Molecular Characterization of Patched-associated Rhabdomyosarcoma by Conditional Gene Targeting

Gorlin综合征是一种常染色体显性遗传病，其特征是发育缺陷与肿瘤形成易感性的结合，是由果蝇片段极性基因补丁（PTCH）人类同源物的种系突变引起的。Ptch1突变小鼠自发发展横纹肌肉瘤（RMS）依赖于遗传背景。CD-1背景突变小鼠对RMS敏感，而C57BL/6背景突变小鼠对RMS不敏感。Ptch1的下游信号伙伴Gli1在所有分析的RMSs中都过表达，这表明异常的Sonic Hedgehog/Patched （Shh）信号通路在与该综合征相关的各种肿瘤中应该是常见的。胰岛素样生长因子2 （Igf2）也过表达，提示Shh和Igf2通路在肿瘤发生过程中存在交叉对话。然而，RMS的发生和发展背后的遗传和分子病变在很大程度上仍然是未知的。在这项研究中，我们通过RT-PCR、实时PCR分析比较了RMS与正常骨骼肌的分子谱。我们的结果为RMS的分子分类提供了第一步。

Gorlin syndrome, which is an autosomal dominant disorder characterized by a combination of developmental defects with a predisposition to tumor formation, is cause by germline mutations of the human homolog of the drosophila segment polarity gene patched (PTCH). The Ptch1 mutant mice spontaneously develop rhabdomyosarcoma (RMS) dependent on the genetic background. The mutant mice on CD-1 background, but not C57BL/6 one, were sensitive to RMS. The downstream signaling partner of Ptch1,Gli1 was overexpressed in all RMSs analyzed, indicating that abnormal Sonic Hedgehog/Patched (Shh) signaling pathway should be common for the various tumors associated with this syndrome. Insulin-like growth factor 2 (Igf2) was also overexpressed, suggesting cross-talk between Shh and Igf2 pathways in tumorigenesis. However, the genetic and molecular lesions of RMS underlying its genesis and progression remain largely unknown. In this study we have compared the molecular profiles of RMS versus normal skeletal muscle by RT-PCR, real time PCR analysis. Our results provide a first step towards a molecular classification of RMS.