Achlaug Laris, Sarfstein Rive, Nagaraj Karthik, Lapkina-Gendler Lena, Bruchim Ilan, Dixit Manisha, Laron Zvi, Yakar Shoshana, Werner Haim
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Gynecologic Oncology Division, Hillel Yaffe Medical Center, Affiliated with the Technion Institute of Technology, Haifa, Hadera 38100, Israel.
Oncotarget. 2019 Jul 9;10(43):4437-4448. doi: 10.18632/oncotarget.27055.
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 () 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 , 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 gene expression by IGF1 and insulin in endometrial cancer cell lines and to assess the impact of tumor suppressor p53 on expression and biological action. Using USC-derived cell lines expressing a wild type or a mutant p53 gene, we demonstrate that IGF1 inhibited mRNA and protein levels in cells containing a wild type . 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.
胰岛素样生长因子（IGF）在包括子宫内膜肿瘤在内的妇科癌症发展中起关键作用。子宫浆液性癌（USC）是子宫内膜癌中一种明确的组织学类型。拉伦综合征（LS）是一种由生长激素受体（）基因突变导致的遗传性侏儒症，是先天性IGF1缺乏症谱系中特征最明显的实体。流行病学研究表明，LS患者对癌症发展具有抵抗力。最近对源自LS的淋巴母细胞进行的全基因组关联研究导致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。我们的分析导致鉴定出一种潜在的细胞周期调节因子作为IGF1作用的新下游靶点。本文的目的是研究IGF1和胰岛素对子宫内膜癌细胞系中基因表达的调节，并评估肿瘤抑制因子p53对表达和生物学作用的影响。使用表达野生型或突变型p53基因的源自USC的细胞系，我们证明IGF1抑制含有野生型的细胞中的mRNA和蛋白质水平。另一方面，IGF1强烈刺激表达突变型p53的细胞中的ZYG11A表达。此处提供的数据将IGF1和p53信号通路与ZYG11A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必须进一步研究。
