Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Oncogene. 2019 Oct;38(41):6781-6793. doi: 10.1038/s41388-019-0920-5. Epub 2019 Aug 12.
Despite multi-modality treatments, prognosis for advanced stage neuroblastoma (NB) remains challenging with residual long-term disabilities in survivors. Advanced stage NB is metastatic, which is a principal cause of cancer-related deaths. We presently document a primary role of MDA-9 in NB progression and define the molecular mechanisms by which MDA-9 promotes transformed phenotypes. NB cell lines and clinical samples display elevated MDA-9 expression and bioinformatic analysis supports an association between elevated MDA-9 and bone metastasis and poor prognosis. Genetic (shmda-9, mda-9 siRNA) or pharmacological (small molecule inhibitor of protein-protein interactions; PDZ1i) blockade of MDA-9 decreases NB migration, invasion, and metastasis. Blocking mda-9 expression or disrupting MDA-9 partner protein interactions downregulates integrin α6 and β4, diminishing Src activity and suppressing Rho-Rac-Cdc42 activity. These signaling changes inhibit cofilin and matrix metalloproteinases reducing in vitro and in vivo NB cell migration. Overexpression of integrin α6 and β4 rescues the invasion phenotype and increases Src activity, supporting integrins as essential regulators of MDA-9-mediated NB migration and invasion. We identify MDA-9 as a key contributor to NB pathogenesis and show that genetic or pharmacological inhibition suppresses NB pathogenesis by an integrin-mediated Src-disruption pathway.
尽管采用了多种治疗方法，但晚期神经母细胞瘤（NB）的预后仍然具有挑战性，幸存者仍存在长期残疾。晚期 NB 是转移性的，这是癌症相关死亡的主要原因。我们目前证明 MDA-9 在 NB 进展中具有主要作用，并确定了 MDA-9 促进转化表型的分子机制。NB 细胞系和临床样本显示 MDA-9 表达升高，生物信息学分析支持 MDA-9 升高与骨转移和预后不良之间存在关联。MDA-9 的遗传（shmda-9、mda-9 siRNA）或药理学（蛋白-蛋白相互作用的小分子抑制剂；PDZ1i）阻断可降低 NB 的迁移、侵袭和转移。阻断 mda-9 表达或破坏 MDA-9 伴侣蛋白相互作用可下调整合素 α6 和 β4，降低Src 活性并抑制 Rho-Rac-Cdc42 活性。这些信号变化抑制了丝切蛋白和基质金属蛋白酶，减少了体外和体内 NB 细胞的迁移。整合素 α6 和 β4 的过表达可挽救侵袭表型并增加 Src 活性，表明整合素是 MDA-9 介导的 NB 迁移和侵袭的重要调节剂。我们确定 MDA-9 是 NB 发病机制的关键因素，并表明遗传或药理学抑制通过整合素介导的 Src 破坏途径抑制 NB 发病机制。
