Role of Intracellular and Extracellular MicroRNA-92a in Colorectal Cancer

Colorectal cancer is one of the leading causes of cancer-related death worldwide. Previous studies have shown that miR-92a has an oncogenic function in several cancers and that its up-regulation is correlated with malignant clinicopathologic behaviors of colorectal cancer. It also has been suggested that circulating miR-92a in patients' plasma can be a potential biomarker for colorectal cancer. However, the precise roles of intracellular and extracellular miR-92a are not yet understood. In this study, we examined the expression levels of miR-92a in colorectal tumors (38 cancer specimens and 56 adenoma specimens) and paired adjacent nontumorous tissues. Increased expression of miR-92a was frequently observed in the cancers compared with that in the adenomas and was correlated with advanced clinical stages, tumor depth, and size. We also demonstrated that the levels of miR-92a within microvesicles (MVs) in the plasma of mice bearing colon cancer xenografts were significantly increased compared with those in control mice. One of the roles of intracellular and extracellular miR-92a was shown to be down-regulation of Dickkopf-3 (Dkk-3), a presumed tumor suppressor gene. Within the colon cancer cells, suppression of Dkk-3 by miR-92a contributed to the cell proliferation. Extracellular miR-92a packed within MVs secreted by colon cancer cells was delivered into endothelial cells and contributed to the proliferation and motility of these cells through down-regulation of the same target gene, Dkk-3. These data suggest that intracellular and extracellular miR-92a had important roles in tumor growth and the tumor microenvironment in colorectal cancer.