Overexpression of miR-221 and miR-222 in the cancer stroma is associated with malignant potential in colorectal cancer

The cancer stroma is important in cancer development, however, whether the aberrant expression of microRNAs (miRNAs) in the cancer stroma is associated with cancer progression remains to be fully elucidated. The aim of the present study was to identify the miRNAs associated with liver metastasis in the cancer stroma of human colorectal cancer (CRC). Using laser capture microdissection, cancer stroma was obtained from the primary lesion of six patients with CRC with liver metastasis (CRCwLM) and six patients with CRC without liver metastasis (CRCwoLM), and miRNA microarray analysis was performed. Candidate miRNA expression status in the stroma was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis in 40 CRC cases (wLM, n=20; woLM, n=20), and the association between miRNA expression and clinicopathological factors was assessed in 101 advanced CRC samples. The localization of candidate miRNAs in CRCs was analyzed using in situ hybridization analysis (ISH). The microarray analysis identified six miRNAs with expression differing between the CRCwLM and CRCwoLM cancer stroma. Validation using RT-qPCR analysis of the stroma showed that the expression levels of miR-221 and miR-222 in the cancer stroma were significantly higher in CRCwLM than in CRCwoLM. The RT-qPCR analysis of 101 CRC samples showed that a high expression level of miR-221 or miR-222 in the cancer stroma was associated with liver metastasis, distant metastasis, and shorter overall survival rate of patients with CRC (P<0.05). Increased levels of miR-221 and miR-222 were observed in cancer cells and in fibroblasts in the stromal tissue in the ISH analysis. The results suggested that the overexpression of miR-221 and miR-222 in the cancer stroma is associated with the metastatic activity and malignant potential in patients with CRC.