GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis
GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis
复制标题
DOI：
10.1677/erc-10-0041
复制
发表时间：
2010-09-01
影响因子：
3.9
通讯作者：
Heikinheimo, Markku
中科院分区：
文献类型：
--
作者：
Kyronlahti, Antti;Kauppinen, Marjut;Heikinheimo, Markku
颗粒细胞凋亡的干扰与人类颗粒细胞肿瘤（GCT）的发病机制有关。肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 是一种有效的细胞因子，可在多种恶性肿瘤中诱导细胞凋亡，而对良性细胞没有毒性作用。本研究的目的是研究 TRAIL 受体 DR4 和 DR5 在人类 GCT 中的表达和功能。此外，我们还研究了 GATA4（一种在正常和恶性颗粒细胞中表达的转录因子）在 TRAIL 诱导的 GCT 细胞凋亡中的作用。为此，对 80 个原代 GCT 和 12 个复发 GCT 的组织微阵列进行 DR4 和 DR5 的免疫组织化学分析，并利用新鲜分离的原代 GCT 培养物来评估 TRAIL 对 GCT 细胞的功能影响。为了阐明 GATA4 在调节 TRAIL 诱导的细胞凋亡中的作用，用表达针对 GATA4 的小发夹 RNA 的慢病毒载体转导人 GCT 衍生细胞系 (KGN)，或用表达野生型或显性失活突变体 GATA4 的腺病毒转染。我们发现受体 DR4 和 DR5 在绝大多数 GCT 以及原代 GCT 培养物中表达，并且 TRAIL 在原代 GCT 培养物中诱导细胞凋亡。此外，我们发现过表达 GATA4 可以在体外保护 GCT 免受 TRAIL 诱导的细胞凋亡，而破坏 GATA4 功能会诱导细胞凋亡并增强 TRAIL 给药的细胞凋亡作用。我们的结果表明 TRAIL 通路在 GCT 细胞中发挥作用，并表明转录因子 GATA4 可能作为这种卵巢恶性肿瘤的生存因子。内分泌相关癌症（2010）17 709-717
Disturbances in granulosa cell apoptosis have been implicated in the pathogenesis of human granulosa cell tumors (GCTs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cytokine that induces apoptosis in a variety of malignancies without toxic effects on benign cells. The aim of this study was to investigate the expression and functionality of the TRAIL receptors DR4 and DR5 in human GCTs. Additionally, we examined the role of GATA4, a transcription factor expressed in normal and malignant granulosa cells, in TRAIL-induced GCT apoptosis. For this purpose, a tissue microarray of 80 primary and 12 recurrent GCTs was subjected to immunohistochemistry for DR4 and DR5, and freshly isolated primary GCT cultures were utilized to evaluate the functional effects of TRAIL on GCT cells. To clarify the role of GATA4 in the regulation of TRAIL-induced apoptosis, a human GCT-derived cell line (KGN) was transduced with lentiviral vectors expressing small hairpin RNAs targeting GATA4 or transfected with adenovirus expressing either wild-type or dominant negative mutant GATA4. We found that receptors DR4 and DR5 are expressed in a vast majority of GCTs as well as in primary GCT cultures, and that TRAIL induces apoptosis in the primary GCT cultures. Moreover, we showed that overexpressing GATA4 protects GCTs from TRAIL-induced apoptosis in vitro, whereas disrupting GATA4 function induces apoptosis and potentiates the apoptotic effect of TRAIL administration. Our results demonstrate that the TRAIL pathway is functional in GCT cells, and suggest that transcription factor GATA4 may function as a survival factor in this ovarian malignancy. Endocrine-Related Cancer (2010) 17 709-717