ZIC1 overexpression is oncogenic in liposarcoma.
ZIC1 overexpression is oncogenic in liposarcoma.
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DOI：
10.1158/0008-5472.can-10-0745
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发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Singer S
中科院分区：
文献类型：
--
作者：
Brill E;Gobble R;Angeles C;Lagos-Quintana M;Crago A;Laxa B;Decarolis P;Zhang L;Antonescu C;Socci ND;Taylor BS;Sander C;Koff A;Singer S
脂肪肉瘤是一种侵袭性间叶性癌症，预后较差，表现出显着的组织学多样性，有五种公认的亚型。目前，脂肪肉瘤的主要治疗方法是手术切除，因为脂肪肉瘤通常对传统化疗有抵抗力。鉴于与脂肪肉瘤相关的高死亡率和缺乏有效的全身治疗，我们寻找驱动脂肪肉瘤发生的新基因组改变，这些改变可能作为治疗靶点。 ZIC1 是神经元发育的关键转录因子，与正常脂肪相比，在所有五种脂肪肉瘤亚型中以及与脂肪源性干细胞 (ASC) 相比，在脂肪肉瘤细胞系中均过度表达。在这里，我们表明 ZIC1 有助于脂肪肉瘤的发病机制。 ZIC1 敲低可抑制去分化和粘液样/圆形细胞脂肪肉瘤细胞系的增殖、减少侵袭并诱导细胞凋亡，但在 ASC 或低 ZIC1 表达的肺癌细胞系中则不然。 ZIC1 敲低与 p27 蛋白核表达增加以及促生存靶基因 BCL2L13、JunD、Fam57A 和 EIF3M 的下调相关。我们的结果表明，ZIC1 表达对于脂肪肉瘤发生至关重要，针对 ZIC1 或其下游靶点可能会带来脂肪肉瘤的新疗法。
Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity, with five recognized subtypes. Currently, the mainstay of therapy for liposarcoma is surgical excision since liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of liposarcoma compared with normal fat and in liposarcoma cell lines compared with adipose-derived stem cells (ASC). Here we show that ZIC1 contributes to the pathogenesis of liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round cell liposarcoma cell lines, but not in either ASC or a lung cancer cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 protein, and the down-regulation of pro-survival target genes: BCL2L13, JunD, Fam57A, and EIF3M. Our results demonstrate that ZIC1 expression is essential for liposarcomagenesis and that targeting ZIC1 or its downstream targets may lead to novel therapy for liposarcoma.