A role of PDGFRalpha in basal cell carcinoma proliferation.
A role of PDGFRalpha in basal cell carcinoma proliferation.
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PDGFRα 在基底细胞癌增殖中的作用。
DOI：
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发表时间：
2001
影响因子：
11.1
通讯作者：
F. McCormick
中科院分区：
文献类型：
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作者：
J. Xie;M. Aszterbaum;X. Zhang;J. Bonifas;C. Zachary;E. Epstein;F. McCormick
由于 patched 缺失 (PTC) 或 smoothened 激活 (SMO)，hedgehog 通路的激活经常发生在最常见的人类癌症基底细胞癌 (BCC) 中。然而，这种肿瘤效应的分子基础尚不清楚。已知下游分子 Gli1 介导该途径的生物效应，并且其本身在所有 BCC 中上调。当 Gli1 在表皮中过度表达时，可以驱动小鼠 BCC 的产生。在这里，我们证明 Gli1 可以激活 C3H10T(1/2) 细胞中的血小板源性生长因子受体 α (PDGFRα)。 Gli1 对 PDGFRα 的功能性上调伴随着 ras-ERK 通路的激活，该通路与细胞增殖相关。 PDGFRα 在小鼠和人类 BCC 中的高水平表达支持了这种机制在体内的相关性。在小鼠 BCC 细胞系 ASZ001 中，PTC 基因的两个拷贝均失活，可以通过重新表达 PTC（下调 PDGFRα 表达）或通过中和抗体下游抑制 PDGFRα 来减慢 DNA 合成和细胞增殖。因此，我们得出结论，PDGFRα表达增加可能是hedgehog通路突变导致BCC的重要机制。
Activation of the hedgehog pathway, through the loss of patched (PTC) or the activation of smoothened (SMO), occurs frequently in basal cell carcinoma (BCC), the most common human cancer. However, the molecular basis of this neoplastic effect is not understood. The downstream molecule Gli1 is known to mediate the biological effect of the pathway and is itself up-regulated in all BCCs. Gli1 can drive the production of BCCs in the mouse when overexpressed in the epidermis. Here we show that Gli1 can activate platelet-derived growth factor receptor alpha (PDGFRalpha) in C3H10T(1/2) cells. Functional up-regulation of PDGFRalpha by Gli1 is accompanied by activation of the ras-ERK pathway, a pathway associated with cell proliferation. The relevance of this mechanism in vivo is supported by a high level expression of PDGFRalpha in BCCs of mice and humans. In the murine BCC cell line ASZ001, in which both copies of the PTC gene are inactivated, DNA synthesis and cell proliferation can be slowed by re-expression of PTC, which down-regulates PDGFRalpha expression, or by downstream inhibition of PDGFRalpha with neutralizing antibodies. Therefore, we conclude that increased expression of PDGFRalpha may be an important mechanism by which mutations in the hedgehog pathway cause BCCs.