Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer
Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer
复制标题
DOI：
10.1093/carcin/bgp222
复制
发表时间：
2010-02-01
期刊：
影响因子：
4.7
通讯作者：
Oya, Mototsugu
中科院分区：
文献类型：
--
作者：
Ishida, Masaru;Mikami, Shuji;Oya, Mototsugu
芳烃受体（Aryl hydrocarbon receptor, AhR）及其通路的激活参与了外生物诱导的毒性和致癌性。尽管诸如香烟烟雾等外源性药物可导致尿路上皮癌（UC）的发生，但AhR与UC之间的关系尚不清楚。在本研究中，我们研究了209例上尿路UC患者AhR的表达。AhR的核表达与组织学分级、病理T分期、淋巴血管浸润及淋巴结受累有显著相关性。多因素Cox分析显示，核AhR表达是疾病特异性生存的重要独立预测因子（风险比= 2.469,P = 0.013）。为了确定AhR通路是否可以在T24 UC细胞系中被激活，我们检测了暴露于AhR的配体2,3,7,8-四氯二苯并-对苯二英（TCDD）后AhR通路靶基因细胞色素P450 (CYP) 1A1和CYP1B1的表达。TCDD治疗上调AhR、CYP1A1和CYP1B1的表达水平。TCDD增强T24细胞侵袭与基质金属蛋白酶(MMP)-1和MMP-9的上调有关。此外，用小干扰RNA （siRNA）靶向T24细胞中AhR信使RNA （mRNA）的表达，下调AhR、CYP1A1、CYP1B1、MMP-1、MMP-2和MMP-9 mRNA的表达；此外，与转染非靶向siRNA的细胞相比，转染siRNA进行AhR的细胞显示出较低的侵袭活性。因此，我们的研究结果表明，AhR在UC细胞的侵袭性中起作用，可以作为上尿路UC预后的标志。
Aryl hydrocarbon receptor (AhR) and the activation of the AhR pathway are involved in xenobiotic-induced toxicity and carcinogenesis. Although xenobiotics, such as cigarette smoke, contribute to the development of urothelial carcinoma (UC), the relationship between AhR and UC is unclear. In the present study, we investigated AhR expression in 209 patients with upper urinary tract UC. The nuclear expression of AhR was significantly associated with histological grade, pathological T stage, lymphovascular invasion and lymph node involvement. A multivariate Cox analysis revealed that nuclear AhR expression was a significant and independent predictor for disease-specific survival (hazard ratio = 2.469, P = 0.013). To determine whether the AhR pathway can be activated in the T24 UC cell line, we examined the expression of cytochrome P450 (CYP) 1A1 and CYP1B1, which are target genes of the AhR pathway, following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR. TCDD treatment upregulated the expression levels of AhR, CYP1A1 and CYP1B1. TCDD enhanced T24 cell invasion associated with the upregulation of matrix metalloproteinase (MMP)-1 and MMP-9. Furthermore, targeting AhR messenger RNA (mRNA) expression in T24 cells with small interfering RNA (siRNA) downregulated the mRNA expression of AhR, CYP1A1, CYP1B1, MMP-1, MMP-2 and MMP-9; furthermore, the cells transfected with siRNA for AhR showed decreased invasion activity in comparison with the cells transfected with a non-targeting siRNA. Our results therefore suggest that AhR plays a role in the invasiveness of UC cells and can serve as a marker for the prognosis of upper urinary tract UC.