Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Oncogene. 2013 May 16;32(20):2576-85. doi: 10.1038/onc.2012.266. Epub 2012 Jul 2.
A lack of expression of miR-143 and miR-145 has been demonstrated to be a frequent feature of colorectal tumors. Activating KRAS mutations have been reported in 30-60% of colorectal cancers and an inverse correlation between Kras and miR-143/145 expression has been observed. Previously, we have demonstrated that oncogenic Kras leads to repression of the miR-143/145 cluster in pancreatic cancer and is dependent on the Ras responsive element (RRE) binding protein (RREB1), which negatively regulates miR-143/145 expression. In the present study, we have found that RREB1 is overexpressed in colorectal adenocarcinoma tumors and cell lines, and the expression of the miR-143/145 primary transcript is inversely related to RREB1 expression. In colorectal cancer cell lines, the miR-143/145 cluster is repressed by RREB1 downstream of constitutively active KRAS. RREB1 is activated by the MAPK pathway and negatively represses the miR-143/145 promoter through interaction with two RREs. In addition, overexpression of miR-143 or miR-145 in HCT116 cells abrogates signaling through the MAPK, PI3K and JNK pathways by downregulation of both KRAS and RREB1 in addition to downregulation of a cohort of genes in the MAPK signaling cascade. These results establish a complex network of regulation through which the miR-143/145 cluster is able to modulate KRAS signaling in colorectal cancer.
miR-143 和 miR-145 的表达缺失已被证实是结直肠肿瘤的一个常见特征。据报道，在 30%-60%的结直肠癌中存在 KRAS 激活突变，并且已经观察到 Kras 与 miR-143/145 表达之间存在反相关。先前，我们已经证明致癌性 Kras 导致胰腺癌中 miR-143/145 簇的抑制，并且依赖于 Ras 反应元件 (RRE) 结合蛋白 (RREB1)，其负调节 miR-143/145 的表达。在本研究中，我们发现 RREB1 在结直肠腺癌肿瘤和细胞系中过表达，并且 miR-143/145 初级转录物的表达与 RREB1 表达呈负相关。在结直肠癌细胞系中，RREB1 通过组成性激活的 KRAS 下游抑制 miR-143/145 簇的表达。RREB1 被 MAPK 途径激活，并通过与两个 RRE 相互作用负向抑制 miR-143/145 启动子。此外，在 HCT116 细胞中过表达 miR-143 或 miR-145 通过下调 KRAS 和 RREB1 以及下调 MAPK 信号级联中的一组基因，阻断 MAPK、PI3K 和 JNK 途径的信号传导。这些结果建立了一个复杂的调控网络，通过该网络，miR-143/145 簇能够调节结直肠癌中的 KRAS 信号。
