Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands.
Toxicology. 2014 Jun 5;320:67-73. doi: 10.1016/j.tox.2014.03.002. Epub 2014 Mar 21.
β-Carotene (BC) is omnipresent in our diet, both as natural food component as well as an additive. BC and its metabolites have important biological functions. For this reason, BC is generally considered to be a health promoting compound. Two human trials, however, have described adverse effects in lung tissue, increasing the risk of lung cancer. We previously applied transcriptomic analyses in a unique animal model, beta-carotene 15,15'-monooxygenase 1 knockout (Bcmo1(-/-)) mice that are, like humans, able to accumulate intact BC. In our search to unravel the molecular action of BC in the lung, we previously identified two genes particularly strongly down-regulated by BC in lung tissue of the male Bcmo1(-/-) mice: frizzled homologue 6 (Fzd6) and collagen triple helix repeat containing 1 (Cthrc1). In the present study, our aim was to further elucidate the role of FZD6 in lung epithelial cells and to provide a mechanistic explanation for BC increased lung cancer risk in humans. We performed whole genome microarray analysis on silenced FZD6 in non-tumor human type II bronchial epithelial BEAS-2B cells using RNAi. To directly link FZD6 to BC-effects on the lung, we compared the FZD6-silenced BEAS-2B gene expression profile to the BC-dependent gene expression profile of Bcmo1(-/-) mouse lungs. A number of relevant genes were regulated in the same direction in FZD6(-) BEAS-2B and in BC-exposed lungs of Bcmo1(-/-) mice and revealed enrichment of the Gene Ontology terms "oncogenes", "cell proliferation" and "cell cycle", which suggests a mediating role of FZD6 in BC-induced uncontrolled proliferation of lung cells.
β-胡萝卜素（BC）存在于我们的饮食中，既是天然食物成分，也是添加剂。BC 及其代谢物具有重要的生物学功能。因此，BC 通常被认为是一种促进健康的化合物。然而，两项人类临床试验描述了肺组织中的不良反应，增加了肺癌的风险。我们之前在一个独特的动物模型中转录组分析中应用了β-胡萝卜素 15,15'-单加氧酶 1 敲除（Bcmo1(-/-)）小鼠，这些小鼠像人类一样能够积累完整的 BC。在我们试图揭示 BC 在肺部的分子作用的过程中，我们之前在雄性 Bcmo1(-/-)小鼠的肺部组织中发现了两个特别受 BC 下调的基因：卷曲同源物 6（Fzd6）和三螺旋重复胶原蛋白 1（Cthrc1）。在本研究中，我们的目的是进一步阐明 FZD6 在肺上皮细胞中的作用，并为 BC 增加人类肺癌风险提供机制解释。我们使用 RNAi 在非肿瘤人类 II 型支气管上皮细胞 BEAS-2B 中对沉默的 FZD6 进行全基因组微阵列分析。为了将 FZD6 直接与 BC 对肺部的影响联系起来，我们将沉默 FZD6 的 BEAS-2B 的基因表达谱与 Bcmo1(-/-)小鼠肺部中依赖 BC 的基因表达谱进行了比较。一些相关基因在 FZD6(-)BEAS-2B 和 Bcmo1(-/-)小鼠的 BC 暴露肺中以相同的方向受到调节，并揭示了“癌基因”、“细胞增殖”和“细胞周期”的基因本体术语富集，这表明 FZD6 在 BC 诱导的肺细胞不受控制的增殖中起介导作用。
