【关键词】 膀胱肿瘤
Length of CAG repeat at exon 1 of androgen receptor gene is associated to development of bladder carcinoma in males
【Abstract】 AIM: To study the possible association between the length of the polymorphic CAG short tandem repeat (STR) at androgen receptor (AR) first exon and bladder cancer development. METHODS: Genomic DNA was extracted from the paraffinembedded bladder carcinoma tissues from male patients and amplified by PCR and then the products were resolved by electrophoresis on denaturing polyacrylamide gels and visualized through silver staining. The CAG repeat numbers were assessed by the mobility of their products and direct sequencing for some representative samples. The samples with appendicitis from 94 male patients were examined in a parallel way as a reference group. RESULTS: A total number of 95 of bladder cancer samples were examined. Six of them (6.3%) showed microsatellite instability, with one excluded from the following assessment due to the difficulty in determining precisely the normal position of its amplification product. The CAG repeat numbers for the 94 patients with bladder cancer and the reference patients with appendicitis were 8-26 (20.07±3.12) and 14-30 (21.06±3.39), respectively, with statistically significant difference. CONCLUSION: CAG STR at the first exon of AR gene is associated to the development and/or progression of bladder carcinoma in male patients. A shorter CAG STR at the locus may predispose the male individuals to the development of bladder cancer.
【Keywords】 gene, androgen receptor; CAG repeat; gene polymorphism; bladder neoplasms
【摘要】 目的： 探讨人雄激素受体（AR）基因第一外显子CAG串联短重复序列（STR）多态性与男性膀胱癌发生之间的关系. 方法： 石蜡包埋的男性膀胱癌标本进行基因组DNA提取，PCR扩增，变性聚丙烯酰胺凝胶电泳，经银染显示单股DNA链片段长度. 根据标本的泳动度推算CAG STR的n值；选取代表性的标本产物直接测序，验证上述检测的准确性. 以男性阑尾炎标本作为参照组. 结果： 95例膀胱癌标本中有6例（6.3%）出现微卫星不稳定（MSI）现象，其中1例因正常组织过少而无法确定其产物的正常泳动位置，不做以下分析. 94例膀胱癌及相同例数参照标本的CAG STR n值范围分别为8~26和14~30，均数分别为20.07±3.12和21.06±3.39，两者有统计学意义（P<0.05）. 结论： AR基因第一外显子CAG STR与男性膀胱癌的发生或（和）发展有关，CAG STR较短的男性个体患膀胱癌的危险性可能增加.
【关键词】 雄激素受体基因；CAG重复序列；基因多态性；膀胱肿瘤
0引言
膀胱癌是最常见的泌尿系统恶性肿瘤，男性发病率是女性的3.5倍［1］. 除了吸烟和职业因素等环境因素外，性激素的影响可能与这种性别差异有关. 动物实验研究显示，雄性动物对膀胱癌发生比雌性易感，这可能与雄激素或(和)雌激素的作用有关［2］. 雄激素通过雄激素受体（androgen receptor, AR）发挥作用，已经在人膀胱尿路上皮和膀胱尿路上皮癌（urothelial carcinoma, UTC）组织中检测到AR存在［3］. 我们设想，AR介导的反应可能在一定程度上决定了膀胱癌发生率的性别差异；同时，AR功能的差异也可能影响不同个体对这一肿瘤的易感性.
AR是核受体家族的一员，其编码基因位于X染色体的q1112区，有8个外显子组成［4］. 由第一外显子编码的N（氨基）末端区含有正常受体活性所需的转录激活单位，其活性可能与该区域内几个多态性结构有关［5］，其中最为明显的是位于第一外显子的CAG串联短重复序列（shorttandem repeat, STR）. 体外研究显示，AR的转录活性与AR基因 CAG STR的重复次数（n值）呈负相关，n值越小，AR的转录活性越强［6,7］. 已经知道AR基因CAG STR异常与雄激素不敏感征和延髓脊髓性肌萎缩有关［8,9］，并影响对前列腺癌［10］、肝细胞癌［11］、乳腺癌［12］、卵巢癌［13］、子宫内膜癌［14］以及子宫肌瘤的易感性［15］. 到目前为止，文献中少见有关这一多态性位点与膀胱尿路上皮肿瘤发生或发展关系的报道. 此研究对陕西地区人群的AR编码基因中的CAG STR长度与男性膀胱癌之间的关系进行了探讨.
1材料和方法
1.1材料
95例男性膀胱癌和94例男性阑尾炎石蜡包埋的标本来自第四军医大学唐都医院病理科. 膀胱组年龄为17~84岁，中位数年龄为63岁；均为尿路移性上皮癌，其中病理分级Ⅰ级20例，Ⅱ级55例，Ⅲ级20例.
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