JunB is a key regulator of multiple myeloma bone marrow angiogenesis.
JunB is a key regulator of multiple myeloma bone marrow angiogenesis.
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DOI：
10.1038/s41375-021-01271-9
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发表时间：
2021-12
期刊：
影响因子：
11.4
通讯作者：
Podar K
中科院分区：
文献类型：
--
作者：
Fan F;Malvestiti S;Vallet S;Lind J;Garcia-Manteiga JM;Morelli E;Jiang Q;Seckinger A;Hose D;Goldschmidt H;Stadlbauer A;Sun C;Mei H;Pecherstorfer M;Bakiri L;Wagner EF;Tonon G;Sattler M;Hu Y;Tassone P;Jaeger D;Podar K
骨髓（BM）血管生成显著影响多发性骨髓瘤（MM）患者的疾病进展，并与不良预后相关。本研究显示AP-1家族成员JunB与MM中VEGF、VEGFB和IGF 1表达水平具有统计学显著相关性。与血管生成主调节因子HIF-1α相比，JunB蛋白水平不依赖于缺氧。在肿瘤细胞模型中分别诱导JunB敲低或JunB活化的结果证实了JunB在这些血管生成因子（AF）的产生和分泌中的功能作用。因此，在JunB敲低或JunB活化后，来自MM细胞的条件培养基抑制或刺激体外血管生成。JunB对MM BM血管生成的影响最终在BM微环境的动态3D模型、异种移植小鼠模型以及患者来源的BM切片中得到证实。总之，在我们先前研究的继续中（Fan等人，2017），本报告首次揭示了JunB不仅是MM细胞存活，增殖和耐药性的介导者，而且是AF转录的启动子，因此也是MM BM血管生成的启动子。因此，我们的研究结果强调了全世界靶向AP-1转录因子如JunB作为MM治疗中有前途的策略的努力。
Bone marrow (BM) angiogenesis significantly influences disease progression in multiple myeloma (MM) patients and correlates with adverse prognosis. The present study shows a statistically significant correlation of the AP-1 family member JunB with VEGF, VEGFB, and IGF1 expression levels in MM. In contrast to the angiogenic master regulator Hif-1α, JunB protein levels were independent of hypoxia. Results in tumor-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs). Consequently, conditioned media derived from MM cells after JunB knockdown or JunB activation either inhibited or stimulated in vitro angiogenesis. The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections. In summary, in continuation of our previous study (Fan et al., 2017), the present report reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of AF transcription and consequently of MM BM angiogenesis. Our results thereby underscore worldwide efforts to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy.
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