Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog
Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog
复制标题
DOI：
10.1038/nm0797-788
复制
发表时间：
1997-07-01
期刊：
影响因子：
82.9
通讯作者：
Khavari, PA
中科院分区：
文献类型：
--
作者：
Fan, HR;Oro, AE;Khavari, PA
刺猬（HH）信号蛋白在动物发育过程中调节诱导事件（1 - 11）。唯一已知的HH受体基因——斑点（PTC）的突变最近被认为与最常见的人类癌症——基底细胞癌（BCC）的遗传型和散发型有关（12 - 14）。在果蝇中，HH通过使PTC功能失活而起作用（1，3），这增加了一种可能性，即人表皮中刺猬索尼克（SHH）的过度表达可能具有等同于PTC功能缺失的致瘤效应。我们利用逆转录病毒转导正常人角质形成细胞以组成性表达SHH。表达SHH的细胞显示已知的HH靶标BMP - 2B以及bcl - 2的表达增加，bcl - 2是一种在基底细胞癌中的角质形成细胞显著表达的蛋白质。然后将这些角质形成细胞用于在免疫缺陷小鼠上再生由长末端重复序列驱动的SHH（LTR - SHH）转基因的人皮肤。LTR - SHH人皮肤始终显示出在基底细胞癌中所见的异常特异性组织学特征，包括上皮芽向下生长进入真皮、基底细胞栅栏状排列以及表皮与下方真皮的分离。此外，LTR - SHH皮肤显示出先前针对人基底细胞癌所描述的基因表达异常，包括BP180/BPAG2和层粘连蛋白5黏附蛋白减少以及基底表皮角蛋白的表达。这些数据表明，SHH在人皮肤中的表达在体内重现了人基底细胞癌的特征，提示这条保守的信号通路的激活有助于上皮肿瘤的发展，并描述了一种新的肿瘤转基因人组织模型。
Hedgehog (HH) signaling proteins mediate inductive events during animal development(1-11). Mutation of the only known HH receptor gene, Patched (PTC) has recently been implicated in inherited and sporadic forms of the most common human cancer, basal cell carcinoma (BCC)(12-14). In Drosophila, HH acts by inactivating PTC function(1,3), raising the possibility that overexpression of Sonic Hedgehog (SHH) in human epidermis might have a tumorigenic effect equivalent to loss of PTC function. We used retroviral transduction of normal human keratinocytes to constitutively express SHH. SHH-expressing cells demonstrated increased expression of both the known HH target, BMP-2B, as well as bcl-2, a protein prominently expressed by keratinocytes in BCCs. These keratinocytes were then used to regenerate human skin transgenic for long terminal repeat-driven SHH (LTR-SHH) on immune-deficient mice. LTR-SHH human skin consistently displays the abnormal specific histologic features seen in BCCs, including downgrowth of epithelial buds into the dermis, basal cell palisading and separation of epidermis from the underlying dermis. In addition, LTR-SHH skin displays the gene expression abnormalities previously described for human BCCs, including decreased BP180/BPAG2 and laminin 5 adhesion proteins and expression of basal epidermal keratins. These data indicate that expression of SHH in human skin recapitulates features of human BCC in vivo, suggest that activation of this conserved signaling pathway contributes to the development of epithelial neoplasia and describe a new transgenic human tissue model of neoplasia.