Mesenchymal-epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas
Mesenchymal-epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas
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DOI：
10.1073/pnas.0712397105
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发表时间：
2008-03-04
影响因子：
11.1
通讯作者：
Darling, Thomas N.
中科院分区：
文献类型：
--
作者：
Li, Shaowei;Takeuchi, Fumiko;Darling, Thomas N.
结节性硬化症（TSC）患者发生含有TSC1或TSC2双等位基因失活突变的错构瘤，导致哺乳动物雷帕霉素靶点（mTOR）激活。错构瘤在TSC皮肤中过度生长上皮和间充质细胞。这些变化的发病机制尚未被研究。双等位基因突变细胞（“双击”细胞）的存在或位置尚不清楚。我们将TSC皮肤错构瘤（血管纤维瘤和趾周纤维瘤）与同一患者的正常皮肤进行比较，我们观察到错构瘤表皮中更多的增殖和mTOR激活。表皮未见双击细胞。然而，真皮中的成纤维细胞样细胞在新鲜肿瘤样品的接触制剂和从TSC皮肤肿瘤中生长的细胞中都表现出TSC2的等位基因缺失，这表明表皮增殖和mTOR激活的增加不是由角化细胞的二次撞击突变引起的，而是由间充质-上皮细胞相互作用引起的。用于鉴定间充质细胞释放的潜在旁分泌因子的基因表达阵列显示，与来自同一患者正常皮肤的成纤维细胞相比，成纤维细胞样血管纤维瘤和趾周纤维瘤细胞中有更多的表调节蛋白mRNA。real-time PCR检测表调节蛋白mRNA表达水平升高，免疫沉淀检测表调节蛋白表达水平升高。表调节蛋白在体外刺激角化细胞增殖和核糖体蛋白S6磷酸化。这些结果表明，错构瘤性TSC皮肤肿瘤是由真皮中二次撞击细胞释放的旁分泌因子诱导的，而上覆表皮的mTOR活化增殖是表调节蛋白的作用。
Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the. existence or location of cells with biallelic mutations ("two-hit" cells) was unclear. We compared TSC skin hamartomas (angiofibromas and periungual fibromas) with normal-appearing skin of the same patient, and we observed more proliferation and mTOR activation in hamartoma epidermis. Two-hit cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal-epithelia l interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed with real-time PCR, and increased amounts of epiregulin protein were demonstrated with immunoprecipitation. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by two-hit cells in the dermis and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin.