Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis.
Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis.
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发表时间：
2003-08
期刊：
影响因子：
11.2
通讯作者：
Takashi Matsumoto;Jianghong Jiang;K. Kiguchi;L. Ruffino;S. Carbajal;L. Beltrán;D. Bol;M. P. Rosenberg;J. DiGiovanni
中科院分区：
文献类型：
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作者：
Takashi Matsumoto;Jianghong Jiang;K. Kiguchi;L. Ruffino;S. Carbajal;L. Beltrán;D. Bol;M. P. Rosenberg;J. DiGiovanni
在这项研究中，我们产生的转基因小鼠，过度表达无论是组成型活性的人c-src突变体（src（530））或野生型人c-src（src（wt））在表皮基底细胞驱动的人角蛋白14（HK 14）或牛角蛋白5（BK 5）启动子，分别。HK14.src（530）转基因小鼠出现严重的表皮增生和角化过度，并且不能存活超过3周龄。在注射具有可变表型的BK5.src（wt）构建体后获得四个转基因建立者，并建立三个品系（品系A-C）。BK5.src（wt）founder D表现出与HK14.src（530）转基因小鼠相似的严重皮肤表型，并在出生后5天死亡。C系转基因小鼠也表现出显著的表皮增生和角化过度，并在约3个月龄时开始发生自发性皮肤鳞状细胞癌（SCC）（1岁时发生率为70%）。来自品系A和B的小鼠未显示显著的表型;然而，品系B小鼠表皮中升高的人src（wt）蛋白是明显的。对B系转基因小鼠的其他分析显示，对12-O-十四烷酰佛波醇-13-乙酸酯诱导的表皮增生和细胞增殖的反应性增强。分析B系小鼠对两阶段皮肤癌发生的易感性发现，与非转基因同窝出生的小鼠相比，乳头状瘤和SCC出现得更早，数量更多。此外，恶性转化发生得更快，并且在B系转基因小鼠中发展的SCC具有更大的转移到外周淋巴结和其他器官的倾向。这些观察结果支持c-src在皮肤肿瘤促进中起重要作用的假设。此外，数据显示，在该模型系统中，升高的c-src活性增强恶性进展和转移。
In this study, we generated transgenic mice that overexpressed either a constitutively active human c-src mutant (src(530)) or a wild-type human c-src (src(wt)) in epidermal basal cells driven by human keratin 14 (HK14) or bovine keratin 5 (BK5) promoters, respectively. HK14.src(530) transgenic mice developed severe epidermal hyperplasia and hyperkeratosis, and did not survive beyond 3 weeks of age. Four transgenic founders were obtained after injection of a BK5.src(wt) construct with variable phenotypes, and three lines (lines A-C) were established. BK5.src(wt) founder D exhibited a severe skin phenotype similar to HK14.src(530) transgenic mice and died 5 days after birth. Line C transgenic mice also exhibited significant epidermal hyperplasia and hyperkeratosis, and developed spontaneous squamous cell carcinomas (SCCs) of the skin beginning at approximately 3 months of age (70% incidence at 1 year). Mice from lines A and B did not show a marked phenotype; however, elevated human src(wt) protein in the epidermis of line B mice was clearly evident. Additional analyses of line B transgenic mice showed an enhanced responsiveness to 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and cell proliferation. Analysis of the susceptibility of line B mice to two-stage skin carcinogenesis revealed that papillomas and SCCs arose earlier and in greater numbers compared with nontransgenic littermates. In addition, malignant conversion occurred more rapidly, and the SCCs that developed in line B transgenic mice had a greater propensity to metastasize to peripheral lymph nodes and other organs. These observations support the hypothesis that c-src plays an important role in skin tumor promotion. In addition, the data show that elevated c-src activity enhances malignant progression and metastasis in this model system.