GW2974对实验性口腔癌中EGFR及p-EGFR表达的抑制作用研究

Inhibitng effects of GW2974 on EGFR and p-EGFR in DMBA-induced hamster buccal pouch carcinogenesis model.

目的:观察小分子酪氨酸激酶抑制剂GW2974对实验性口腔癌中EGFR及p-EGFR表达的抑制作用。方法:选取100只金黄地鼠,其中10只为阴性对照,其余90只于左侧颊囊涂0.5%DMBA,每周3次。6周后实验组随机分为阳性对照组、GW2974低浓度组、GW2974高浓度组。阳性对照组不做处理,其余两组于左侧颊囊涂抹不同浓度的GW2974(4mM/L,mM/L)。24周末处死所有动物,取左侧颊囊黏膜,用免疫组化方法检测各组癌灶中EGFR及p-8EGFR表达情况。结果:通过局部应用4mM/L和8mM/L的GW2974,用药后p-EGFR表达水平均降低,呈现一定的剂量-效应关系;而EGFR的表达未见明显变化。结论:GW2974可以明显抑制实验性口腔癌中p-EGFR的表达,即抑制EGFR的活化,但对EGFR的表达影响不大。GW2974可能通过抑制EGFR胞内区酪氨酸激酶的活化,进而抑制癌细胞EGFR/ErbB2的磷酸化作用,从而达到抑制口腔癌发生的目的。

Objective：To study the inhibiting effects of GW2974,a tyrosine kinase inhibitors （TKIs）,on EGFR and p-EGFR in DMBA-induced hamster buccal pouch carcinogenesis model. Method：10 male Syrian golden hamsters served as negative control. The left buccal pouches of 90 hamsters were painted with 0.5% DMBA three times a week for 6 weeks. Afterwards, they were divided into 3 groups according to mean body weight,including positive control and two differently treated groups. Positive control received no further treatment. The two differently treated groups were continuously topically painted with 4mM/L GW2974 and 8mM/L GW2974 three times a week,respectively. Tissue samples of the left cheek pouch were obtained at the 24 th week. The various expression of EGFR,p-EGFR in specimens of each group were detected by immunohistochemical staining. Result：After GW2974（4 mM/L and 8 mM/L） applied topically,the expression of p-EGFR declined significantly （P〈0.05） in a dose-dependent manner, but there was no significant difference on the expression of EGFR. Conclusion：GW2974 applied topically can inhibit the expression of p-EGFR in an oral cancer model, but not the expression of EGFR. These findings suggested that GW2974 may interfere in the downstream signaling pathway of EGFR via c-Fos and c-Jun,which results in inhibiting tumor cell proliferation and oral cancinogenesis. The results indicated that GW2974 applied topically can inhibit activation but not the expression of EGFR. It indicated that GW2974 may prevent phosphorylation EGFR/ErbB2,which resulted in inhibiting tumor cell proliferation and oral cancinogenesis.