United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan ; United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
Transl Oncol. 2013 Aug 1;6(4):482-92. doi: 10.1593/tlo.13280. Print 2013 Aug.
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.
结直肠癌是全球癌症相关死亡的主要原因之一。先前的研究表明，miR-92a 在几种癌症中具有致癌功能，其上调与结直肠癌的恶性临床病理行为相关。也有人提出，患者血浆中的循环 miR-92a 可以作为结直肠癌的潜在生物标志物。然而，细胞内和细胞外 miR-92a 的精确作用尚不清楚。在这项研究中，我们检查了结直肠肿瘤（38 例癌症标本和 56 例腺瘤标本）和配对的相邻非肿瘤组织中的 miR-92a 表达水平。与腺瘤相比，癌症中 miR-92a 的表达水平经常升高，并且与晚期临床分期、肿瘤深度和大小相关。我们还证明了携带结肠癌异种移植的小鼠血浆中微泡（MVs）内 miR-92a 的水平与对照小鼠相比显着升高。细胞内和细胞外 miR-92a 的作用之一是下调假定的肿瘤抑制基因 Dickkopf-3 (Dkk-3)。在结肠癌细胞内，miR-92a 通过 Dkk-3 的抑制促进了细胞增殖。结直肠癌细胞分泌的 MV 内包装的细胞外 miR-92a 通过下调相同的靶基因 Dkk-3 被递送至内皮细胞，并促进这些细胞的增殖和迁移。这些数据表明，细胞内和细胞外 miR-92a 在结直肠癌的肿瘤生长和肿瘤微环境中具有重要作用。
