Di Marco E, Pierce J H, Fleming T P, Kraus M H, Molloy C J, Aaronson S A, Di Fiore P P
Laboratory of Molecular and Cellular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Oncogene. 1989 Jul;4(7):831-8.
Alterations affecting the epidermal growth factor (EGF)/transforming growth factor alpha (TGF alpha)-responsive mitogenic pathway are frequently detected in malignancies. In particular, the EGF-receptor (EGFR) molecule has been found overexpressed in a number of human tumors, and TGF alpha is produced by a large array of tumor cells. Gene transfer experiments have previously demonstrated that expression of either TGF alpha or EGFR alone is not sufficient to induce the transformed phenotype in NIH3T3 cells. In this study we sought to investigate the biological effect of expression of TGF alpha and high levels of EGFR in this model system. We demonstrate that the gene for TGF alpha acts as a potent oncogene in NIH3T3 cells overexpressing EGFR (NIH-EGFR, greater than 10(6) EGFR). We further show that TGF alpha directly stimulates proliferation of the cell in which it is produced and provide evidence that the extracellular compartment of the transformed cell is the major site of interaction between TGF alpha and EGFR. Analysis of human tumor cell lines revealed a strong correlation between expression of TGF alpha and overexpression of EGFR. Moreover, high levels of EGF-independent tyrosine phosphorylation of the EGFR were detected both in NIH-EGFR expressing TGF alpha and in high EGFR and TGF alpha coexpressing human tumor cell lines. Thus, the two events instituting the EGFR/TGF alpha autocrine loop responsible for transformation in vitro may play a role in the development of some human malignancies.
在恶性肿瘤中经常检测到影响表皮生长因子（EGF）/转化生长因子α（TGFα）反应性促有丝分裂途径的改变。特别是，已发现表皮生长因子受体（EGFR）分子在许多人类肿瘤中过度表达，并且大量肿瘤细胞可产生TGFα。基因转移实验先前已证明，单独表达TGFα或EGFR不足以在NIH3T3细胞中诱导转化表型。在本研究中，我们试图在该模型系统中研究TGFα表达和高水平EGFR表达的生物学效应。我们证明，TGFα基因在过度表达EGFR的NIH3T3细胞（NIH-EGFR，EGFR大于10^6）中作为一种有效的癌基因发挥作用。我们进一步表明，TGFα直接刺激其产生细胞的增殖，并提供证据表明转化细胞的细胞外区室是TGFα与EGFR之间相互作用的主要部位。对人类肿瘤细胞系的分析揭示了TGFα表达与EGFR过度表达之间存在强相关性。此外，在表达TGFα的NIH-EGFR以及高EGFR和TGFα共表达的人类肿瘤细胞系中均检测到EGFR的高水平不依赖于EGF的酪氨酸磷酸化。因此，在体外导致转化的EGFR/TGFα自分泌环的这两个事件可能在某些人类恶性肿瘤的发生发展中起作用。
