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

转化生长因子（Transforming growth factor，TGF）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，我们和其他研究小组分别建立了TGF α转基因小鼠（T）和ras转基因小鼠（R），两种转基因小鼠均表现出特征性的表型，如肝细胞癌、胰腺纤维化（T）和脾肉瘤、皮肤乳头状瘤（R）。建立了TGF α和ras双转基因小鼠（T+R），并对其表型、肿瘤形成和肝再生进行了分析。首先，T+R组的体重和肝重比均低于T组和R组;出生后12个月，15例T + R中有4例出现大肝癌和腺瘤。15例（R）中4例发生皮肤乳头状瘤，15例（T）中2例发生肝腺瘤。增殖细胞核抗原（PCNA）在T+R组肝肿瘤中阳性率超过10%，在T+R组非肿瘤肝组织中阳性率约为1%，而在非肿瘤肝组织中阳性率低于1%。皮肤肿瘤和脾肉瘤在T + R组较R组无明显增强，胰腺重量在T + R组较T或兰德重，胰腺纤维化在T+R组较T或R组增强。TGF-α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.