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Identification of key differentially expressed microRNAs in cancer patients through pan-cancer analysis Open Access

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MicroRNA (miRNA) is a small RNA that functions in gene silencing. Recent studies have identified a number of miRNAs associated with cancer progression, some of which demonstrate distinct expression profiles in different cancers. However, the unique expression patterns of key differentially expressed miRNAs (between corresponding tumor and normal samples), thought to be primarily responsible for development of different cancer types, have not yet been comprehensively evaluated for each cancer. Furthermore, functional and regulatory mechanisms are not well understood for miRNAs with similar differential expression profiles across multiple cancers. In this study, we performed differential expression analysis using miRNA-seq data of 575 patients from 14 cancer types, from which we identified 47 significantly over-expressed and 18 significantly under-expressed miRNAs associated with at least eight cancer types. 21 of these miRNAs (nine over-expressed and 12 under-expressed) were highly enriched in patients of each cancer. We then analyzed potential regulatory mechanisms of miRNAs in different biological processes with respect to 7,186 experimentally validated protein coding gene targets with known differential gene expression profiles in cancer. Of the top five over- and under-expressed miRNAs (ranked by average log2 fold change values) two over-expressed miRNAs (hsa-mir-1269a and hsa-mir-210) and all five under-expressed miRNAs (hsa-mir-206, hsa-mir-204, hsa-mir-1-2, hsa-mir-133a-2, hsa-mir-133b) were significantly differentially expressed in more than 60% of patients across eight or more cancers. These findings, along with functional analysis, suggest the general importance of these enriched miRNAs and their potentially similar functions in cell proliferation control through multiple molecular processes across several cancer types. These findings provide evidence for miRNAs not previously identified in cancer, especially hsa-mir-4746. Better understanding of these miRNAs and their targets could enable construction of the regulatory network of miRNAs on certain cancer-related pathways, such as the PI3K pathway, and their potential roles as biomarkers and therapeutic targets for cancer diagnosis, prognosis, and treatment.

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