Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), 700 Tiverton Avenue, Los Angeles, CA 90095‑1732, USA.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), 700 Tiverton Avenue, Los Angeles, CA 90095‑1732, USA.
Int J Oncol. 2019 Apr;54(4):1422-1432. doi: 10.3892/ijo.2019.4703. Epub 2019 Jan 30.
Human colorectal cancer is the third most common cancer disease with a 5‑year survival rate of 55% in USA in 2016. The investigation to identify novel biomarker factors with molecular classification may provide notable clinical information to prolong the survival of patients with colorectal cancer. The aryl hydrocarbon receptor (AHR) binds the AHR nuclear translocator in the cytoplasm of various types of cells, including liver cells, and then binds to the xenobiotic responsive element on various genes. AHR was initially discovered via its ligand, the polychlorinated hydrocarbon, 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin (TCDD). The present study was undertaken to determine whether TCDD, an agonist of AHR signaling, impacts the growth of RKO human colorectal cancer cells in vitro. Treatment with TCDD (0.1‑100 nM) revealed suppressive effects on colony formation and proliferation of RKO cells, and stimulated death of these cells with subconfluence. These effects of TCDD were abolished by pretreatment with CH223191, an inhibitor of AHR signaling. Western blot analysis demonstrated that TCDD treatment decreased AHR levels and elevated cytochrome P450 family 1 subfamily A member 1 (CYP1A1) levels, indicating a stimulation of AHR signaling. TCDD treatment caused an increase in nuclear factor‑κB p65 and β‑catenin levels, although it did not have an effect on Ras levels. Notably, TCDD treatment increased the levels of p53, retinoblastoma, p21 and regucalcin, which are depressors of carcinogenesis. Additionally, action of TCDD on cell proliferation and death were not revealed in regucalcin‑overexpressing RKO cells, and regucalcin overexpression depressed AHR signaling associated with CYP1A1 expression. Thus, AHR signaling suppresses the growth of colorectal cancer cells, indicating a role as a significant targeting molecule for colorectal cancer.
人类结直肠癌是 2016 年美国第三大常见癌症，其 5 年生存率为 55%。通过鉴定新型生物标志物和分子分类，可为延长结直肠癌患者的生存提供重要的临床信息。芳香烃受体（AHR）在细胞质中与各种类型的细胞（包括肝细胞）中的 AHR 核转位蛋白结合，然后与各种基因上的外源性反应元件结合。最初，AHR 是通过其配体多氯二苯并对二恶英（TCDD）发现的。本研究旨在确定 TCDD（AHR 信号通路的激动剂）是否会影响体外 RKO 人结直肠癌细胞的生长。用 TCDD（0.1-100 nM）处理可抑制 RKO 细胞集落形成和增殖，并刺激亚汇合细胞死亡。AHR 信号通路抑制剂 CH223191 预处理可消除 TCDD 的这些作用。Western blot 分析表明，TCDD 处理降低了 AHR 水平并升高了细胞色素 P450 家族 1 亚家族 A 成员 1（CYP1A1）水平，表明 AHR 信号通路被激活。TCDD 处理导致核因子-κB p65 和 β-连环蛋白水平增加，尽管它对 Ras 水平没有影响。值得注意的是，TCDD 处理增加了抑癌基因 p53、视网膜母细胞瘤、p21 和 Regucalcin 的水平。此外，Regucalcin 过表达的 RKO 细胞中未显示 TCDD 对细胞增殖和死亡的作用，并且 Regucalcin 过表达抑制了与 CYP1A1 表达相关的 AHR 信号通路。因此，AHR 信号通路抑制结直肠癌细胞的生长，表明其作为结直肠癌的重要靶向分子的作用。
