Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma.
Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma.
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正常和突变形式的 HRAS 过度表达会诱导人类移行细胞癌的原位膀胱侵袭。
DOI：
10.1073/pnas.87.22.9047
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发表时间：
1990
影响因子：
11.1
通讯作者：
Kerbel,RS
中科院分区：
文献类型：
--
作者：
Theodorescu,D;Cornil,I;Fernandez,BJ;Kerbel,RS
最近的研究表明，原位（经尿道）移植人膀胱癌细胞系到裸鼠允许肿瘤生长，准确地反映了他们的临床恶性状态在原始主机。因此，这样的系统提供了一个独特的机会来分析低度膀胱癌（其中绝大多数是可治愈的）转化为高度危及生命的疾病形式所涉及的遗传事件。由于5-10%的移行细胞癌（TCC）已被证明含有突变的HRAS基因，并且所有形式的HRAS的蛋白表达水平与TCC进展相关，因此我们选择研究HRAS癌基因在膀胱肿瘤进展中的作用。我们评估了正常或突变的HRAS基因转染到人TCC（称为RT-4）中的效果，RT-4在经尿道原位接种到无胸腺裸鼠后表现为浅表非侵袭性乳头状肿瘤。我们发现，无论是转染正常或突变的HRAS基因的过度表达转化RT-4细胞表达的侵袭性表型非常相似的性质，高级别膀胱癌的临床行为。这些结果表明正常或突变RAS基因在人膀胱癌进展中的作用，并强调了使用原位接种系统评价癌基因对恶性肿瘤进展的贡献的重要性。
Recent studies have shown that orthotopic (transurethral) transplantation of human bladder cancer cell lines into nude mice permits tumor growth that accurately reflects their clinical malignant status in the original host. Thus, such a system allows a unique opportunity to analyze the genetic events involved in the conversion of low-grade bladder cancer, the vast majority of which are curable, to the high-grade life-threatening form of the disease. Since 5-10% of transitional cell carcinomas (TCCs) have been shown to contain a mutated HRAS gene, and protein expression levels of all forms of HRAS have been correlated with TCC progression, we chose to study the contribution of the HRAS oncogene in bladder tumor progression. We evaluated the effects of transfection of normal or mutated HRAS genes into a human TCC, called RT-4, that behaves as a superficial noninvasive papillary tumor after transurethral orthotopic inoculation into athymic nude mice. We found that overexpression of either transfected normal or mutated HRAS genes converted RT-4 cells to express an invasive phenotype remarkably similar in nature to the clinical behavior of high-grade bladder carcinomas. These results suggest a role for overexpressed normal or mutated RAS genes in human bladder carcinoma progression, and highlight the importance of using orthotopic inoculation systems for evaluation of the contribution of oncogenes to malignant tumor progression.