Mercola D, Carpenter P M, Grover-Bardwick A, Mercola M
Department of Pathology, University of California, San Diego, La Jolla 92093.
Oncogene. 1992 Sep;7(9):1793-803.
v-sis is the oncogene of simian sarcoma virus, but whether tumor growth is maintained by v-sis expression alone or requires additional changes is unknown. To distinguish these possibilities we studied a model of reversible transformation including tumorigenicity using NIH3T3 cells bearing a metallothionein promoter-v-sis construction. Cells subcultured from 10 out of 18 tumors from athymic mice, all less than 0.1 g and less than or equal to 21 days in age, reverted to a normal phenotype but exhibited transformation upon addition of zinc as judged by morphology, growth rate, saturation density and anchorage independence of growth. Thus, activation of v-sis alone is sufficient for initiation and early autocrine-based growth of tumors. However, the cells from the remaining and predominantly larger, 0.5 +/- 0.7 g, tumors did not revert and exhibited zinc-independent transformation as judged by the same criteria. Southern analysis and examination of the regulation of v-sis product expression in cells derived from these tumors showed no change in zinc-dependent and reversible regulation of v-sis sequences. These results suggest that subsequent tumor growth strongly favors acquisition of additional irreversible change(s) in the tumor cell genome at high frequency (44%). Thus an early event of a multistep process stimulated by v-sis-dependent transformation best accounts for the sum of results.
v-sis是猿猴肉瘤病毒的致癌基因，但肿瘤生长是仅由v-sis表达维持，还是需要其他变化，目前尚不清楚。为了区分这些可能性，我们研究了一种可逆转化模型，该模型利用携带金属硫蛋白启动子-v-sis构建体的NIH3T3细胞，包括致瘤性。从无胸腺小鼠的18个肿瘤中选取10个进行传代培养，这些肿瘤均小于0.1 g，年龄小于或等于21天，细胞恢复为正常表型，但在添加锌后，根据形态、生长速率、饱和密度和生长的锚定非依赖性判断，细胞表现出转化。因此，单独激活v-sis足以启动肿瘤并使其早期基于自分泌生长。然而，其余主要较大（0.5±0.7 g）肿瘤的细胞没有恢复，并且根据相同标准判断表现出不依赖锌的转化。对这些肿瘤来源细胞进行Southern分析以及对v-sis产物表达调控的检查表明，v-sis序列的锌依赖性和可逆调控没有变化。这些结果表明，随后的肿瘤生长强烈倾向于肿瘤细胞基因组高频（44%）获得额外的不可逆变化。因此，由v-sis依赖性转化刺激的多步骤过程的早期事件最能解释这些结果的总和。
