Zhou P, Jiang W, Zhang Y J, Kahn S M, Schieren I, Santella R M, Weinstein I B
Department of Pharmacology, Columbia-Presbyterian Cancer Center, New York, New York, USA.
Oncogene. 1995 Aug 3;11(3):571-80.
The cyclin D1 gene is amplified and overexpressed in a significant fraction of human esophageal tumors, and several other types of human cancer, but the functional significance of this overexpression has not been established. To further address the roles of cyclin D1 in growth control and tumorigenesis, we have overexpressed an antisense cyclin D1 cDNA construct, either constitutively or inducibly, in the HCE7 human esophageal cancer cell line in which cyclin D1 is amplified and expressed at high levels. The expression of antisense cyclin D1 led to decreased expression of cyclin D1 at both mRNA and protein levels, and this was associated with a marked inhibition of cell proliferation. Antisense cyclin D1 expressing cells displayed a decreased plating efficiency, increased doubling time, decreased saturation density, increased cell size, decreased cyclin D1-associated in vitro kinase activity, decreased anchorage-independent growth, and a loss of tumorigenicity in nude mice. These findings provide direct evidence that the overexpression of cyclin D1 in certain tumor cells contributes to their abnormal growth and tumorigenicity. The ability to revert the transformed phenotype of these cells with antisense cyclin D1 suggests that cyclin D1 may be a useful target in cancer therapy.
细胞周期蛋白D1基因在相当一部分人类食管肿瘤以及其他几种类型的人类癌症中发生扩增并过表达，但其过表达的功能意义尚未明确。为了进一步探讨细胞周期蛋白D1在生长调控和肿瘤发生中的作用，我们在细胞周期蛋白D1基因发生扩增且高水平表达的HCE7人食管癌细胞系中，组成型或诱导型过表达反义细胞周期蛋白D1 cDNA构建体。反义细胞周期蛋白D1的表达导致细胞周期蛋白D1在mRNA和蛋白质水平的表达均下降，这与细胞增殖受到显著抑制有关。表达反义细胞周期蛋白D1的细胞表现出接种效率降低、倍增时间延长、饱和密度降低、细胞体积增大、与细胞周期蛋白D1相关的体外激酶活性降低、非贴壁依赖性生长减少以及在裸鼠中致瘤性丧失。这些发现提供了直接证据，表明细胞周期蛋白D1在某些肿瘤细胞中的过表达有助于其异常生长和致瘤性。用反义细胞周期蛋白D1逆转这些细胞转化表型的能力表明，细胞周期蛋白D1可能是癌症治疗中的一个有用靶点。
