Stove Christophe, Stove Veronique, Derycke Lara, Van Marck Veerle, Mareel Marc, Bracke Marc
Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Ghent, Belgium.
J Invest Dermatol. 2003 Oct;121(4):802-12. doi: 10.1046/j.1523-1747.2003.12522.x.
In a screening for new growth factors released by melanoma cells, we found that the p185-phosphorylating capacity of a medium conditioned by a melanoma cell line was due to the secretion of heregulin, a ligand for the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Expression of heregulin, including a new isoform, and secretion of functionally active protein was found in several cell lines. Receptor activation by heregulin, either autocrine or paracrine, resulted in a potent growth stimulation of both melanocytes and melanoma cells. Heregulin receptor HER3 and coreceptor HER2 were the main receptors expressed by these cells. Nevertheless, none of the cell lines in our panel overexpressed HER2 or HER3. In contrast, loss of HER3 was found in two cell lines, whereas one cell line showed loss of functional HER2, both types of deregulations resulting in unresponsiveness to heregulin. This implies the heregulin/HER system as a possible important physiologic growth regulatory system in melanocytes in which multiple deregulations may occur during progression toward melanoma, all resulting in, or indicating, growth factor independence.
在一项对黑色素瘤细胞释放的新型生长因子的筛选中，我们发现一种黑色素瘤细胞系条件培养基的p185磷酸化能力归因于神经调节蛋白的分泌，神经调节蛋白是人类表皮生长因子受体（HER）家族受体酪氨酸激酶的一种配体。在几种细胞系中发现了神经调节蛋白的表达，包括一种新的异构体，以及功能活性蛋白的分泌。神经调节蛋白通过自分泌或旁分泌激活受体，导致黑色素细胞和黑色素瘤细胞均受到强力的生长刺激。神经调节蛋白受体HER3和共受体HER2是这些细胞表达的主要受体。然而，我们研究小组中的细胞系均未过表达HER2或HER3。相反，在两个细胞系中发现了HER3的缺失，而一个细胞系显示功能性HER2缺失，这两种失调类型均导致对神经调节蛋白无反应。这意味着神经调节蛋白/HER系统可能是黑色素细胞中一个重要的生理生长调节系统，在向黑色素瘤进展的过程中可能会发生多种失调，所有这些失调都会导致或表明生长因子非依赖性。
