A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway
A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway
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新型HDGF-ALCAM轴通过调节GTPase信号通路促进尤文肉瘤转移
DOI：
10.1038/s41388-020-01485-8
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发表时间：
2020-11-25
期刊：
影响因子：
8
通讯作者：
Han, Anjia
中科院分区：
文献类型：
--
作者：
Yang, Yang;Ma, Yuedong;Han, Anjia
尤文肉瘤是一种高度侵袭性的小儿骨和软组织肿瘤，其转移扩散仍然是预后不良的最有力预测因素。我们以前发现，转录因子肝癌衍生生长因子（HDGF）促进ES肿瘤发生。然而，ES转移的机制仍不清楚。在这里，我们表明，HDGF驱动ES转移在体外和体内，和HDGF减少转移无生存期（MFS）在两个独立的大队列的人类ES患者。HDGF ChIP-seq和ES细胞基因表达谱的综合分析表明，HDGF调节多个转移相关基因，其中活化的白细胞粘附分子（ALCAM）是HDGF的主要靶点，也是ES细胞中新的转移抑制因子。HDGF下调ALCAM，诱导下游效应物Rho-GTdR ac 1和Cdc 42的表达和激活，并促进肌动蛋白细胞骨架重塑和细胞-基质粘附。此外，ALCAM的抑制和Rac 1和Cdc 42的激活是体外HDGF的促转移功能所必需的。此外，在ES肿瘤原位植入和实验性转移的鼠模型中以及在人ES样品中的分析证明了HDGF、ALCAM和GTP酶表达水平之间的关联。此外，高HDGF/低ALCAM表达定义了具有最差MFS的患者亚组。这些发现表明HDGF/ALCAM/GTP酶轴代表了限制ES转移的有希望的治疗靶点。
Ewing sarcoma (ES) is a type of highly aggressive pediatric tumor in bones and soft tissues and its metastatic spread remains the most powerful predictor of poor outcome. We previously identified that the transcription factor hepatoma-derived growth factor (HDGF) promotes ES tumorigenesis. However, the mechanisms underlying ES metastasis remain unclear. Here, we show that HDGF drives ES metastasis in vitro and in vivo, and HDGF reduces metastasis-free survival (MFS) in two independent large cohorts of human ES patients. Integrative analyses of HDGF ChIP-seq and gene expression profiling in ES cells reveal that HDGF regulates multiple metastasis-associated genes, among which activated leukocyte cell adhesion molecule (ALCAM) emerges as a major HDGF target and a novel metastasis-suppressor in ES. HDGF down-regulates ALCAM, induces expression and activation of the downstream effectors Rho-GTPase Rac1 and Cdc42, and promotes actin cytoskeleton remodeling and cell-matrix adhesion. In addition, repression of ALCAM and activation of Rac1 and Cdc42 are required for the pro-metastatic functions of HDGF in vitro. Moreover, analyses in murine models with ES tumor orthotopic implantation and experimental metastasis, as well as in human ES samples, demonstrate the associations among HDGF, ALCAM, and GTPases expression levels. Furthermore, high HDGF/low ALCAM expression define a subgroup of patients harboring the worst MFS. These findings suggest that the HDGF/ALCAM/GTPases axis represents a promising therapeutic target for limiting ES metastasis.