Aberrant expression of HMGA2 in uterine leiomyoma associated with loss of TSC2 tumor suppressor gene function.
Aberrant expression of HMGA2 in uterine leiomyoma associated with loss of TSC2 tumor suppressor gene function.
复制标题
DOI：
--
复制
发表时间：
2002-07
期刊：
影响因子：
11.2
通讯作者：
D. Hunter;M. Klotzbücher;H. Kugoh;S. Cai;Johanna P Mullen;G. Manfioletti;U. Fuhrman;C. Walker
中科院分区：
文献类型：
--
作者：
D. Hunter;M. Klotzbücher;H. Kugoh;S. Cai;Johanna P Mullen;G. Manfioletti;U. Fuhrman;C. Walker
平滑肌瘤、脂肪瘤、错构瘤和其他疾病中间充质细胞不受控制的增殖与 DNA 结构蛋白的高迁移率基团 (HMGA) 家族有关。 HMGA 基因主要在胚胎发育过程中表达，在成人组织中沉默，但在肿瘤形成时由于染色体重排而重新激活。尽管表明 HMGA 蛋白在肿瘤发生中的作用的遗传数据令人信服，但这些蛋白在间充质增殖和分化中的生物学作用尚未完全确定。对来自 Eker 大鼠的子宫肌层和自发性平滑肌瘤进行了分析，以了解 Tsc2 和 HMGA 蛋白的遗传缺陷和表达，该大鼠携带结节性硬化症复合体 2 (Tsc2) 肿瘤抑制基因的种系突变。 Eker 平滑肌瘤表现出 50% 的野生型 Tsc2 等位基因缺失发生率和几乎一致的蛋白质表达缺失，表明这些肿瘤中 Tsc2 基因功能缺失。与此同时，正常子宫肌层中完全不存在的 HMGA2 蛋白在 19 个 Eker 平滑肌瘤中的 16 个中表达。 HMGA1 在平滑肌瘤和正常子宫肌层中均表达。在原发性大鼠平滑肌瘤或表达 HMGA2 的平滑肌瘤衍生细胞系中，未观察到 HMGA2 基因座发生结构改变。这些数据支持 HMGA2 在平滑肌肿瘤发展中的作用，并表明 HMGA2 表达是人类疾病和 Eker 大鼠模型之间的汇合点。此外，这些数据表明，在不存在涉及 HMGA2 基因座的结构改变的情况下，异常的 HMGA2 表达可能是由于 Tsc2 肿瘤抑制基因的功能障碍所致。
Unregulated proliferation of mesenchymal cells in leiomyomas, lipomas, hamartomas,and other diseases has been linked to the high mobility group (HMGA) family of DNA architectural proteins. HMGA genes are primarily expressed during embryonal development and silenced in adult tissues but can become reactivated in neoplasia as a result of chromosomal rearrangements. Although the genetic data suggesting a role for HMGA proteins in tumorigenesis are compelling, the biological role of these proteins in mesenchymal proliferation and differentiation is incompletely defined. Uterine myometria and spontaneous leiomyomas from the Eker rat, which carries a germ-line mutation in the tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene, were analyzed for genetic defects in and expression of the Tsc2 and HMGA proteins. Eker leiomyomas exhibited a 50% incidence of loss of the wild-type Tsc2 allele and an almost uniform loss of protein expression, implicating loss of function of the Tsc2 gene in these tumors. Concomitantly, HMGA2 protein, which was completely absent in normal myometria, was expressed in 16 of 19 Eker leiomyomas. HMGA1 was expressed in both leiomyoma and normal myometria. No structural alterations were observed at the HMGA2 locus in either primary rat leiomyomas or leiomyoma-derived cell lines that expressed HMGA2. These data support a role for HMGA2 in the development of smooth muscle neoplasms and suggest HMGA2 expression is a point of convergence between the human disease and the Eker rat model. Furthermore, these data indicate that aberrant HMGA2 expression can result from dysfunction of the Tsc2 tumor suppressor gene, in the absence of structural alterations involving the HMGA2 locus.