鉛離子誘發發炎基因之分子機制

The molecular mechanism of Pb2+-induced inflammatory genes

蔡耀庭(Yao-Ting Tsai)

指導教授 ： 張偉嶠

高雄醫學大學/醫學院/醫學遺傳學研究所/碩士(2012年)

摘要

金屬鉛是一種廣泛出現於我們日常生活中的重金屬，像清潔劑、化妝品、餐具、玩具等..皆含有鉛的成分。而鉛離子會對人類或其他動物造成許多的發炎性的疾病。本研究主要利用細胞模型來探討當鉛離子進入人體後，所造成的反應之分子機制。首先，我們用人類子宮頸上皮癌細胞(A431)作為細胞模型，探討鉛離子活化COX-2的信號分子傳遞路徑以及表基因體學的影響。在實驗中，發現鉛離子誘發COX-2是經由表皮生長因子受體/NFκB信號傳遞路徑。此外，鉛離子也會經由Rb/E2F1路徑使DNMA3a的表現量下降，進而調控COX-2的基因活化。然而，在鉛中毒的病患中，常常會有為胃部不適以及胃炎的發生。因此，利用胃部腺癌細胞(AGS)做為細胞模型，探討鉛離子是否會影響胃泌素(Gastrin)的表現以及相關的分子機轉。結果發現，鉛離子會經由EGFR和ERK1/2活化AP1，進而使胃泌素的表現上升。在本研究發現鉛離子主要會經由EGFR調控下游的發炎相關基因，這代表EGFR為調控鉛離子毒性的一個重要角色。因此，為了探討EGFR上的單核甘酸多型性(SNP)在鉛中毒的病患中是否是一個重要的調控角色。然而，在本研究的結果中， 發現EGFR SNP與鉛中毒病患並無相關性。

關鍵字

鉛 ； 表皮生長因子受體 ； 環氧化酶-2 ； 去氧核醣核酸甲基轉移酵素 ； 胃泌素

並列摘要

In our life, the metal lead is widely used in many things, such as detergents, cosmetics, tableware, toys. Divalent lead cations may contribute to inflammatory diseases in people and animals. To further clarify the mechanism by which Pb2+ induces such mediators of inflammation, we tested human epidermoid carcinoma cell line A431. We found Pb2+ ions incite inflammation by inducing COX-2 gene expression via the EGFR/ NF-κB signal transduction pathway. Furthermore, Pb2+ ions induce COX-2 expression indirectly by reducing DNMT3a methylation of the COX-2 promoter via EGFR and transcription factors Rb and E2F1. In lead poisoning patients, gastralgia or gastritis made them uncomfortable. To further clarify the molecular mechanism by which Pb2+ induces gastrin gene expression, we tested human Stomach Adenocarcinoma cell line AGS. Our finding highlights the ERK1/2 and AP1 pathways, and its potential role in Pb2+-induced gastrin gene expression. According to our results, the EGFR played an important role in Pb2+-induced inflammatory genes expression. The association between EGFR SNPs and lead poisoning patients is unclear. Our results indicated that EGFR genetic polymorphism had no association with the lead poisoning patients.

並列關鍵字

Lead ； Epidermal growth factor receptor ； Cyclooxygenase-2 ； DNA methyltransferase ； Gastrin

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