International PhD Program in Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
PLoS One. 2019 Feb 26;14(2):e0211968. doi: 10.1371/journal.pone.0211968. eCollection 2019.
Liver metastases are the major cause of colorectal cancer (CRC)-related deaths. However, there is no reliable clinical predictor for CRC progression to liver metastasis. In this study, we investigated possible predictors (miRNAs and biomarkers) for clinical application.
The Gene Expression Omnibus (GEO) datasets GSE49355, GSE41258 and GSE81558 for genes and GSE54088 and GSE56350 for miRNAs were used to identify common differentially expressed genes (DEGs) and miRNAs between primary CRC tissues and liver metastases. The identified miRNAs and their targets from the DEGs were verified in datasets comprising gene, miRNA and miRNA exosome profiles of CRC patients with no distant metastases (M0) and distant metastases (M1); the interaction networks and pathways were also mapped.
There were 49 upregulated and 13 downregulated DEGs and 16 downregulated and 14 upregulated miRNAs; between the DEGs and miRNA targets, there were five upregulated and four downregulated genes. MiR-20a was strongly correlated with the status of liver metastasis. MiR-20a, miR499a, and miR-576-5p were highly correlated with the metastatic outcomes. MiR-20a was significantly highly expressed in the M1 group. In an analysis of the miRNA target genes, we found that CDH2, KNG1, and MMP2 were correlated with CRC metastasis. We demonstrated a new possible pathway for CRC metastasis: miR-576-5p/F9, miR20a/MMP2, CTSK, MMP3, and miR449a/P2RY14. The regulation of IGF transport and uptake by IGFBPs, extracellular matrix organization, signal transduction and the immune system were the enriched pathways.
This model can predict CRC to liver metastases and the pathways involved, which can be clinically applicable.
肝转移是结直肠癌（CRC）相关死亡的主要原因。然而，CRC 进展为肝转移尚无可靠的临床预测指标。在本研究中，我们研究了可能的预测指标（miRNA 和生物标志物）用于临床应用。
使用基因表达综合（GEO）数据集 GSE49355、GSE41258 和 GSE81558 中的基因数据和 GSE54088 和 GSE56350 中的 miRNA 数据，以鉴定原发性 CRC 组织与肝转移之间的常见差异表达基因（DEG）和 miRNA。从 DEG 中鉴定出的 miRNA 及其靶基因，在包含无远处转移（M0）和远处转移（M1）CRC 患者的基因、miRNA 和 miRNA 外泌体谱的数据集进行验证；并对相互作用网络和途径进行映射。
发现有 49 个上调和 13 个下调的 DEG，以及 16 个下调和 14 个上调的 miRNA；在 DEG 和 miRNA 靶基因之间，有五个上调和四个下调的基因。miR-20a 与肝转移状态密切相关。miR-20a、miR499a 和 miR-576-5p 与转移结果高度相关。miR-20a 在 M1 组中表达明显升高。在对 miRNA 靶基因的分析中，我们发现 CDH2、KNG1 和 MMP2 与 CRC 转移相关。我们证明了 CRC 转移的一个新的可能途径：miR-576-5p/F9、miR20a/MMP2、CTSK、MMP3 和 miR449a/P2RY14。IGFBPs 调节 IGF 转运和摄取、细胞外基质组织、信号转导和免疫系统是富集的途径。
该模型可以预测 CRC 肝转移及其涉及的途径，具有临床应用价值。
