MicroRNA expression profiling in colorectal cancer : a focus on miR-133a, miR-139-3p and miR-187

Abstract

MicroRNAs (miRNAs) are vital small non-coding RNAs that play key roles in many crucial biological processes. In recent decades, more evidence has emerged showing that miRNAs are also involved in cancer development, and aberrant expression of miRNAs is detected in various types of cancer including colorectal cancer (CRC), through regulating expression of many known oncogenes and tumor suppressor genes. Studying the specific function of miRNAs in CRC will help to identify new targets for cancer research, diagnosis and treatment.

In this study, miRNA profiling was performed in 8 sets of normal mucosa, adenoma and adenocarcinoma specimens. Thirty-nine miRNAs were found to be aberrantly expressed with 30 up-regulated and 9 down-regulated. Among these dysregulated miRNAs, miR-139-3p which showed the strongest down-regulation in CRC, miR-139-3p and miR-187 which were frequently unexpressed in CRC, and miR-622 which was significantly up-regulated along the normal mucosa to adenoma to adenoma transformation process, were chosen for further study due to their novelty in CRC.

Further evaluation of miR-133a expression in a large cohort of CRC patients demonstrated that this miRNA was significantly down-regulated in CRC when compared to the normal mucosa, but its high expression in tumor tissues was correlated with poor prognosis, advanced stage and distant metastasis, indicating that the tumor suppressive role of miR-133a is much more sophisticated than initially reported. In addition, the association of miR-133a expression with its target genes reported in other cancers including LIM and SH3 protein 1 (LASP1), caveolin 1 (CAV1) and fascin actin-bundling protein 1 (FSCN1) varied in CRC with and without distant metastasis, suggesting that further investigation is required to fully elucidate the role of miR-133a in CRC.

The expression of miR-139-3p and miR-622 in a large cohort of CRC samples confirmed that miR-139-3p and miR-622 were consistently unexpressed and upregulated in CRC tissue, respectively. Their levels in serum samples between normal donor and CRC patients were further compared to evaluate their roles as diagnostic biomarkers for CRC. Serum miR-139-3p level in CRC patients was significantly lower than that in control subjects. Receiver operating characteristic (ROC) analysis demonstrated that serum miR-139-3p showed high area under the curve (AUC) value, sensitivity and specificity in CRC diagnosis, indicating its promising diagnostic ability in CRC screening. In addition, serum miR-139-3p was apparently appropriate for all kinds of CRC patients, which was able to overcome the limitations of some current screening methods and potential biomarkers suggested for CRC diagnosis.

The last part of this study determined the expression of miR-187 in a large cohort of CRC samples, and investigated its functional roles and the underlying mechanisms in CRC cells. MiR-187 was expressed in 41 out of 55 normal mucosa samples but in only 8 out of 55 CRCs, confirming this miRNA was frequently unexpressed in CRC. Overexpression of miR-187 impaired cell migration, colony formation and induced chemosensitivity, and its expression was associated with Mothers against decapentaplegic homolog 1 (SMAD1) expression, suggesting its regulatory effect on transforming growth factor beta (TGFβ)/SMAD pathway.