, ROS levels, which are directly regulated by AIF, show a significant reduction in SNHG15-depleted cells. Moreover, knockdown of SNHG15 increases the sensitiveness of the cells to 5-FU, while its overexpression renders them more resistant to the chemotherapeutic drug.ConclusionAltogether, these results describe an important role of SNHG15 in promoting colon cancer and mediating drug resistance, suggesting its potential as prognostic marker and target for RNA-based therapies.
Highlights
Thousands of long noncoding RNAs are aberrantly expressed in various types of cancers, our understanding of their role in the disease is still very limited
Small Nucleolar RNA Host Gene 15 (SNHG15) is upregulated in colorectal cancer and is highly correlated with poor survival To characterize Long Noncoding RNA (lncRNA) deregulated in CRC and correlated with survival, we profiled their expression in Tumor Cancer Genome Atlas (TCGA) cohort of 456 tumoral and 41 normal tissue samples
We found 14 lncRNAs as the most significantly deregulated transcripts (Fig. 1a, Additional file 3: Table S3), for which their upregulation was related to a significant decrease in survival of CRC patients (Table S3)
Summary
Thousands of long noncoding RNAs (lncRNAs) are aberrantly expressed in various types of cancers, our understanding of their role in the disease is still very limited. Different classes of ncRNAs are expressed in diverse biological processes and cellular pathways, including small ncRNAs (miRNAs, piRNAs and siRNAs) and long ncRNAs, which have at least 200 nucleotides of length and can be spliced [2,3,4,5]. The functional roles of these molecules remain mostly unclear, but recent studies have revealed that they contribute to various cellular processes such as transcription regulation, nuclear architecture, epigenetic regulation, enhancer association (in nucleus), maintenance of mRNA stability, sponging microRNA or regulation of protein translation (in cytoplasm) [7]. By next-generation sequencing, thousands of lncRNAs have been found to be aberrantly expressed in various types of cancers [8]. While some of them may play oncogenic roles promoting proliferation, invasion and metastasis, others may have a tumor suppressor function, by modulating growth arrest pathways [9,10,11]
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