Centro de Investigación y Estudios de Posgrado, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Mexico.
Toxicol Appl Pharmacol. 2012 Jan 1;258(1):10-8. doi: 10.1016/j.taap.2011.10.002. Epub 2011 Oct 10.
The association between chronic human exposure to arsenicals and bladder cancer development is well recognized; however, the underlying molecular mechanisms have not been fully determined. We propose that inflammatory responses can play a pathogenic role in arsenic-related bladder carcinogenesis. In previous studies, it was demonstrated that chronic exposure to 50 nM monomethylarsenous acid [MMA(III)] leads to malignant transformation of an immortalized model of urothelial cells (UROtsa), with only 3 mo of exposure necessary to trigger the transformation-related changes. In the three-month window of exposure, the cells over-expressed pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), consistent with the sustained activation of NFKβ and AP1/c-jun, ERK2, and STAT3. IL-8 was over-expressed within hours after exposure to MMA(III), and sustained over-expression was observed during chronic exposure. In this study, we profiled IL-8 expression in UROtsa cells exposed to 50 nM MMA(III) for 1 to 5 mo. IL-8 expression was increased mainly in cells after 3 mo MMA(III) exposure, and its production was also found increased in tumors derived from these cells after heterotransplantation in SCID mice. UROtsa cells do express both receptors, CXCR1 and CXCR2, suggesting that autocrine cell activation could be important in cell transformation. Supporting this observation and consistent with IL-8 over-expression, CXCR1 internalization was significantly increased after three months of exposure to MMA(III). The expression of MMP-9, cyclin D1, bcl-2, and VGEF was significantly increased in cells exposed to MMA(III) for 3 mo, but these mitogen-activated kinases were significantly decreased after IL-8 gene silencing, together with a decrease in cell proliferation rate and in anchorage-independent colony formation. These results suggest a relevant role of IL-8 in MMA(III)-induced UROtsa cell transformation.
慢性人类暴露于砷剂与膀胱癌发展之间的关联已得到充分认识；然而，其潜在的分子机制尚未完全确定。我们提出炎症反应可能在砷相关膀胱癌发生中起致病作用。在以前的研究中，已经证明慢性暴露于 50 nM 一甲基砷酸[MMA（III）]可导致尿路上皮细胞（UROtsa）永生化模型发生恶性转化，仅需 3 个月的暴露即可引发转化相关变化。在暴露的三个月窗口期内，细胞过度表达促炎细胞因子（IL-1β、IL-6 和 IL-8），这与 NFKβ 和 AP1/c-jun、ERK2 和 STAT3 的持续激活一致。暴露于 MMA（III）后数小时内过表达 IL-8，并在慢性暴露期间持续过表达。在这项研究中，我们对暴露于 50 nM MMA（III）1 至 5 个月的 UROtsa 细胞中的 IL-8 表达进行了分析。IL-8 的表达在暴露于 MMA（III）3 个月后主要在细胞中增加，并且在将这些细胞异种移植到 SCID 小鼠中产生的肿瘤中也发现其产量增加。UROtsa 细胞确实表达两种受体 CXCR1 和 CXCR2，表明自分泌细胞激活可能在细胞转化中很重要。支持这一观察结果，并且与 IL-8 过表达一致，暴露于 MMA（III）三个月后 CXCR1 内化显著增加。暴露于 MMA（III）3 个月后，MMP-9、细胞周期蛋白 D1、bcl-2 和 VGEF 的表达显著增加，但这些丝裂原激活的激酶在 IL-8 基因沉默后显著减少，同时细胞增殖率和锚定非依赖性集落形成减少。这些结果表明 IL-8 在 MMA（III）诱导的 UROtsa 细胞转化中起相关作用。
