Specific allelic loss of p16INK4A tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis
Specific allelic loss of p16INK4A tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis
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DOI：
10.1016/s0002-9440(10)64860-2
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发表时间：
2002-02-01
影响因子：
6
通讯作者：
Toyokuni, S
中科院分区：
文献类型：
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作者：
Hiroyasu, M;Ozeki, M;Toyokuni, S
氧化性组织损伤已被证明与致癌作用有关。在人类癌症中，p16（INK 4A）是最常突变的肿瘤抑制基因之一。本研究采用次氮基三乙酸铁（Fe-NTA）诱导的大鼠肾癌模型，以确定是否氧化损伤可以引起特定的等位基因丢失p16（INK 4A）。通过荧光原位杂交结合单细胞分辨率的印片细胞学，我们发现肾小管细胞非整倍体的数量p16（INK 4A）位点的（1或3个信号）显着且特异性增加（1周，37.2 +/- 2.3%; 3周，37.8 +/- 1.3% vs对照组，22.5 +/- 1.9%;平均SE +/- 5 N = 8; P < 0.001和P < 0.0001）。在p53或vhl肿瘤抑制基因位点未观察到非整倍体增加。此外，在具有3个信号的细胞中的增加之后是具有1个信号的细胞的连续增加。因此，p16（INK 4A）基因座特别容易受到氧化损伤，导致其等位基因在几周内丢失，可能是由于两个等位基因的复制缺陷。
Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16(INK4A) is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16(INK4A). By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (I or 3 signals) at the p16(INK4A) locus was significantly and specifically increased (1 week, 37.2 +/- 2.3%; 3 weeks, 37.8 +/- 1.3% vs control, 22.5 +/- 1.9%; mean SE +/- 5 N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to 10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16(INK4A) locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.