Howell G M, Sun L, Ziober B L, Wu S P, Brattain M G
Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo 43699.
Cancer Metastasis Rev. 1993 Sep;12(3-4):275-86. doi: 10.1007/BF00665958.
Colon carcinoma is a multistage disease. Most malignancies arise from pre-existing benign tumors. Multiple chromosomal defects affecting oncogene and tumor suppressor gene function are associated with disease progression. These aberrations result in an imbalance between the normal positive and negative growth effectors, which contribute further to disease progression. We have studied how changes in the expression of TGF alpha and TGF beta affect colon carcinoma cell behavior. Overexpression of the stimulatory factor TGF alpha in a relatively benign cell line with weak TGF alpha autocrine activity converted the cell type to an aggressive, progressed phenotype in vivo and in vitro. In contrast, disruption of TGF alpha expression by constitutive expression of TGF alpha antisense RNA in a progressed cell line with a strong, internalized autocrine loop resulted in the development of clones with decreased tumorigenicity in vitro and in vivo. Suppression of the inhibitory effects of TGF beta by constitutive expression of TGF beta antisense RNA increased the tumorigenicity of the cell lines in vitro and in vivo. None of these alterations in TGF alpha or TGF beta expression affected the doubling time of the cells. The changes in tumorigenicity were due to effects on the lag phase of growth. We conclude that TGF beta functions to maintain the cells in a quiescent state while TGF alpha drives reentry into the cell cycle. We have identified a unique cis-element that mediates TGF alpha autoregulation. The transcription factor binding this element is also involved in the cell-cycle regulation of TGF alpha expression. We hypothesize that this factor may be a convergent point TGF alpha and TGF beta interact in controlling movement into and out of quiescence.
结肠癌是一种多阶段疾病。大多数恶性肿瘤起源于先前存在的良性肿瘤。影响癌基因和肿瘤抑制基因功能的多个染色体缺陷与疾病进展相关。这些畸变导致正常的正向和负向生长效应器之间失衡，这进一步促进了疾病进展。我们研究了转化生长因子α（TGFα）和转化生长因子β（TGFβ）表达的变化如何影响结肠癌细胞行为。在具有弱TGFα自分泌活性的相对良性细胞系中过表达刺激因子TGFα，在体内和体外都将细胞类型转变为侵袭性、进展性表型。相反，在具有强大的内化自分泌环的进展细胞系中通过组成型表达TGFα反义RNA破坏TGFα表达，导致在体外和体内产生致瘤性降低的克隆。通过组成型表达TGFβ反义RNA抑制TGFβ的抑制作用，在体外和体内均增加了细胞系的致瘤性。TGFα或TGFβ表达的这些改变均未影响细胞的倍增时间。致瘤性变化是由于对生长延迟期的影响所致。我们得出结论，TGFβ的功能是使细胞维持在静止状态，而TGFα驱动细胞重新进入细胞周期。我们鉴定出了一个介导TGFα自调节的独特顺式元件。结合该元件的转录因子也参与TGFα表达的细胞周期调控。我们假设该因子可能是TGFα和TGFβ在控制进入和离开静止状态的过程中相互作用的汇聚点。
