Targeted delivery of NRASQ61R and Cre-recombinase to post-natal melanocytes induces melanoma in Ink4a/Arflox/lox mice.
Targeted delivery of NRASQ61R and Cre-recombinase to post-natal melanocytes induces melanoma in Ink4a/Arflox/lox mice.
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DOI：
10.1111/j.1755-148x.2010.00717.x
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发表时间：
2010-08
影响因子：
4.3
通讯作者：
Holmen SL
中科院分区：
文献类型：
--
作者：
VanBrocklin MW;Robinson JP;Lastwika KJ;Khoury JD;Holmen SL
我们开发了一种黑色素瘤体细胞基因传递小鼠模型，可以快速验证在这种疾病中发现的基因改变。该系统的一个主要优点是能够在免疫功能正常的小鼠中模拟致癌的多步骤过程，而无需产生和交叉育种多个品系。我们使用该模型来评估 RAS 异构体在条件性 Ink4a/Arf 缺失的情况下在黑色素瘤发生中的作用。将在多巴色素互变异构酶 (DCT) 启动子控制下的黑素细胞中特异表达 TVA 受体的小鼠与 Ink4a/Arflox/lox 小鼠杂交，并对新生的 DCT-TVA/Ink4a/Arflox/lox 小鼠注射含有激活的 KRAS、NRAS 和/或 Cre 重组酶的逆转录病毒。注射含有 KRAS 和 Cre 或单独 NRAS 的病毒的小鼠没有出现肿瘤；然而，注射 NRAS 和 Cre 病毒的 DCT-TVA/Ink4a/Arflox/lox 小鼠中，超过三分之一的小鼠出现黑色素瘤，而当 NRAS 和 Cre 表达相关时，三分之二的小鼠出现黑色素瘤。
We have developed a somatic cell gene delivery mouse model of melanoma that allows for the rapid validation of genetic alterations identified in this disease. A major advantage of this system is the ability to model the multi-step process of carcinogenesis in immune-competent mice without the generation and cross breeding of multiple strains. We have used this model to evaluate the role of RAS isoforms in melanoma initiation in the context of conditional Ink4a/Arf loss. Mice expressing the TVA receptor specifically in melanocytes under control of the dopachrome tautomerase (DCT) promoter were crossed to Ink4a/Arflox/lox mice and newborn DCT-TVA/Ink4a/Arflox/lox mice were injected with retroviruses containing activated KRAS, NRAS and/or Cre-recombinase. No mice injected with viruses containing KRAS and Cre or NRAS alone developed tumors; however, more than one-third of DCT-TVA/Ink4a/Arflox/lox mice injected with NRAS and Cre viruses developed melanoma and two-thirds developed melanoma when NRAS and Cre expression was linked.