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首页> 外文期刊>American Journal of Physiology >Carcinogens induce loss of the primary cilium in human renal proximal tubular epithelial cells independently of effects on the cell cycle
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Carcinogens induce loss of the primary cilium in human renal proximal tubular epithelial cells independently of effects on the cell cycle

机译：致癌物诱导人肾近端肾小管上皮细胞中初级纤毛的丢失，而与细胞周期的影响无关

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The primary cilium is an immotile sensory and signaling organelle found on the majority of mammalian cell types. Of the multitude of roles that the primary cilium performs, perhaps some of the most important include maintenance of differentiation, quiescence, and cellular polarity. Given that the progression of cancer requires disruption of all of these processes, we have investigated the effects of several carcinogens on the primary cilium of the RPTEC/TERT1 human proximal tubular epithelial cell line. Using both scanning electron microscopy and immunofluorescent labeling of the ciliary markers acetylated tubulin and Arl13b, we confirmed that RPTEC/TERT1 cells express primary cilium upon reaching confluence. Treatment with the carcinogens ochratoxin A (OTA) and potassium bromate (KBrO 3) caused a significant reduction in the number of ciliated cells, while exposure to nifedipine, a noncarcinogenic renal toxin, had no effect on primary cilium expression. Flow cytometric analysis of the effects of all three compounds on the cell cycle revealed that only KBrO 3 resulted in an increase in the proportion of cells entering the cell cycle. Microarray analysis revealed dysregulation of multiple pathways affecting ciliogenesis and ciliary maintenance following OTA and KBrO 3 exposure, which were unaffected by nifedipine exposure. The primary cilium represents a unique physical checkpoint with relevance to carcinogenesis. We have shown that the renal carcinogens OTA and KBrO 3 cause significant deciliation in a model of the proximal tubule. With KBrO 3, this was followed by reentry into the cell cycle; however, deciliation was not found to be associated with reentry into the cell cycle following OTA exposure. Transcriptomic analysis identified dysregulation of Wnt signaling and ciliary trafficking in response to OTA and KBrO 3 exposure. ? 2012 the American Physiological Society.
机译：初级纤毛是在大多数哺乳动物细胞类型中发现的一种运动的感觉和信号细胞器。在初级纤毛发挥的众多作用中，也许最重要的一些作用包括维持分化，静止和细胞极性。鉴于癌症的进展需要破坏所有这些过程，因此我们研究了几种致癌物对RPTEC / TERT1人近端肾小管上皮细胞系初级纤毛的作用。使用扫描电子显微镜和纤毛标记乙酰化微管蛋白和Arl13b的免疫荧光标记，我们证实RPTEC / TERT1细胞达到汇合时表达初级纤毛。用致癌物曲霉毒素A（OTA）和溴酸钾（KBrO 3）处理可显着减少纤毛细胞的数量，而暴露于非致癌性肾脏毒素硝苯地平对初级纤毛的表达无影响。所有三种化合物对细胞周期的影响的流式细胞术分析表明，只有KBrO 3导致进入细胞周期的细胞比例增加。芯片分析显示，OTA和KBrO 3暴露后，影响纤毛发生和纤毛维持的多种途径失调，而不受硝苯地平暴露的影响。初级纤毛代表与致癌相关的独特物理检查点。我们已经表明，肾致癌物OTA和KBrO 3在近端肾小管模型中引起显着偏斜。用KBrO 3，然后再进入细胞周期。然而，未发现极化与OTA暴露后重新进入细胞周期有关。转录组学分析确定了响应OTA和KBrO 3暴露而引起的Wnt信号传导异常和纤毛运输。 ？ 2012年美国生理学会。

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