COLLABORATION OF GROWTH FACTOR AND ONCOGENE PRODUCT IN HEPATOCARCINOGENESIS AND LIVER REGENERATION -ANALYSIS BY DOUBLE TRANSGENIC MICE-

转化生长因子α和原癌基因ras通过激活酪氨酸激酶参与细胞内信号转导。我们和其他小组分别建立了转化生长因子α转基因小鼠(T)和ras转基因小鼠(R)，这两种转基因小鼠都表现出肝细胞癌、胰腺纤维化(T)和脾肉瘤和皮肤乳头状瘤(R)等特征性表型。我们制作了TGFα和ras(T+R)双转基因小鼠，并对其表型、成瘤和肝再生进行了分析。首先，T+R组的体重和肝脏重量比T和R组低。T+R组出生后体重显著高于单纯T组和R组，出生后12个月有4例出现大肝癌和腺瘤。15例(R)中有4例发生皮肤乳头状瘤，15例(T)中有2例发生双肝腺瘤。T+R组和T+R组的肝细胞增殖细胞核抗原阳性率均在10%以上，T+R组的非肿瘤组织中约有1%的细胞增殖细胞核抗原染色阳性，而非肿瘤性肝组织仅有不到1%的增殖细胞核抗原表达。T+R组胰腺重量大于T或R组，胰腺纤维化程度高于T或R组，TGFa和ras同时过表达抑制小鼠生长，促进肝脏生长，促进肝肿瘤的形成和再生。TGFα和ras也可促进胰腺纤维化，从而促进胰腺生长。

Transforming growth factor(TGF)alpha and protooncogene ras are involved inthe intracellular signal transduction through the activation of tyrosine kinase.We and other group have developed TGFalpha transgenic mice(T) and ras transgenicmice(R) independently, Both of the transgenic mice showed characteristicphenotypes e.g. hepatocellular carcinoma, pancreatic fibrosis for (T) andsplenic sarcoma and skin papilloma for (R). We made the double transgenic miceof TGFalpha and ras(T+R) and analyzed the phenotype, tumor formation, and liverregeneration. First of all, T+R had lower body weight than T and R and the rate ofliver weight! body weight was significantly higher in T+R than single T or R.Large hepato cellular carcinoma and adenoma were observed in 4 of 15 T+R 12months after birth. Four of 15(R) developed skin papilloma and 2 of 15 (T) didhepatic adenoma. More than 10% of hepatocytes were positively stained byproliferating cell nuclear antigen(PCNA) in liver tumors of T+R and about 1% ofnon-tumor tissue of T+R.On the other hand, non-tumor liver showed less than1% by PCNA.Compared with T and R, T+R showed enhanced regeneration of theliver after 2/3 hepatectomy. Skin tumor and splenic sarcoma was not enhancedin T+R compared with R.he weight of pancreas was heavier in T+R than T or Rand pancreatic fibrosis was enhanced in T+R than T or R.Thus simultaneous overexpression of TGFa and ras inhibited the growth ofthe mice and enhanced the growth of the liver, hepatic tumor formation andregeneration. Pancreatic fibrosis was also enhanced by TGFalpha and ras, resultingin enhanced growth of pancreas.