文章：

ADAM家族成员与多发性骨髓瘤增殖信号传导及疾病进展的关联

Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma

原文发布日期：2024-09-11

DOI: 10.1038/s41408-024-01133-4

类型: Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8, ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL). High ADAM8/9/15 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease. Furthermore, ADAM8/15 expression increased with MM progression and in relapsed/refractory MM compared to untreated patient samples. RNA sequencing and gene set enrichment analysis comparing ADAM8/9/15high/low patient samples revealed an upregulation of proliferation markers and proliferation-associated gene sets in ADAM8/9/15high patient samples. High ADAM8/9/15 expression correlated with high Ki67 and high ADAM8/15 expression with high MYC protein expression in immunohistochemical stainings of patient tissue. Conversely, siRNA-mediated knockdown of ADAM8/9/15 in HMCL downregulated proliferation-related gene sets. Western blotting revealed that ADAM8 knockdown regulated IGF1R/AKT signaling and ADAM9 knockdown decreased mTOR activation. Lastly, high ADAM8/9/15 expression levels were verified as prognostic markers independent of Ki67/MYC expression and/or high-risk abnormalities. Overall, these findings suggest that ADAM8/9/15 play a role in MM progression and proliferation signaling.
 

摘要翻译： 

多发性骨髓瘤是一种血液系统恶性肿瘤，患者反复复发和治疗耐药性对其可治愈性构成巨大挑战。我们先前曾提出ADAM8、ADAM9和ADAM15（解整合素金属蛋白酶8/9/15）的高表达可作为多发性骨髓瘤的不良预后标志物。本研究通过两个患者队列和七种人多发性骨髓瘤细胞系，聚焦于目前研究较少的ADAM8/9/15在多发性骨髓瘤中的作用。研究发现，ADAM8/9/15高表达与高危细胞遗传学异常及髓外病变相关。此外，与未经治疗的患者样本相比，ADAM8/15表达在多发性骨髓瘤进展期和复发/难治性患者中呈现上升趋势。通过对ADAM8/9/15高/低表达患者样本进行RNA测序和基因集富集分析，发现高表达组中增殖标志物及增殖相关基因集表达上调。患者组织免疫组化染色显示，ADAM8/9/15高表达与Ki67高表达相关，ADAM8/15高表达与MYC蛋白高表达相关。相反，在人多发性骨髓瘤细胞系中通过siRNA敲低ADAM8/9/15表达后，增殖相关基因集表达下调。蛋白质印迹实验表明，ADAM8敲低可调节IGF1R/AKT信号通路，而ADAM9敲低则降低mTOR活化水平。最后，研究证实ADAM8/9/15高表达可作为独立于Ki67/MYC表达和/或高危异常的预后标志物。总体而言，这些发现提示ADAM8/9/15在多发性骨髓瘤进展和增殖信号传导中发挥重要作用。

原文链接：

Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma