Changes in gene activity of growth factors and their receptorsand the contentsof growth factors in urine during bladder carcinogenesis.

为探讨生长因子在膀胱癌发生中的作用，检测了N-丁基-N-(4-羟基丁基)亚硝胺(BBN)诱发大鼠膀胱癌过程中及临床标本中多种生长因子及其受体表达的变化。Northern印迹分析显示，BBN可使转化生长因子-α(TGF-α)和c-met/肝细胞生长因子(HGF)受体的mRNAs含量增加，而表皮生长因子(EGF)受体的mRNAs含量略有增加。而成纤维细胞生长因子受体1和转化生长因子β2受体的表达在BBN治疗后下降。其他因子(EGF、bFGF、KGF、HGF、TGF-β1)的mRNAs含量几乎不受治疗的影响或低于检测水平。人膀胱癌组织(6例)中c-met基因表达水平较高，而转化生长因子-α基因表达水平不高。大鼠膀胱肿瘤细胞株NBT-II同时表达转化生长因子-α和c-MET的mRNAs，肝细胞生长因子对细胞有明显的分散和促进生长作用。人膀胱癌细胞株(UM-UC-3和T-24)也对HGF的细胞分散作用敏感。这些结果表明，除尿EGF外，膀胱癌产生的转化生长因子-α可能在大鼠膀胱癌的发生发展中起作用，c-Met/HGF受体激活导致的细胞运动增强参与了大鼠和人膀胱癌细胞的侵袭和转移。

To investigate the roles of growth factors in bladder cancer, changes in expression of mRNAs for several growth factors and their receptors were examined during rat bladder carcinogenesis induced with N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and in clinical specimens. Northern blot analysis showed that the contents of mRNAs for transforming growth factor-alpha (TGF-alpha) and c-met/hepatocyte growth factor (HGF) receptor increased on BBN treatment, Epidermal growth factor (EGF) receptor mRNA was slightly increased with the treatment. While those for fibroblast growth factor (FGF) receptor 1 and transforming growth factor beta (TGF-beta) type II receptor decreased on BBN treatment. The contents of mRNAs for the other factors investigated (EGF,bFGF,KGF,HGF,TGF-beta1) were hardly affected with the treatment or below detectable level. In case of human bladder specimens, the content of c-met mRNA but not TGF-alpha mRNA was high in all the tumor tissues (6 specimens) examined. A rat bladder tumor cell line, NBT-II,expressed both TGF-alpha and c-met mRNAs, and HGF showed apparent scattering and growth stimulating effects on the cells. Human bladder tumor cell lines (UM-UC-3 and T-24) were also susceptible to the cell scattering action of HGF.These results indicate the possibilities that TGF-alpha produced by a bladder cancer in addition to urinary EGF play a role in the development of rat bladder cancer, and that enhanced cell motility due to activation of the c-met/HGF receptor participates in the invasion and metastasis of both rat and human bladder cancer cells.