Abstract
Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Liver metastasis is the major cause of CRC patient mortality, occurring in 60% patients with no effective therapies. Although studies have indicated the role of miRNAs in CRC, an in-depth miRNA expression analysis is essential to identify clinically relevant miRNAs and understand their potential in targeting liver metastasis. Here we analyzed miRNA expressions in 405 patient tumors from publicly available colorectal cancer genome sequencing project database. Our analyses showed miR-132, miR-378f, miR-605 and miR-1976 to be the most significantly downregulated miRNAs in primary and CRC liver metastatic tissues, and CRC cell lines. Observations in CRC cell lines indicated that ectopic expressions of miR-378f, -605 and -1976 suppress CRC cell proliferation, anchorage independent growth, metastatic potential, and enhance apoptosis. Consistently, CRC patients with higher miR-378f and miR-1976 levels exhibited better survival. Together, our data suggests an anti-tumorigenic role of these miRNAs in CRC and warrant future in vivo evaluation of the molecules for developing biomarkers or novel therapeutic strategies.
Highlights
Colorectal cancer (CRC) is the fourth most common malignancy worldwide[1,2]
Based on miRNA-gene target analysis and experimental validation in primary and metastatic CRC patient tumors, and CRC cancer cell lines, we show that restored expression of three miRNAs- miR-378f, miR-605 and miR-1976 reduces cancer cell proliferation, anchorage independent growth, migration, invasion, and induces cellular apoptosis, with profound impact on metastatic cells
To identify the clinically relevant miRNAs that are differentially expressed in CRC tumors, we analyzed publicly available colorectal adenocarcinoma (COAD) sequencing project miRNA expression data from 405 CRC tumors covering 705 human miRNAs
Summary
Colorectal cancer (CRC) is the fourth most common malignancy worldwide[1,2]. Liver metastasis occurs in >60% of CRC patients and is the major cause of their mortality[3,4,5]. Based on miRNA-gene target analysis and experimental validation in primary and metastatic CRC patient tumors, and CRC cancer cell lines, we show that restored expression of three miRNAs- miR-378f, miR-605 and miR-1976 reduces cancer cell proliferation, anchorage independent growth, migration, invasion, and induces cellular apoptosis, with profound impact on metastatic cells. This implicates their potential use as anti-cancer agents to target CRC metastasis. Because the selected miRNAs are associated either with colorectal liver metastasis, or with genomic loci that are commonly deleted in metastatic CRC, these miRNAs might have significant clinical relevance, or may be useful as biomarkers
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