Kita driven expression of oncogenic HRAS leads to early onset and highly penetrant melanoma in zebrafish.
Kita driven expression of oncogenic HRAS leads to early onset and highly penetrant melanoma in zebrafish.
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DOI：
10.1371/journal.pone.0015170
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发表时间：
2010-12-10
期刊：
影响因子：
3.7
通讯作者：
Mione M
中科院分区：
文献类型：
--
作者：
Santoriello C;Gennaro E;Anelli V;Distel M;Kelly A;Köster RW;Hurlstone A;Mione M
黑色素瘤是最具侵略性和致命性的皮肤癌。由于黑色素瘤的发病率和高致死率的增加，需要用于连续观察黑色素瘤形成和进展以及用于测试药理学药剂的动物模型。使用组合Gal4-UAS系统，我们已经开发了一个斑马鱼转基因株系，其在kita启动子下表达致癌HRAS。在第3天，转基因kita-GFP-RAS幼虫已经显示出色素沉着过度表型，作为异常黑素细胞生长的最早证据。到2 - 4周时，在大多数kita-GFP-RAS转基因鱼的尾柄中形成大量转化的黑素细胞。在1 - 3个月龄之间明显的成人肿瘤忠实地再现了人黑色素瘤的免疫学、组织学和分子表型，但在浓缩的时间线上。此外，它们显示出可移植性，依赖于mitfa表达，并且不需要肿瘤抑制因子的额外突变。与有效发展黑素瘤的表达kita的黑素细胞祖细胞相比，在三个月的观察期内，第二Gal4-驱动系中表达mitfa的祖细胞在发展黑素瘤方面的效率低4倍。这表明，斑马鱼kita启动子是一个强大的工具，用于驱动癌基因在正确的细胞中表达，并在正确的水平，以诱导早发性黑色素瘤的肿瘤抑制剂的存在。因此，我们的斑马鱼模型提供了表达kita的黑素细胞祖细胞和黑色素瘤之间的联系，并提供了适合于大规模药物和遗传修饰剂筛选的幼虫表型的优势。
Melanoma is the most aggressive and lethal form of skin cancer. Because of the increasing incidence and high lethality of melanoma, animal models for continuously observing melanoma formation and progression as well as for testing pharmacological agents are needed. Using the combinatorial Gal4 –UAS system, we have developed a zebrafish transgenic line that expresses oncogenic HRAS under the kita promoter. Already at 3 days transgenic kita-GFP-RAS larvae show a hyper-pigmentation phenotype as earliest evidence of abnormal melanocyte growth. By 2–4 weeks, masses of transformed melanocytes form in the tail stalk of the majority of kita-GFP-RAS transgenic fish. The adult tumors evident between 1–3 months of age faithfully reproduce the immunological, histological and molecular phenotypes of human melanoma, but on a condensed time-line. Furthermore, they show transplantability, dependence on mitfa expression and do not require additional mutations in tumor suppressors. In contrast to kita expressing melanocyte progenitors that efficiently develop melanoma, mitfa expressing progenitors in a second Gal4-driver line were 4 times less efficient in developing melanoma during the three months observation period. This indicates that zebrafish kita promoter is a powerful tool for driving oncogene expression in the right cells and at the right level to induce early onset melanoma in the presence of tumor suppressors. Thus our zebrafish model provides a link between kita expressing melanocyte progenitors and melanoma and offers the advantage of a larval phenotype suitable for large scale drug and genetic modifier screens.
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影响因子：
--
作者：
Bevona, C;Goggins, W;Tsao, H
通讯作者：
Tsao, H
影响因子：
3.6
作者：
Knudson, AG
通讯作者：
Knudson, AG
影响因子：
2
作者：
Anelli, Viviana;Santoriello, Cristina;Mione, Marina
通讯作者：
Mione, Marina
DOI：
10.1073/pnas.97.21.11403
发表时间：
2000-10-10
影响因子：
11.1
作者：
Kawakami, K;Shima, A;Kawakami, N
通讯作者：
Kawakami, N
影响因子：
6.4
作者：
Ashida, Atsuko;Takata, Minoru;Saida, Toshiaki
通讯作者：
Saida, Toshiaki