TCDD會對多種囓齒類動物具有毒性並且可能會對人類造成不良的健康影響。流行病學上證據顯示TCDD的暴露會增加肺癌的風險，但是只有少數研究探討TCDD對肺的影響。因此，本研究主要目的為探討TCDD在肺腫瘤生成過程中是否具有促進的功能。在長期動物實驗方面，分別以NNK當作腫瘤起始劑，在施打TCDD，並於24週後犧牲。實驗結果發現，在NNK誘發肺腫瘤模式中，合併TCDD處理的組別相對於NNK組別，肺線瘤有明顯的增加。此結果證實TCDD在肺腫瘤生成過程中可能具有促進的功能。由於抑制細胞凋亡是促癌作用的重要機轉之一，我們利用正常人類肺部支氣管表皮細胞(Beas-2B cells)驗證TCDD是否具有抑制staurosporine所誘發細胞凋亡的可能性。結果顯示，TCDD能抑制由staurosporine所誘發早期細胞凋亡之指標Annexin V，且發現前處理TCDD可以增加bcl-2，bcl-xl，和減少bad、caspase-3、9及PARP的表現量，而其機轉是藉由增加AKT或ERK路徑的磷酸化，進一步利用AKT的抑制劑(Ly294002)及ERK的抑制劑(U0126)並發現可以減少TCDD所抑制的Annexin V的量。這結果顯示TCDD所誘發肺部腫瘤促進的功能可能是藉由活化AKT及ERK路徑造成抑制細胞凋亡而來。

TCDD is highly toxic to several rodent species and may have adverse health effects in exposed human populations. Epidemiologic studies indicated that increased risk of lung cancer could be found in populations of TCDD exposure. However, only few experimental studies have been attempted to characterize pulmonary effects of TCDD exposure. The present study was conducted to determine the tumor promoting capability of TCDD in lung tumorigenesis. In in vivo study, following tumor initiation with NNK, A/J mouse were given repeated injections of TCDD and sacrificed at 24 weeks. The result indicated that treatment of TCDD in NNK-initiated animals for 24 weeks led to increase incidence of lung adenoma, which demonstrated the potent tumor promoting capability of TCDD in mouse lung. Inhibition of apoptosis is one of the important mechanisms of tumor promotion. In in vitro study, we applied cell culture model with Beas-2B cells to determine if TCDD may inhibit apoptosis induced by staurosporine. We found that TCDD can attenuate staurosporine-induced early apoptosis determined by Annexin V. These results were corroborated by the increased protein expression of bcl-2, bcl-xl and decreased bad, caspase-3, 9, PARP pretreated with TCDD. Furthermore,TCDD can increase AKT and ERK phosphorylation, and the up-stream signaling. The inhibitors of AKT (Ly294002) and ERK (U0126) can reduce the anti-apoptosis effect of TCDD determined by Annexin V. Take together, the results suggest that one possible mechanism of lung tumor promotion of TCDD could be inhibition of apoptosis through activation of the AKT and ERK signaling pathway.

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