Li Yuxiang, Zhang Lin, Xu Tianxin, Zhao Xia, Jiang Xiaona, Xiao Fengjun, Sun Huiyan, Wang Lisheng
Laboratory of Molecular Diagnosis and Regenerative Medicine, the Affiliate Hospital of Qingdao University, Qingdao, P. R. China.
Department of Neuroimmune and Antibody Engineering, Beijing Institute of Basic Medical Sciences, Beijing, P.R. China.
Leuk Lymphoma. 2022 Apr;63(4):963-974. doi: 10.1080/10428194.2021.2010055. Epub 2021 Nov 30.
Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) disease progression remains unclear. Here, we demonstrated that CD138+ cells isolated from MM patients presented with higher expression of ENPP2 compared with CD138- cells. Treatment of MM cells with IL-6 resulted in ENPP2 upregulation. ENPP2 overexpression promoted proliferation, inhibited apoptosis, increased lysophosphatidic acid (LPA) generation, and upregulated osteoclastogenesis mediator expression in MM cells. In contrast, ENPP2 inhibition induced apoptosis, suppressed proliferation and survival, decreased LPA generation and downregulated osteoclastogenesis mediator expression. In an MM xenograft mouse model, ENPP2 knockdown significantly reduced MM tumor burden by inhibiting cell proliferation and inducing apoptosis. Furthermore, ENPP2 knockdown decreased the levels of LPA, osteoclastogenesis mediators in sera of mice with MM. Our findings revealed the tumor-promoting role of ENPP2 in MM, thus providing new molecular evidence for targeting the ENPP2-LPA axis in MM therapy.
胞外核苷酸焦磷酸酶/磷酸二酯酶2（ENPP2）最近被认为与肿瘤发展有关。然而，其在调节多发性骨髓瘤（MM）疾病进展中的作用仍不清楚。在此，我们证明，与CD138-细胞相比，从MM患者中分离出的CD138+细胞中ENPP2的表达更高。用白细胞介素-6处理MM细胞会导致ENPP2上调。ENPP2过表达促进增殖、抑制凋亡、增加溶血磷脂酸（LPA）生成，并上调MM细胞中破骨细胞生成介质的表达。相反，ENPP2抑制诱导凋亡、抑制增殖和存活、减少LPA生成并下调破骨细胞生成介质的表达。在MM异种移植小鼠模型中，ENPP2基因敲低通过抑制细胞增殖和诱导凋亡显著降低了MM肿瘤负荷。此外，ENPP2基因敲低降低了MM小鼠血清中LPA和破骨细胞生成介质的水平。我们的研究结果揭示了ENPP2在MM中的促肿瘤作用，从而为MM治疗中靶向ENPP2-LPA轴提供了新的分子证据。
