Small Non-coding RNA Transcriptome in Sessile Serrated Colon Polyps

Abstract

Introduction: Serrated colon polyps are found in 15-20% of patients undergoing screening colonoscopy and may account for up to a third of all colorectal cancers (CRC). Sessile serrated adenomas/polyps (SSA/Ps) have a high risk for development into CRC. However, the molecular biology of serrated pathway to cancer is poorly understood. We describe multiple unique non-coding RNA differentially expressed in SSA/Ps and provide an insight into the potential pathways to serrated carcinoma. Methods: Small RNA sequencing was performed on 66 colon RNA samples including 13 SSA/P's, 9 Hyperplastic polyps, 7 Adenomas, 22 uninvolved colon and 15 control colon. The small (< 200 bases) RNA transcriptome of SSA/Ps and other polyp types were characterized to identify unique non-coding RNA expression in SSA/Ps. Gene targets for each of our differentially expressed microRNAs (miRNAs) were identified using multiple miRNA databases. Results: We found 104 small RNAs including 53 miRNA, 46 small nucleolar RNA and 5 nuclear RNA differentially expressed (Fold change >1.5, False discovery rate MIR31) was most differentially expressed (>6 fold) followed by MIR135B expression (>4-fold) in SSA/Ps. MIR378A was downregulated by twofold in SSA/Ps. We identified 14 gene targets for MIR378A that were statistically overexpressed in miRNA sequencing data, four of which are involved in insulin growth factor signaling. Conclusion: We describe a comprehensive analysis of the small non-coding RNA transcriptome in SSA/Ps and HPs. Increased expression of MIR31 has beendescribed in SSA/Ps and our data is consistent with recent studies. MIR135B overexpression and its role in the APC/Wnt pathway has been described in CRC and our study suggests disruption of Wnt signaling possibly playing a role in the serrated pathway. MIR378A is a tumor suppressor gene and we present the first evidence of decreased expression of MIR378A in SSA/Ps. 4 of the 14 MIR378A gene targets identified in our study are important in insulin growth factor signaling pathway which may be contributing to serrated cancer development. Our data provides insights into small RNA expression unique to SSA/Ps and potential oncological pathways which may help understand the molecular biology of progression of SSA/Ps into CRC.