Allelic imbalance and altered expression of genes in chromosome 2q11-2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Allelic imbalance and altered expression of genes in chromosome 2q11-2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
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DOI：
10.1038/sj.onc.1206233
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发表时间：
2003-02-27
期刊：
影响因子：
8
通讯作者：
Snyderwine, EG
中科院分区：
文献类型：
--
作者：
Qiu, CP;Yu, MS;Snyderwine, EG
2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）是一种在熟肉中发现的化合物，是大鼠乳腺致癌物。phip诱导的大鼠乳腺癌的比较基因组杂交显示2q的着丝粒区缺失，该区域已知携带乳腺癌易感性1 （Mcs1）基因和其他一些与癌变相关的基因。在Sprague-Dawley (SD) x Wistar Furth F1杂交大鼠中，研究了PhIP诱导的乳腺癌中等位基因失衡，特别是微卫星不稳定性和杂合性丧失。在一项基于聚合酶链反应（PCR）的分析中，34个微卫星标记与2q11-2q16一致，其中9个标记显示等位基因不平衡。肿瘤中失衡的频率从10%到100%不等，取决于特定的标志物。然而，与Mcs1基因位点一致的标记均未出现等位基因失衡，这表明该位点的改变与phip诱导的大鼠乳腺癌无关。通过实时荧光定量PCR和免疫组化（IHC）检测了在大量phip诱导的SD大鼠乳腺癌中物理定位于2q11-2q16并可能参与癌变的几个基因的表达，包括Ccnb （cyclin B1）、Ccnh （cyclin H）、Rasa （Ras GAP）、RasgrJ2、Pi3kr1 （p85alpha）和Il6st （gp130）。通过实时荧光定量PCR检测，肿瘤组织中Rasa、Pi3kr1、Ccnh和116st mRNA的表达量分别比对照乳腺组织高22倍、20倍、3倍和3倍(P
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a compound found in cooked meat, is a mammary gland carcinogen in rats. Comparative genomic hybridization of PhIP-induced rat mammary gland carcinomas revealed loss in the centromeric region of 2q, a region known to carry the mammary carcinoma susceptibility 1 (Mcs1) gene and several other genes relevant to carcinogenesis. Allelic imbalance, specifically microsatellite instability and loss of heterozygosity, was examined in mammary gland carcinomas induced by PhIP in Sprague-Dawley (SD) x Wistar Furth F1 hybrid rats. In a polymerase chain reaction (PCR)-based assay with 34 microsatellite markers coinciding to 2q11-2q16, nine markers revealed allelic imbalance. The frequency of imbalance in the tumors varied from 10 to 100% depending on the specific marker. However, none of the markers coinciding with the Mcs1 gene locus showed allelic imbalance, suggesting that alterations at this locus were not associated with PhIP-induced rat mammary gland cancer. The expression of several genes physically mapped to 2q11-2q16 and potentially involved in carcinogenesis including Ccnb (cyclin B1), Ccnh (cyclin H), Rasa (Ras GAP), RasgrJ2, Pi3kr1 (p85alpha), and Il6st (gp130) was also examined by quantitative real-time PCR and immunohistochemistry (IHC) across a large bank of PhIP-induced SD rat mammary gland carcinomas. By quantitative real-time PCR, the mRNA expression of Rasa, Pi3kr1, Ccnh, and 1l6st in carcinomas was, respectively, 22-, 20-, three- and threefold higher in carcinomas than in control mammary gland tissues (P