IRX2调控雌激素受体表达在子宫内膜癌中的作用及分子机制

Endometrial cancer is one of the most common malignancies of the female reproductive system. It is known that the pathogenesis of endometrial cancer is related to estrogen and estrogen receptor, but the concrete mechanism is not quite clear yet. Both screening in the GEO database and testing on RNA and protein level showed significant difference in IRX2 expression between normal endometrial tissues and endometrial cancer tissues, which suggest that IRX2 may play a role in endometrial cancer. More detailed studies showed that over expression of IRX2 can up-regulate the expression of estrogen receptor and inhibit the proliferation and invasion of cancer cells. So we pose the hypothesis that 'IRX2 plays a role in endometrial cancer by regulating estrogen receptor'. In order to test and verify it, we will use tissue chip, CCK-8, transwell, flow cytometry, scratch test, and so on. to test the effect of IRX2 on the biological behavior of endometrial cancer. We will use luciferase report system and chromatin immunoprecipitation to study the regulating mechanism of IRX2 on the estrogen receptor in endometrial cancer. And we will use in vivo experiments to confirm the effect of IRX2 on tumorigenicity and metastasis. The completing of our project will provide new basis for the targeted therapy of endometrial cancer and new ideas for clarifying the pathogenetic mechanism of endometrial cancer.

子宫内膜癌是女性生殖系统中最常见的恶性肿瘤之一，其发病与雌激素及其受体相关，但具体机制尚未完全明确。经GEO数据库筛选及在RNA和蛋白水平进行验证，我们发现IRX2在正常子宫内膜与内膜癌组织中的表达差异显著，提示IRX2可能在子宫内膜癌中发挥作用。进一步研究结果显示过表达IRX2可抑制内膜癌增殖和侵袭，并上调雌激素受体(ER)表达，提示IRX2可能通过调控ER表达在子宫内膜癌中发挥作用。于是我们提出假设"IRX2通过调控雌激素受体在子宫内膜癌中发挥作用"。为验证该假说，我们将采用组织芯片、CCK-8、transwell、流式细胞仪、划痕实验等检测IRX2对内膜癌细胞生物学行为的影响；采用荧光素酶报告系统、染色质免疫共沉淀研究IRX2对ER的调控机制；采用体内实验验证IRX2对内膜癌成瘤及转移的影响。本课题的完成为子宫内膜癌靶向治疗提供依据，为阐明内膜癌发病机制提供新思路。

子宫内膜癌是女性生殖系统中最常见的恶性肿瘤之一，但发病机制尚未完全明确。手术是治疗早期内膜癌患者的有效方式。但是，晚期或复发的内膜癌患者则预后不佳。因此，探究子宫内膜癌的发病机制、早期发现及预防是改善子宫内膜癌预后的重要议题。.经GEO数据库筛选并在RNA及蛋白水平进行验证，我们发现，与正常子宫内膜相比，IRX2在子宫内膜癌组织中表达显著下调，提示IRX2可能在子宫内膜癌中发挥作用。进一步地对IRX2在子宫内膜癌中的功能进行探究，发现过表达IRX2可抑制内膜癌细胞增殖和侵袭， 裸鼠移植瘤模型表明，过表达IRX2后，子宫内膜癌细胞的成瘤能力显著下调。以上体内外实验表明IRX2在子宫内膜癌中发挥抑癌基因的作用。进一步地，我们对IRX2在子宫内膜癌中下调地机制进行探究发现，IRX2的表达水平与其甲基化水平呈正相关。去甲基化药物DAC可显著上调IRX2的表达。进而，我们对IRX2发挥抑癌功能的机制进行探究，经过GSEA分析并WB验证，IRX2通过调控PI3K-AKT-MYC轴参与子宫内膜癌的形成。.本课题的完成为子宫内膜癌的靶向治疗提供理论依据，为阐明内膜癌发病机制提供新思路。