Abstract
Colorectal cancer is the third most common cancer in the world and liver is the most frequent site of distant metastasis with poor prognosis. The aim of this study is to investigate microRNAs leading to liver metastasis. We applied microarray analysis and quantitative PCR to identify and validate dysregulated miRNAs in liver metastases when compared to primary CRCs. Functional significance and the underlying molecular mechanism of selected miRNA was demonstrated by a series of in vitro and in vivo assays. Our microarray analysis and subsequent quantitative PCR validation revealed that miR-885-5p was strongly up-regulated in liver metastases and in CRC cell-lines derived from distant metastases. Overexpression of miR-885-5p significantly induced cell migration, cell invasion, formation of stress fibre in vitro and development of liver and lung metastases in vivo. MiR-885-5p induced metastatic potential of CRC by repressing cytoplasmic polyadenylation element binding protein 2 transcription through directly binding to two binding sites on its 3′ untranslated region, and consequently led to up-regulation of TWIST1 and hence epithelial-mesenchymal transition. Our findings demonstrated the overexpression of miR-885-5p in liver metastasis and its roles in inducing CRC metastasis, potentiating development of miR-885-5p inhibitor to treat advanced CRC in the future.
Highlights
Colorectal cancer (CRC) is third most common malignancy and the third leading cause of cancer death in the United States and Hong Kong [1]
This study aimed at identifying miRNAs responsible for CRC metastasis by comparing the miRNA profiles between primary CRCs and liver metastases
Comparing the miR-885-5p level in two paired primary CRCs and liver metastases samples, both of them demonstrated much higher level in their liver metastases. These results clearly demonstrated that high miR-885-5p was associated with liver metastasis
Summary
Colorectal cancer (CRC) is third most common malignancy and the third leading cause of cancer death in the United States and Hong Kong [1]. The patients with metastasis have a higher mortality rate than primary tumor development alone [2]. Liver is the most common site of distant metastasis with poor prognosis. MicroRNAs (miRNAs) have been identified as important molecules in regulating protein expression for metastasis [3, 4]. Understanding the biological mechanism of miRNAs in regulating liver metastasis is beneficial for developing new therapies. Metastasis formation is a complex multi-step process which is regulated by different signaling pathways and cell adhesion molecules (CAMs) [5, 6]. Epithelialmesenchymal transition (EMT), which is characterized by the cell reprogramming and transition from epithelial phenotype to mesenchymal phenotype, is a pivotal process that affects the tumor cell metastasis by altering cell-cell contact and cell-extracellular matrix (ECM) interactions [7, 8]. E-cadherin, which is expressed in epithelial cells and promotes cell-cell adhesion, is one of the decreased epithelial markers during EMT while www.impactjournals.com/oncotarget
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