Kotsinas Athanassios, Evangelou Konstantinos, Sideridou Maria, Kotzamanis George, Constantinides Constantinos, Zavras Athanasios I, Douglass Chester W, Papavassiliou Athanasios G, Gorgoulis Vassilis G
Department of Histology & Embryology, Molecular Carcinogenesis Group, School of Medicine, University of Athens, Athens, Greece.
Cancer Lett. 2008 Feb 8;259(2):177-85. doi: 10.1016/j.canlet.2007.10.013. Epub 2007 Nov 26.
Normal function of insulin-like growth factor II receptor (IGF2R) gene has been associated with negative control of tumor growth in vivo and in vitro. Rare alleles at a 3' UTR short tandem repeat polymorphism of IGF2R are known to decrease transcript stability. One such allele (A2/B2) increases significantly the risk of oral squamous cell carcinoma and non-small cell lung carcinoma (NSCLC) in Caucasians. To determine potential association(s) between A2/B2 presence and development and/or progression of disease, we examined in 103 NSCLC patients, free of IGF2R allelic imbalance aberrations, the 3' UTR allelic status in relation to tumor kinetic parameters (proliferation index-PI and apoptotic index-AI) and clinicopathological data. PCR and automated sequence analyses were employed to genotype the IGF2R 3' UTR polymorphism. Given that, oncogenic mitogens, which escape degradation by IGF2R, can also activate p53 through a DNA damage response, the patterns between p53 status and IGF2R genetic constitution were also evaluated in relation to the above parameters. The A2/B2 variant was significantly more common (p=0.005, chi2-test) in lung cancer patients (25% vs 15%). Its presence was accompanied by high cellular proliferation (p=0.028, t-test) along with increased tumor cell growth (GI=PI/AI) (p=0.022, t-test) and it was significantly found in advanced stages. Also, patients carrying the A2/B2 in their genetic constitution that exhibit aberrant p53 expression have faster growing tumors and progress more rapidly to advanced stages. In conclusion, the IGF2R-A2/B2 variant probably provides a selective advantage for NSCLC progression through increased tumor growth.
胰岛素样生长因子II受体（IGF2R）基因的正常功能与体内外肿瘤生长的负调控相关。已知IGF2R的3'非翻译区短串联重复多态性的罕见等位基因会降低转录稳定性。其中一个这样的等位基因（A2/B2）显著增加了高加索人口腔鳞状细胞癌和非小细胞肺癌（NSCLC）的风险。为了确定A2/B2的存在与疾病发生和/或进展之间的潜在关联，我们在103例无IGF2R等位基因失衡异常的NSCLC患者中，研究了3'非翻译区等位基因状态与肿瘤动力学参数（增殖指数 - PI和凋亡指数 - AI）以及临床病理数据的关系。采用聚合酶链反应（PCR）和自动序列分析对IGF2R 3'非翻译区多态性进行基因分型。鉴于逃避IGF2R降解的致癌有丝分裂原也可通过DNA损伤反应激活p53，还评估了p53状态与IGF2R基因构成之间的模式与上述参数的关系。A2/B2变异在肺癌患者中明显更常见（p = 0.005，卡方检验）（25%对15%）。其存在伴随着高细胞增殖（p = 0.028，t检验）以及肿瘤细胞生长增加（生长指数 = PI/AI）（p = 0.022，t检验），并且在晚期显著出现。此外，基因构成中携带A2/B2且p53表达异常的患者肿瘤生长更快，进展到晚期的速度也更快。总之，IGF2R - A2/B2变异可能通过增加肿瘤生长为NSCLC进展提供了选择性优势。
