Reiss M, Santoro V, de Jonge R R, Vellucci V F
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8032, USA.
Cell Growth Differ. 1997 Apr;8(4):407-15.
Cytogenetic, allelotype, and somatic cell hybrid studies of human head and neck cancers had suggested that the long arm of chromosome 18 might carry a tumor suppressor gene locus. To directly test this hypothesis, we introduced a wild-type copy of chromosome 18 into FaDu-Hyg-R head and neck squamous carcinoma cells. Five of 10 chromosome 18 hybrid clones formed invasive carcinomas in nude mice at a significantly lower rate and after a longer latency than the parental tumor cells, whereas the five remaining clones were tumorigenic. These results indicate that tumor formation was suppressed by chromosome 18. A homozygously deleted region of 18q in FaDu-Hyg-R cells included the candidate tumor suppressor gene, Smad4/DPC4, and extended into the DCC tumor suppressor gene locus, but not Smad2/MADR2. Each of the hybrid cell lines carried a full-length donor copy of the DCC gene, independently of their capability to form tumors in vivo. In contrast, each of the hybrid clones that were either completely or partly suppressed carried an intact copy of Smad4/DPC4, whereas this gene was deleted in the two most highly tumorigenic clones. Furthermore, the presence of Smad4/DPC4 correlated with partial restoration of cellular responsiveness to transforming growth factor beta. These results provide strong evidence for tumor suppression by Smad4/DPC4.
对人类头颈癌的细胞遗传学、等位基因分型和体细胞杂交研究表明，18号染色体长臂可能携带一个肿瘤抑制基因位点。为了直接验证这一假设，我们将18号染色体的野生型拷贝导入FaDu-Hyg-R头颈鳞状癌细胞。10个18号染色体杂交克隆中有5个在裸鼠中形成侵袭性癌的速率明显低于亲代肿瘤细胞，且潜伏期更长，而其余5个克隆具有致瘤性。这些结果表明18号染色体抑制了肿瘤形成。FaDu-Hyg-R细胞中18q的纯合缺失区域包括候选肿瘤抑制基因Smad4/DPC4，并延伸至DCC肿瘤抑制基因位点，但不包括Smad2/MADR2。每个杂交细胞系都携带DCC基因的全长供体拷贝，与它们在体内形成肿瘤的能力无关。相反，完全或部分受到抑制的每个杂交克隆都携带Smad4/DPC4的完整拷贝，而在两个致瘤性最强的克隆中该基因被删除。此外，Smad4/DPC4的存在与细胞对转化生长因子β的反应性部分恢复相关。这些结果为Smad4/DPC4抑制肿瘤提供了有力证据。
