Identification of ZYG11A as a candidate IGF1-dependent proto-oncogene in endometrial cancer.
Identification of ZYG11A as a candidate IGF1-dependent proto-oncogene in endometrial cancer.
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DOI：
10.18632/oncotarget.27055
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发表时间：
2019-07-09
期刊：
影响因子：
--
通讯作者：
Werner, Haim
中科院分区：
文献类型：
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作者：
Achlaug, Laris;Sarfstein, Rive;Werner, Haim
胰岛素样生长因子（IGF）在妇科癌症（包括子宫内膜肿瘤）的发展中起着关键作用。子宫浆液性癌（USC）是子宫内膜癌中一个明确的组织学分类。Laron综合征（LS）是一种由生长激素受体（GHR）基因突变引起的遗传性侏儒症，是先天性IGF1缺陷谱系下最具特征的实体。流行病学研究表明，LS患者不会患上癌症。最近对ls衍生淋巴母细胞进行的全基因组关联研究鉴定出一系列代谢基因，这些基因在这种情况下的过度表达可能与癌症保护有关。我们的分析鉴定了ZYG11A，一个潜在的细胞周期调节因子，作为IGF1作用的一个新的下游靶点。本研究旨在探讨IGF1和胰岛素对子宫内膜癌细胞ZYG11A基因表达的调控作用，并评估抑癌因子p53对ZYG11A基因表达和生物学作用的影响。使用usc衍生的表达野生型或突变型p53基因的细胞系，我们证明IGF1抑制含有野生型p53的细胞中ZYG11A mRNA和蛋白水平。另一方面，IGF1在表达p53的突变细胞中强烈刺激ZYG11A的表达。本文提供的数据将IGF1和p53信号通路与ZYG11A的作用联系起来。本研究在子宫内膜癌和其他类型癌症中的临床意义有待进一步研究。
The insulin-like growth factors (IGF) have a key role in the development of gynecological cancers, including endometrial tumors. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Laron syndrome (LS) is a genetic type of dwarfism that results from mutation of the growth hormone receptor (GHR) gene, and is the best characterized entity under the spectrum of the congenital IGF1 deficiencies. Epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide association studies conducted on LS-derived lymphoblastoid cells led to the identification of a series of metabolic genes whose over-representation in this condition might be linked to cancer protection. Our analyses led to the identification of ZYG11A, a potential cell cycle regulator, as a new downstream target for IGF1 action. The aim of the present paper was to investigate the regulation of ZYG11A gene expression by IGF1 and insulin in endometrial cancer cell lines and to assess the impact of tumor suppressor p53 on ZYG11A expression and biological action. Using USC-derived cell lines expressing a wild type or a mutant p53 gene, we demonstrate that IGF1 inhibited ZYG11A mRNA and protein levels in cells containing a wild type p53. On the other hand, IGF1 potently stimulated ZYG11A expression in mutant p53-expressing cells. Data presented here links the IGF1 and p53 signaling pathways with ZYG11A action. The clinical implications of the present study in endometrial and other types of cancer must be further investigated.