Identification of microRNA 885-5p as a novel regulator of tumor metastasis in colorectal cancer

Abstract

MicroRNAs (miRNAs) are a small non-coding RNAs that play a crucial role in cellular proliferation, differentiation and apoptosis by regulating gene expression via post-translation repression or degradation. They are involved in the regulation of various human diseases including colorectal cancer (CRC). CRC is the third most common cancer in the world and second leading cause of cancer death in Hong Kong and United States. Distant metastasis is the main cause of high mortality rate. In most CRC patients, liver is the most common site of distant metastasis, which is often associated with treatment failure and poor prognosis. While some patients with liver metastasis may still be amenable to surgical resection, most patients can only be treated with chemotherapy, which has limited in controlling the tumor progression. The pathological mechanism of metastasis in CRC is poorly understood. Cell motility is important for tumor invasion and metastasis, which require the interaction between tumor cells and their extracellular matrix. This interaction is regulated by the focal adhesion molecules. Recent evidence suggested that miRNAs affect the cell motility and invasiveness of various cancers, and regulate key steps in metastatic cascade. Investigation of the role of miRNAs in tumor development and metastasis can provide potential novel targets for treatment of colorectal liver metastasis or even other advanced cancers. In this study, expression of miR-885-5p was examined in CRC surgical specimens. Overexpression of miR-885-5p was observed in liver metastasis when compared with primary tumor and adjacent non-tumorous colon. The high expression level of miR-885-5p in primary colorectal tumors was positively associated with late TNM stage and development of metastasis, suggesting that its expression level can act a predictive marker for liver metastasis. Functional studies demonstrated that overexpression of miR-885-5p could significantly enhance the invasive phenotypes and metastatic properties of colorectal cancer cells through a series of in vitro and in vivo assays. Overexpression of miR-885-5p was correlated with increased expression of mesenchymal markers such as N-cadherin, vimentin and Snail, and decreased expression of epithelial marker such as E-cadherin. Moreover, overexpression of miR-885-5p enhanced the expression of Rho GTPases, which is a regulator of polarity, protrusion and adhesion. These results suggested that miR-885-5p overexpression might be a key step in tumor progression and metastasis via regulation of EMT pathway and Rho GTPases family. Knockdown of miR-885-5p enhanced chemosensitivity of CRC cells through induction of apoptosis. On the other hand, overexpression of miR-885-5p increased tumor proliferation through upregulation of the expression level of cyclin D1.