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在高级软组织肉瘤 (STS) 中,HMGA1调节了trabectedin敏感性:西班牙肉瘤研究小组 (GEIS) 的研究

David S Moura^1,2, Jose L Mondaza-Hernandez³, Paloma Sanchez-Bustos⁴

¹Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28015, Madrid, Spain. dmoura@atbsarc.org.

Cellular and molecular life sciences : CMLS

|May 17, 2024

概括

高流动性组AT-hook 1 (HMGA1) 是晚期软组织肉瘤中特拉贝克丁治疗的不良预后因素. 抑制HMGA1或mTOR途径提高了trabectedin的有效性,并在临床前模型中稳定了瘤生长.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

高流动性组AT-hook 1 (HMGA1) 是一种涉及瘤进展和耐药性的表观遗传因素.
特拉贝克特丁是一种用于高级软组织肉瘤 (STS) 的化疗剂.

研究的目的:

为了研究HMGA1的预后和预测价值在trabectedin治疗的高级STS患者中.
评估HMGA1抑制和mTOR通路调节对特拉贝克丁的疗效的影响.

主要方法:

在301名STS患者的mRNA和蛋白质水平上评估了HMGA1的表达,使用了转录学和免疫组织化学.
在leiomyosarcoma细胞和体内肉瘤模型中研究了对trabectedin活性的HMGA1沉默和mTOR抑制效应.

主要成果:

增加的HMGA1表达与STS患者的无进展和整体存活时间的恶化相关,这些患者接受了trabectedin治疗.
HMGA1沉默使敏感细胞对特拉贝克丁素,增加细胞死亡和减少球状体大小.
下调HMGA1影响PI3K/AKT/mTOR通路;mTOR抑制也使细胞对trabectedin敏感.
与拉帕米辛 (一种mTOR抑制剂) 和特拉贝克丁的联合治疗降低了HMGA1的调节,并在体内稳定了瘤的生长.

结论:

在先进的STS中,HMGA1作为特拉贝克丁治疗的负预后标志物.
抑制HMGA1增强了trabectedin的有效性,部分是通过调节mTOR通路.
结合的特拉贝克丁和mTOR抑制剂在肉瘤中显示出临床前活性,减少HMGA1并稳定瘤生长.

关键词:

在HMGA1中,它是HMGA1的.莱奥米奥萨科马 (Leiomyosarcoma) 是一种癌症.软组织肉瘤是软组织肉瘤.在里面被抓走了.在 mTOR 路径上.

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