Wang S, Souza R F, Kong D, Yin J, Smolinski K N, Zou T T, Frank T, Young J, Flanders K C, Sugimura H, Abraham J M, Meltzer S J
Department of Medicine, University of Maryland School of Medicine and Baltimore Veterans Affairs Hospital, 21201, USA.
Cancer Res. 1997 Jul 1;57(13):2543-6.
The insulin-like growth factor II receptor (IGFIIR) gene has been identified as a coding region target of microsatellite instability in human gastrointestinal (GI) tumors. IGFIIR normally has two growth-suppressive functions: it binds and stimulates the plasmin-mediated cleavage and activation of the latent transforming growth factor-beta1 (LTGF-beta1) complex, and it mediates the internalization and degradation of IGFII ligand, a mitogen. We used an immunohistochemical approach to determine whether IGFIIR mutation affected expression of these proteins in GI tumors. Four highly specific antibodies were used: LC(1-30), which recognizes the active form of TGF-beta1; anti-LTGF-beta1, which detects the LTGF-beta1 precursor protein; anti-IGFIIR; and anti-IGFII ligand. Twenty GI tumors either with (6 of 20) or without (14 of 20) known IGFIIR mutation were examined, along with matching normal tissues. Results were statistically significant in the following categories: (a) decreased active TGF-beta1 protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; (b) increased LTGF-beta1 protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; and (c) increased IGFII ligand protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues. These data suggest that in genetically unstable GI tumors, mutation of a microsatellite within the coding region of IGFIIR functionally inactivates this gene, causing both diminished growth suppression (via decreased activation of TGF-beta1) and augmented growth stimulation (via decreased degradation of the IGFII ligand).
胰岛素样生长因子II受体（IGFIIR）基因已被确定为人类胃肠道（GI）肿瘤中微卫星不稳定性的编码区靶点。IGFIIR通常具有两种生长抑制功能：它结合并刺激纤溶酶介导的潜在转化生长因子-β1（LTGF-β1）复合物的切割和激活，并且它介导有丝分裂原IGFII配体的内化和降解。我们采用免疫组化方法来确定IGFIIR突变是否影响这些蛋白在胃肠道肿瘤中的表达。使用了四种高度特异性抗体：识别TGF-β1活性形式的LC(1-30)；检测LTGF-β1前体蛋白的抗LTGF-β1；抗IGFIIR；以及抗IGFII配体。对20例已知有（20例中的6例）或无（20例中的14例）IGFIIR突变的胃肠道肿瘤以及匹配的正常组织进行了检查。结果在以下几类中具有统计学意义：（a）与匹配的正常组织或IGFIIR野生型肿瘤组织相比，IGFIIR突变肿瘤组织中活性TGF-β1蛋白表达降低；（b）与匹配的正常组织或IGFIIR野生型肿瘤组织相比，IGFIIR突变肿瘤组织中LTGF-β1蛋白表达增加；（c）与匹配的正常组织或IGFIIR野生型肿瘤组织相比，IGFIIR突变肿瘤组织中IGFII配体蛋白表达增加。这些数据表明，在基因不稳定的胃肠道肿瘤中，IGFIIR编码区内微卫星的突变使该基因功能失活，导致生长抑制减弱（通过TGF-β1激活减少）和生长刺激增强（通过IGFII配体降解减少）。
