Suppression of EGFRvIII-mediated proliferation and tumorigenesis of breast cancer cells by ribozyme
Suppression of EGFRvIII-mediated proliferation and tumorigenesis of breast cancer cells by ribozyme
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DOI：
10.1002/ijc.11007
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发表时间：
2003-05-10
影响因子：
6.4
通讯作者：
Tang, CK
中科院分区：
文献类型：
--
作者：
Luo, XY;Gong, XQ;Tang, CK
EGFRvIII 是表皮生长因子受体的肿瘤特异性、配体独立性、组成型活性变体。已在包括乳腺癌在内的许多人类恶性肿瘤中检测到其表达。然而，在成人组织（包括正常乳腺组织）中尚未观察到可检测水平的 EGFRvIII。 EGFRvIII 的这些独特特征使其成为生物疗法的绝佳靶标。我们设计并生成了一种针对 EGFRvIII 的肿瘤特异性核酶。这种特定的 EGFRvIII 核酶能够在无细胞系统的生理条件下有效切割 EGFRvIII mRNA，但不会切割野生型 EGFR 和其他 EGF 家族受体。当在乳腺癌细胞中表达这种 EGFRvIII-核酶时，EGFRvIII-核酶能够在 mRNA 和蛋白质水平下调内源 EGFRvIII 表达。在 EGFRvIII-核酶转染子中观察到增殖的抑制。此外，乳腺癌细胞中EGFRvIII的下调显着抑制了无胸腺裸鼠的肿瘤生长。此外，这种核酶对EGF家族受体表达或乳腺癌细胞的增殖没有影响，乳腺癌细胞不表达EGFRvIII，但表达野生型EGFR和其他EGF家族受体。这些结果表明我们已经生成了一种肿瘤特异性、具有生物学功能的核酶，并进一步证明 EGFRvIII 在乳腺癌细胞增殖中发挥着重要作用。这种方法的最终目标是通过专门针对该受体来为乳腺癌提供潜在的治疗方法。 (C) 2003 Wiley-Liss, Inc.
EGFRvIII is a tumor specific, ligand-independent, constitutively active variant of the epidermal growth factor receptor. Its expression has been detected in many human malignancies including breast cancer. No detectable level of EGFRvIII has, however, been observed in adult tissues, including normal breast tissues. These unique features of the EGFRvIII make it an excellent target for biologically based therapies. We have designed and generated a tumor specific ribozyme targeted to EGFRvIII. This specific EGFRvIII ribozyme is able to effectively cleave EGFRvIII mRNA under physiological conditions in a cell-free system, but does not cleave wild-type EGFR and other EGF-family receptors. While expressing this EGFRvIII-ribozyme in breast cancer cells, EGFRvIII-ribozyme is capable of downregulating endogenous EGFRvIII expression at the mRNA and protein levels. Inhibition of proliferation was observed in EGFRvIII-ribozyme transfectants. In addition, downregulation of EGFRvIII in breast cancer cells significantly inhibited tumor growth in athymic nude mice. Furthermore, this ribozyme has no effect on EGF-family receptor expression or the proliferation of breast cancer cells, which do not express EGFRvIII but express wildtype EGFR and other EGF-family receptors. These results suggest that we have generated a tumor-specific, biologically functional ribozyme and further demonstrate that EGFRvIII plays a significant role in breast cancer cell proliferation. The ultimate goal of this approach is to provide a potential treatment for breast cancer by specifically targeting this receptor. (C) 2003 Wiley-Liss, Inc.