Martin D C, Fowlkes J L, Babic B, Khokha R
Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
J Cell Biol. 1999 Aug 23;146(4):881-92. doi: 10.1083/jcb.146.4.881.
Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])-induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1-overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1-overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1-overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer.
胰岛素样生长因子（IGF）II在许多人类癌症中过表达，并且在几种肿瘤模型中被病毒癌基因（SV40 T抗原，[TAg]）诱导的肿瘤发生重新激活且至关重要。使用双转基因小鼠肝肿瘤模型，我们证明金属蛋白酶组织抑制剂1（TIMP-1）在肿瘤发展过程中可阻断肝脏增生，尽管TAg介导IGF-II的重新激活。由于IGF的活性受IGF结合蛋白（IGFBPs）控制，我们研究了TIMP-1过表达是否改变了转基因肝脏中的IGFBP状态。配体印迹显示，在过表达TIMP-1的双转基因同窝仔鼠中，IGFBP-3蛋白水平升高，而IGFBP-3 mRNA水平没有差异，这表明TIMP-1在转录后水平影响IGFBP-3。IGFBP-3蛋白水解分析表明，过表达TIMP-1的肝脏中IGFBP-3的降解较低，酶谱分析显示基质金属蛋白酶（MMPs）存在于肝脏匀浆中，并且能够降解IGFBP-3。由于IGFBP-3蛋白水解减少和IGFBP-3蛋白水平升高，过表达TIMP-1的动物中可解离的IGF-II水平显著降低。这种生物可利用的IGF-II的减少最终导致体内IGF-I受体信号传导减弱，这通过受体激酶活性降低以及IGF-I受体下游效应物胰岛素受体底物1（IRS-1）、细胞外信号调节激酶（Erk）-1和Erk-2的酪氨酸磷酸化减少得以证明。总之，这些结果提供了证据，表明TIMP-1通过降低肿瘤诱导性有丝分裂原IGF-II的活性来抑制肝脏增生，这是TAg介导的肿瘤发生中的一个早期事件。这些数据表明控制MMP介导的IGFBPs降解是控制癌症中IGF生物利用度的一种新疗法。
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