Kuntz Emmanuelle, Hoeller Ulrich, Greatrix Brad, Lankin Christopher, Seifert Nicole, Acharya Samir, Riss Georges, Buchwald-Hunziker Petra, Hunziker Willi, Goralczyk Regina, Wertz Karin
DSM Nutritional Products, R&D, Human Nutrition and Health, P. O. Box 3255, CH-4002 Basel, Switzerland.
Arch Biochem Biophys. 2006 Nov 1;455(1):48-60. doi: 10.1016/j.abb.2006.08.023. Epub 2006 Sep 20.
High dose beta-carotene supplementation of smokers was associated with increased lung cancer risk in two intervention trials. It was proposed that generation of apocarotenals in smoke-exposed lungs impaired retinoic acid (RA) signaling, leading to squamous metaplasia and cell proliferation. To test this, we compared RA target gene regulation by retinoids, apocarotenals or beta-carotene by transcriptomics in BEAS-2B cells cultured to promote squamous differentiation. Retinoids, beta-carotene as well as apocarotenals induced known RA target genes. Retinoids upregulated involucrin, indicating that retinoids did not rescue BEAS-2B cells from squamous differentiation. Muc5AC, a marker for mucous differentiation, was transiently induced. beta-Carotene and apocarotenals less strongly induced involucrin and did not induce muc5AC. In summary, apocarotenals or beta-carotene upregulated RA target genes suggesting promotion, not inhibition, of RA signaling in BEAS-2B cells. Furthermore, apocarotenals and beta-carotene regulated gene expression independently of RA signaling. Squamous differentiation is not unequivocally linked to RA deficiency in BEAS-2B cells.
在两项干预试验中，吸烟者补充高剂量β-胡萝卜素与肺癌风险增加有关。有人提出，暴露于烟雾中的肺部产生的视黄醛会损害视黄酸（RA）信号传导，导致鳞状化生和细胞增殖。为了验证这一点，我们通过转录组学比较了在培养以促进鳞状分化的BEAS-2B细胞中，类视黄醇、视黄醛或β-胡萝卜素对RA靶基因的调控。类视黄醇、β-胡萝卜素以及视黄醛均可诱导已知的RA靶基因。类视黄醇上调了兜甲蛋白，这表明类视黄醇无法使BEAS-2B细胞免于鳞状分化。黏蛋白5AC是黏液分化的标志物，它受到短暂诱导。β-胡萝卜素和视黄醛对兜甲蛋白的诱导作用较弱，且不会诱导黏蛋白5AC。总之，视黄醛或β-胡萝卜素上调了RA靶基因，这表明在BEAS-2B细胞中RA信号传导是被促进而非抑制。此外，视黄醛和β-胡萝卜素独立于RA信号传导来调节基因表达。鳞状分化与BEAS-2B细胞中的RA缺乏并无明确关联。
