Kuznetsov Nikolai V, Andersson Patrik, Gradin Katarina, Stein Petra von, Dieckmann Andreas, Pettersson Sven, Hanberg Annika, Poellinger Lorenz
InDex Pharmaceuticals AB, Scheeles väg 1, S-171 77 Stockholm, Sweden.
Oncogene. 2005 Apr 28;24(19):3216-22. doi: 10.1038/sj.onc.1208529.
The dioxin/aryl hydrocarbon receptor functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding primarily drug-metabolizing enzymes. Expression of a constitutively active mutant of the aryl hydrocarbon receptor (CA-AhR) in transgenic mice results in development of stomach tumours, correlating with increased mortality. We have used suppression subtractive hybridization techniques followed by macroarray analysis to elucidate which genes are differentially expressed during this process. In the glandular stomach of CA-AhR mice, we observed decreased mRNA expression of osteopontin (OPN), a noncollagenous protein of bone matrix that is also involved in several important functions including regulation of cytokine production, macrophage accumulation, cell motility and adhesion. Downregulated expression of OPN during tumour development was confirmed by RT-PCR and RNA blot analysis. Immunohistochemical analysis showed that this decrease was confined to the corpus region, correlating with the restricted localization of the tumours. Decreased OPN mRNA expression was also observed in other organs of CA-AhR mice. Taken together, these results show that OPN is negatively regulated by the dioxin receptor, and that downregulation of its expression correlates with development of stomach tumours in mice expressing a constitutively active mutant of dioxin receptor.
二噁英/芳烃受体作为一种配体激活的转录因子，调控一系列主要编码药物代谢酶的基因的转录。在转基因小鼠中表达芳烃受体的组成型活性突变体（CA-AhR）会导致胃肿瘤的发生，并与死亡率增加相关。我们采用抑制性消减杂交技术，随后进行宏阵列分析，以阐明在此过程中哪些基因存在差异表达。在CA-AhR小鼠的腺胃中，我们观察到骨桥蛋白（OPN）的mRNA表达降低，骨桥蛋白是骨基质的一种非胶原蛋白，也参与多种重要功能，包括细胞因子产生的调节、巨噬细胞聚集、细胞运动和黏附。通过逆转录-聚合酶链反应（RT-PCR）和RNA印迹分析证实了肿瘤发生过程中OPN表达的下调。免疫组织化学分析表明，这种降低仅限于胃体区域，与肿瘤的局限定位相关。在CA-AhR小鼠的其他器官中也观察到OPN mRNA表达降低。综上所述，这些结果表明OPN受二噁英受体负调控，其表达下调与表达二噁英受体组成型活性突变体的小鼠胃肿瘤发生相关。
