Huang Tai-Chung, Renuse Santosh, Pinto Sneha, Kumar Praveen, Yang Yi, Chaerkady Raghothama, Godsey Brian, Mendell Joshua T, Halushka Marc K, Civin Curt I, Marchionni Luigi, Pandey Akhilesh
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mol Biosyst. 2015 Jan;11(1):197-207. doi: 10.1039/c4mb00585f. Epub 2014 Oct 30.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and protein synthesis. To characterize functions of miRNAs and to assess their potential applications, we carried out an integrated multi-omics analysis to study miR-145, a miRNA that has been shown to suppress tumor growth. We employed gene expression profiling, miRNA profiling and quantitative proteomic analysis of a pancreatic cancer cell line. In our transcriptomic analysis, overexpression of miR-145 was found to suppress the expression of genes that are implicated in development of cancer such as ITGA11 and MAGEA4 in addition to previously described targets such as FSCN1, YES1 and PODXL. Based on miRNA profiling, overexpression of miR-145 also upregulated other miRNAs including miR-124, miR-133b and miR-125a-3p, all of which are implicated in suppression of tumors and are generally co-regulated with miR-145 in other cancers. Using the SILAC system, we identified miR-145-induced downregulation of several oncoproteins/cancer biomarkers including SET, RPA1, MCM2, ABCC1, SPTBN1 and SPTLC1. Luciferase assay validation carried out on a subset of downregulated candidate targets confirmed them to be novel direct targets of miR-145. Overall, this multi-omics approach provided insights into miR-145-mediated tumor suppression and could be used as a general strategy to study the targets of individual miRNAs.
微小RNA（miRNA）是一类小的非编码RNA，可调节基因表达和蛋白质合成。为了表征miRNA的功能并评估其潜在应用，我们进行了一项综合多组学分析，以研究miR-145，这是一种已被证明可抑制肿瘤生长的miRNA。我们对一种胰腺癌细胞系进行了基因表达谱分析、miRNA谱分析和定量蛋白质组分析。在我们的转录组分析中，发现miR-145的过表达除了抑制先前描述的靶标如FSCN1、YES1和PODXL外，还抑制了与癌症发展相关的基因如ITGA11和MAGEA4的表达。基于miRNA谱分析，miR-145的过表达还上调了其他miRNA，包括miR-124、miR-133b和miR-125a-3p，所有这些miRNA都与肿瘤抑制有关，并且在其他癌症中通常与miR-145共同调节。使用SILAC系统，我们鉴定了miR-145诱导的几种癌蛋白/癌症生物标志物的下调，包括SET、RPA1、MCM2、ABCC1、SPTBN1和SPTLC1。对一部分下调的候选靶标进行的荧光素酶测定验证证实它们是miR-145的新型直接靶标。总体而言，这种多组学方法为miR-145介导的肿瘤抑制提供了见解，并且可作为研究单个miRNA靶标的通用策略。
