转化生长因子β1及其受体基因过量表达与进展期胃癌分化及临床预后的关系

Relations of transforming growth factor-β1 expression to differentiation and prognosis of advanced gastric cancer

目的明确转化生长因子β1(TGF-β1)及其受体基因和下游Smad基因家族成员在肠型胃癌中的表达变化与临床病理学特征及其预后的关系。方法在建立胃癌差异基因表达谱的基础上,确定胃癌及癌旁形态学正常组织中TGF-β1的mRNA表达水平存在明显差异,进一步利用组织微阵列和免疫组化染色分别检测了胃癌及癌旁形态学正常组织中TGF-β1蛋白表达水平。结果TGF-β1蛋白主要以细胞质着色为主,在90例胃癌组织中32例(36%)阳性表达,58例(64%)为阴性表达。进一步对不同分化程度的胃癌组织中TGF-β1蛋白的表达进行分析,结果表明在39例高中分化组织中23例(59%)呈阳性表达,而51例低分化胃癌中9例(18%)为阳性表达,差异有统计学意义(P<0·01)。进一步分析了TGF-βR-Ⅰ蛋白的表达,在74例胃癌组织中42例(57%)阳性表达,32例(43%)染色阴性。在38例高中分化组织中26例(68%)呈阳性表达,在36例低分化胃癌中16例(44%)阳性表达,差异有统计学意义(P<0·05)。对有随访资料的肠型胃癌的TGF-β1及TGF-βR-Ⅰ蛋白的表达情况与临床病理学特征进行分析。应用Kaplan-Meier法分析蛋白阳性和阴性表达组病例的生存时间,确定TGF-β1蛋白阳性表达组病例生存和预后明显好于TGF-β1阴性表达组病例(P=0·0058)。而TGF-βR-Ⅰ蛋白表达与生存和预后无明显关系(P=0·8453)。结论TGF-β1表达水平与胃癌的分化程度有关,表达阳性组病例的预后明显好于表达阴性组的病例,提示TGF-β1表达对中晚期胃癌的再分型和分类具有重要的临床意义。

Objective To clarify the correlation of transforming growth factor-β1 （TGF-β1） expression with the differentiation and prognosis of advanced gastric cancer （GC）. Methods Whole genome expression chip hybridization, was used to detect the expression of TGF-β1 and TGF-βR1 in 20 specimens of intestinal-type GC and para-cancer tissues. RT-PCR and immunohistochemistry （IHC） analysis were used to detect the mRNA and protein expression of TGF-β1 and TGF-βR1 in 30 specimens of intestinaltype GC tissue and para-cancer tissues. The mixture of gastric mucosa tissues from 20 non-tumor patients was used as common reference. Results The expression level of TGF-β1 and TGF-βR-1 genes was higher in the GC tissues than in the para-cancer tissues. However, the expression of Smad gene family was not significantly different between the GC tissues and para-tumor normal tissues. TGF-β1 gene expression and TGF-βR1 gene expression were higher in the GC tissues. RT-PCR showed that both TGF-β1 and TGF-βR-1 genes were highly expressed in the mRNA level in 21 of the 30 CC patients IHC showed that TGF-β1 protein was expressed mainly in the cytoplasm. 32 of the 90 specimens of GC tissue were highly positive in TGF-β1 protein （64%）, in comparison with the positive rate of 5% （1/20） in the para-cancer normal tissues. The TGF-β1 protein expression rate of the highly and moderately differentiated GC tissues was 59% （59%, 23/ 39）, significantly higher than that of the lowly differentiated GC tissues （ 18%, 9/51, P 〈 0.01 ）. IHC showed that the TGF-βR- Ⅰ rate was 57% （42/74） in the well differentiated specimens, particularly 68% （26/38） in the highly differentiated specimens, and was 44% in the poorly differentiated GC （6/20, P 〈 0.05 ）. Log rank test showed that the prognosis of the patients positive in TGF-β1 was significantly better than those negative in TGF-β1 （P = 0. 0058 ）. However, the survival rate did not differ significantly according to TGF-βR-Ⅰ expression （ P = 0. 8453 ）. Conclusion TGF-β1 expression is significantly correlated with the differentiation degree of GC. Moreover, positive expression of TGF-β1 is a favorable prognostic factor in advanced GC. Expression of TGF-131 may be an important preoperative prognostic variable for advanced GC.