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

转化生长因子(TGF) α和原癌基因ras通过酪氨酸激酶的激活参与细胞内信号转导。我们和其他研究小组独立开发了TGFalpha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特征性表型，如(T)的肝细胞癌、胰腺纤维化和(R)的脾肉瘤和皮肤乳头瘤。我们制备了TGFalpha和ras（T+R）双转基因小鼠，并对其表型、肿瘤形成和肝脏再生进行了分析。首先，T+R的体重低于T和R的体重和肝脏重量的提供率！T+R组体重明显高于单纯T或R组。出生后12个月，15例T+R组中有4例出现大肝癌和腺瘤。15例中有4例(R)发生皮肤乳头状瘤，15例中有2例(T)发生肝腺瘤。T+R肝癌组织中超过10%的肝细胞被增殖细胞核抗原（PCNA）阳性染色，约1%的T+R非肿瘤组织被PCNA阳性染色。另一方面，非肿瘤肝脏的PCNA显示不到1%。与T和R相比，T+R显示2/3肝切除术后肝脏再生增强。皮肤肿瘤和脾肉瘤在T+R组与R组相比没有增强，胰腺重量比T重，胰腺纤维化在T+R组比T或R组增强，TGFa和ras同时过表达抑制小鼠生长，促进肝脏生长，肝脏肿瘤形成和再生。TGFalpha和ras也增强了胰腺纤维化，导致胰腺生长增强。

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.