Tashiro Etsu, Maruki Hiroko, Minato Yusuke, Doki Yuichiro, Weinstein I Bernard, Imoto Masaya
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan.
Cancer Res. 2003 Jan 15;63(2):424-31.
Overexpression of cyclin D1 due to gene rearrangement, gene amplification, or simply increased transcription occurs frequently in several types of human cancers. However, overexpression of cyclin D1 in cell culture system is insufficient, by itself, to cause malignant transformation. In the present study, we found that when rodent fibroblasts that overexpress cyclin D1, but not normal fibroblasts, were treated with basic fibroblast growth factor (bFGF), there was enhanced cell cycle progression, extracellular signal-regulated kinase 2 activation, induction of anchorage-independent growth, and enhanced invasion of a Matrigel barrier. These enhanced responses to bFGF appear to be due to increased expression of fibroblast growth factor receptor 1, at both the mRNA and protein levels, in the cyclin D1-overexpressing cells. We obtained evidence that this increase in fibroblast growth factor receptor 1 expression is mediated through cyclin D1 activation of the pRB/E2F pathway. Taken together, these results suggest that in vivo cyclin D1 overexpression can enhance tumor progression, at least in part, by potentiating the stimulatory efforts of bFGF, which is often produced by stromal cells, and the growth of adjacent tumor cells.
由于基因重排、基因扩增或仅仅是转录增加导致的细胞周期蛋白D1过表达，在几种类型的人类癌症中经常发生。然而，在细胞培养系统中，细胞周期蛋白D1的过表达本身并不足以导致恶性转化。在本研究中，我们发现，当用碱性成纤维细胞生长因子（bFGF）处理过表达细胞周期蛋白D1的啮齿动物成纤维细胞而非正常成纤维细胞时，细胞周期进程加快、细胞外信号调节激酶2激活、非贴壁依赖性生长诱导以及对基质胶屏障的侵袭增强。对bFGF的这些增强反应似乎是由于在过表达细胞周期蛋白D1的细胞中，成纤维细胞生长因子受体1在mRNA和蛋白质水平上的表达增加。我们获得的证据表明，成纤维细胞生长因子受体1表达的这种增加是通过细胞周期蛋白D1对pRB/E2F途径的激活介导的。综上所述，这些结果表明，在体内，细胞周期蛋白D1的过表达至少部分地通过增强bFGF（通常由基质细胞产生）对邻近肿瘤细胞的刺激作用来促进肿瘤进展。
