Mol Cancer Res. 2011 Jul;9(7):960-75. doi: 10.1158/1541-7786.MCR-10-0531. Epub 2011 Jun 8.
Epidermal growth factor receptors (EGFR) contribute to colonic tumorigenesis in experimental models of colon cancer. We previously showed that EGFR was also required for colonic tumor promotion by Western diet. The goal of this study was to identify EGFR-regulated microRNAs that contribute to diet-promoted colonic tumorigenesis. Murine colonic tumors from Egfr(wt) and hypomorphic Egfr(wa2) mice were screened using micro RNA (miRNA) arrays and miR-143 and miR-145 changes confirmed by Northern, real-time PCR, and in situ analysis. Rodent and human sporadic and ulcerative colitis (UC)-associated colon cancers were examined for miR-143 and miR-145. Effects of EGFR on miR-143 and miR-145 expression were assessed in murine and human colonic cells and their putative targets examined in vitro and in vivo. miR-143 and miR-145 were readily detected in normal colonocytes and comparable in Egfr(wt) and Egfr(wa2) mice. These miRNAs were downregulated in azoxymethane and inflammation-associated colonic tumors from Egfr(wt) mice but upregulated in Egfr(wa2) tumors. They were also reduced in human sporadic and UC colon cancers. EGFR signals suppressed miR-143 and miR-145 in human and murine colonic cells. Transfected miR-143 and miR-145 inhibited HCT116 cell growth in vitro and in vivo and downregulated G(1) regulators, K-Ras, MYC, CCND2, cdk6, and E2F3, putative or established targets of these miRNAs. miRNA targets Ras and MYC were increased in colonic tumors from Egfr(wt) but not Egfr(wa2) mice fed a Western diet. EGFR suppresses miR-143 and miR-145 in murine models of colon cancer. Furthermore, Western diet unmasks the tumor suppressor roles of these EGFR-regulated miRNAs.
表皮生长因子受体 (EGFR) 在结肠癌的实验模型中促进结肠肿瘤的发生。我们之前表明，EGFR 对于西方饮食促进结肠肿瘤促进也很重要。本研究的目的是确定 EGFR 调节的 microRNAs，这些 microRNAs有助于饮食促进结肠肿瘤的发生。使用 microRNA (miRNA) 阵列筛选来自 Egfr(wt) 和低功能 Egfr(wa2) 小鼠的鼠结肠肿瘤，并通过 Northern、实时 PCR 和原位分析确认 miR-143 和 miR-145 的变化。检查了啮齿动物和人类散发性和溃疡性结肠炎 (UC) 相关的结肠癌中的 miR-143 和 miR-145。评估了 EGFR 对鼠和人结肠细胞中 miR-143 和 miR-145 表达的影响，并在体外和体内检查了它们的潜在靶标。miR-143 和 miR-145 在正常结肠细胞中很容易检测到，在 Egfr(wt) 和 Egfr(wa2) 小鼠中相当。这些 miRNA 在 Egfr(wt) 小鼠的氧化偶氮甲烷和炎症相关结肠肿瘤中下调，但在 Egfr(wa2) 肿瘤中上调。它们在人类散发性和 UC 结肠癌中也减少了。EGFR 信号在人源和鼠源结肠细胞中抑制 miR-143 和 miR-145。转染的 miR-143 和 miR-145 抑制 HCT116 细胞在体外和体内的生长，并下调 G(1) 调节剂 K-Ras、MYC、CCND2、cdk6 和 E2F3，这些 miRNA 的推定或已建立的靶标。miRNA 靶标 Ras 和 MYC 在喂食西方饮食的 Egfr(wt) 但不是 Egfr(wa2) 小鼠的结肠肿瘤中增加。EGFR 在鼠结肠癌模型中抑制 miR-143 和 miR-145。此外，西方饮食揭示了这些 EGFR 调节的 miRNA 的肿瘤抑制作用。
