Di Marcotullio Lucia, Ferretti Elisabetta, De Smaele Enrico, Argenti Beatrice, Mincione Claudia, Zazzeroni Francesca, Gallo Rita, Masuelli Laura, Napolitano Maddalena, Maroder Marella, Modesti Andrea, Giangaspero Felice, Screpanti Isabella, Alesse Edoardo, Gulino Alberto
Department of Experimental Medicine and Pathology, University La Sapienza, 324 Viale Regina Elena, 00161 Rome, Italy.
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10833-8. doi: 10.1073/pnas.0400690101. Epub 2004 Jul 12.
Hedgehog signaling is suggested to be a major oncogenic pathway in medulloblastoma, which arises from aberrant development of cerebellar granule progenitors. Allelic loss of chromosome 17p has also been described as the most frequent genetic defect in this human neoplasia. This observation raises the question of a possible interplay between 17p deletion and the Hedgehog tumorigenic pathway. Here, we identify the human orthologue of mouse REN(KCTD11), previously reported to be expressed in differentiating and low proliferating neuroblasts. Human REN(KCTD11) maps to 17p13.2 and displays allelic deletion as well as significantly reduced expression in medulloblastoma. REN(KCTD11) inhibits medulloblastoma cell proliferation and colony formation in vitro and suppresses xenograft tumor growth in vivo. REN(KCTD11) seems to inhibit medulloblastoma growth by negatively regulating the Hedgehog pathway because it antagonizes the Gli-mediated transactivation of Hedgehog target genes, by affecting Gli1 nuclear transfer, and its growth inhibitory activity is impaired by Gli1 inactivation. Therefore, we identify REN(KCTD11) as a suppressor of Hedgehog signaling and suggest that its inactivation might lead to a deregulation of the tumor-promoting Hedgehog pathway in medulloblastoma.
刺猬信号通路被认为是髓母细胞瘤中的主要致癌途径，髓母细胞瘤源于小脑颗粒祖细胞的异常发育。17号染色体短臂（17p）的等位基因缺失也被描述为这种人类肿瘤中最常见的基因缺陷。这一观察结果引发了17p缺失与刺猬肿瘤发生途径之间可能存在相互作用的问题。在这里，我们鉴定出小鼠REN（KCTD11）的人类同源物，此前报道该基因在分化和低增殖的神经母细胞中表达。人类REN（KCTD11）定位于17p13.2，在髓母细胞瘤中显示出等位基因缺失以及表达显著降低。REN（KCTD11）在体外抑制髓母细胞瘤细胞增殖和集落形成，并在体内抑制异种移植肿瘤生长。REN（KCTD11）似乎通过负向调节刺猬信号通路来抑制髓母细胞瘤生长，因为它通过影响Gli1核转运拮抗Gli介导的刺猬靶基因的反式激活，并且其生长抑制活性因Gli1失活而受损。因此，我们将REN（KCTD11）鉴定为刺猬信号通路的抑制剂，并表明其失活可能导致髓母细胞瘤中促进肿瘤的刺猬信号通路失调。
