The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis
The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis
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DOI：
10.1158/0008-5472.can-05-1684
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Resar, Linda M. S.
中科院分区：
文献类型：
--
作者：
Tesfaye, Abeba;Di Cello, Francescopaolo;Resar, Linda M. S.
子宫癌是女性生殖道最常见的癌症，也是美国女性癌症死亡的第四大原因。尽管子宫癌的患病率很高，但导致子宫肿瘤转化的分子事件仍知之甚少。此外，研究这些恶性肿瘤的小鼠模型有限。我们产生了高迁移率族Al基因（HMGA-1 α）表达靶向子宫组织的转基因小鼠，所有雌性小鼠在9个月大时都发生了肿瘤。组织学上，该肿瘤类似于人类子宫腺肉瘤，并且是可移植的。为了确定这些结果是否与人类疾病相关，我们评估了原发性人类子宫肿瘤，发现HMGA 1 α mRNA和蛋白水平在大多数高级别肿瘤中升高，但在正常子宫组织、良性肿瘤或大多数低级别肿瘤中不升高。我们还发现，HMGA 1 α上调环氧化酶2（考克斯-2）在转基因肿瘤中的表达。此外，HMG 1 α和考克斯-2的表达在高度恶性的人平滑肌瘤中均上调。使用染色质免疫沉淀，HMGA 1a在体内直接结合人子宫癌细胞中的考克斯-2启动子，并在转染实验中激活其表达。我们还表明，在高级别人子宫癌细胞中阻断HMGA 1 α或考克斯-2可阻断甲基纤维素中的锚定非依赖性细胞生长。这些发现表明，HMGA 1 α在子宫中过表达时作为癌基因发挥作用，并通过激活考克斯-2表达促进人类子宫癌的发病机制。虽然需要更大规模的研究来证实这些结果，但HMGA 1 α可能是侵袭性人类子宫癌的有用标志物。
Uterine cancer is the most common cancer of the female genital tract and is the fourth most frequent cause of cancer death in women in the U.S. Despite the high prevalence of uterine cancers, the molecular events that lead to neoplastic transformation in the uterus are poorly understood. Moreover, there are limited mouse models to study these malignancies. We generated transgenic mice with high-mobility group Al gene (HMGA-1 alpha) expression targeted to uterine tissue and all female mice developed tumors by 9 months of age. Histopathologically, the tumors resemble human uterine adenosarcoma and are transplantable. To determine whether these findings are relevant to human disease, we evaluated primary human uterine neoplasms and found that HMGA1 alpha mRNA and protein levels are increased in most high-grade neoplasms but not in normal uterine tissue, benign tumors, or most low-grade neoplasms. We also found that HMGA1 alpha up-regulates cyclooxygenase 2 (COX-2) expression in transgenic tumors. Moreover, both HMG1 alpha and COX-2 expression are up-regulated in high-grade human leiomyosarcomas. Using chromatin immunoprecipitation, HMGA1a binds directly to the COX-2 promoter in human uterine cancer cells in vivo and activates its expression in transfection experiments. We also show that blocking either HMGA1 alpha or COX-2 in high-grade human uterine cancer cells blocks anchorage-independent cell growth in methylcellulose. These findings show that HMGA1 alpha functions as an oncogene when overexpressed in the uterus and contributes to the pathogenesis of human uterine cancer by activating COX-2 expression. Although a larger study is needed to confirm these results, HMGA1 alpha maybe a useful marker for aggressive human uterine cancers.