Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation.
Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation.
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DOI：
10.1158/0008-5472.1007.65.3
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发表时间：
2005-02
期刊：
影响因子：
11.2
通讯作者：
Z. Lou;S. O'Reilly;Hongyan Liang;V. Maher;S. Sleight;J. Mccormick
中科院分区：
文献类型：
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作者：
Z. Lou;S. O'Reilly;Hongyan Liang;V. Maher;S. Sleight;J. Mccormick
Sp1 是许多基因的转录因子，包括参与肿瘤发生的基因。我们发现，在培养物中通过致癌物或稳定转染癌基因进行恶性转化的人成纤维细胞表达 Sp1 的水平比其亲本细胞高 8 倍至 18 倍。这些细胞系在无胸腺小鼠中形成纤维肉瘤，潜伏期非常短，并且来自肿瘤的细胞表达相同高水平的 Sp1。在所测试的源自患者的纤维肉瘤细胞系以及这些细胞系在无胸腺小鼠中形成的肿瘤中也发现了类似的高水平 Sp1。为了研究 Sp1 过度表达在人类成纤维细胞恶性转化中的作用，我们将 Sp1 U1snRNA/核酶转染到两种人类细胞系中，并转染到患者来源的纤维肉瘤细胞系中，这两种细胞系在培养物中因致癌物或癌基因过度表达而发生恶性转化。这些转染细胞系中 Sp1 的表达水平降低至接近正常。细胞恢复了纺锤形形态，并表现出凋亡增加和与癌症相关的几种基因的表达减少，即上皮生长因子受体、尿激酶纤溶酶原激活物、尿激酶纤溶酶原激活物受体和血管内皮生长因子。当注射到无胸腺小鼠体内时，这些 Sp1 水平接近正常的细胞系未能形成肿瘤，或者仅以大大降低的频率和更长的潜伏期形成肿瘤。这些数据表明，Sp1 的过度表达在人类成纤维细胞的恶性转化中起着因果作用，并表明对于其过度表达的癌症，Sp1 构成了治疗靶点。
Sp1 is a transcription factor for many genes, including genes involved in tumorigenesis. We found that human fibroblast cells malignantly transformed in culture by a carcinogen or by stable transfection of an oncogene express Sp1 at 8-fold to 18-fold higher levels than their parental cells. These cell lines form fibrosarcomas in athymic mice with a very short latency, and the cells from the tumors express the same high levels of Sp1. Similar high levels of Sp1 were found in the patient-derived fibrosarcoma cell lines tested, and in the tumors formed in athymic mice by these cell lines. To investigate the role of overexpression of Sp1 in malignant transformation of human fibroblasts, we transfected an Sp1 U1snRNA/Ribozyme into two human cell lines, malignantly transformed in culture by a carcinogen or overexpression of an oncogene, and into a patient-derived fibrosarcoma cell line. The level of expression of Sp1 in these transfected cell lines was reduced to near normal. The cells regained the spindle-shaped morphology and exhibited increased apoptosis and decreased expression of several genes linked to cancer, i.e., epithelial growth factor receptor, urokinase plasminogen activator, urokinase plasminogen activator receptor, and vascular endothelial growth factor. When injected into athymic mice, these cell lines with near normal levels of Sp1 failed to form tumors or did so only at a greatly reduced frequency and with a much longer latency. These data indicate that overexpression of Sp1 plays a causal role in malignant transformation of human fibroblasts and suggest that for cancers in which it is overexpressed, Sp1 constitutes a target for therapy.