上海交通大学医学院闫华研究团队报道了靶向HuR/E2F7轴与硼替佐米协同治疗多发性骨髓瘤。2025年3月25日出版的《中国药理学报》发表了这项成果。

在这项研究中，该团队通过分析公共数据集发现HuR在MM患者中高表达，并与不良预后相关。该研究团队发现用短发夹RNA （short hairpin RNA, shRNA）或其抑制剂CMLD-2靶向HuR在体外和体内均具有显著的抗mm作用。HuR过表达促进MM细胞体外和体内增殖。

此外，该研究组证明了硼替佐米的药物敏感性分别随着HuR的下调和过表达而增加和降低。这一结果为他们随后将CMLD-2与硼替佐米联合治疗MM提供了理论依据。为了进一步探讨HuR在MM中的作用机制，小组进行了RNA测序并鉴定了其下游分子E2F7。HuR通过增加MM细胞中E2F7 mRNA的稳定性来上调其表达。较高水平的E2F7与较差的预后相关。E2F7敲除在体外和体内均有抗mm作用。E2F7过表达部分恢复了MM细胞的增殖抑制和HuR诱导的细胞凋亡。小组随后在体内和体外证明了CMLD-2与硼替佐米抗mm的协同作用。综上所述，靶向HuR/E2F7轴可与硼替佐米协同抗MM。因此，HuR/E2F7轴可能是MM的一个有希望的治疗靶点。

研究人员表示，多发性骨髓瘤（MM）是一种恶性血液系统疾病，由骨髓中异常浆细胞的增殖引起，目前仍无法治愈。复发和耐药在MM中很常见。MM治疗急需新的治疗靶点。人类抗原R （Human antigen R, HuR）已被报道在多种肿瘤的恶性生物学行为中发挥重要作用，但其在MM中的作用尚不清楚。

附：英文原文

Title: Targeting the HuR/E2F7 axis synergizes with bortezomib against multiple myeloma

Author: Jia, Ming-yuan, Wu, Chao, Fu, Ze, Xu, Wen-bin, Liu, Jia, Wu, Cheng-yu, Zeng, Xin-yi, Wu, Ying-li, Yan, Hua

Issue&Volume: 2025-03-25

Abstract: Multiple myeloma (MM) is a malignant hematological disease caused by the proliferation of abnormal plasma cells in the bone marrow and is still incurable. Relapse and drug resistance are common in MM. New therapeutic targets are urgently needed for MM treatment. Human antigen R (HuR) has been reported to play an important role in the malignant biological behavior of a variety of tumors, but its role in MM remains unclear. In this study, we found that HuR was highly expressed in MM patients and associated with a poor prognosis by analyzing public datasets. We found that targeting HuR with short hairpin RNA (shRNA) or its inhibitor CMLD-2 had significant anti-MM effects both in vitro and in vivo. The overexpression of HuR promotes MM cell proliferation in vitro and in vivo. Moreover, we demonstrated that bortezomib drug sensitivity increased and decreased with the knockdown and overexpression of HuR, respectively. This result provides a rationale for our subsequent combination of CMLD-2 with bortezomib in the treatment of MM. To further explore the mechanism of HuR in MM, we performed RNA sequencing and identified its downstream molecule, E2F7. HuR upregulated E2F7 expression by increasing the stability of its mRNA in MM cells. Higher levels of E2F7 were associated with a poorer prognosis. E2F7 knockdown had anti-MM effects in vitro and in vivo. E2F7 overexpression partially rescued the cell proliferation inhibition and apoptosis caused by targeting HuR in MM cells. We subsequently demonstrated that CMLD-2 synergized with the anti-MM effect of bortezomib both in vitro and in vivo. In conclusion, targeting the HuR/E2F7 axis synergizes with bortezomib against MM. Therefore, the HuR/E2F7 axis may serve as a promising therapeutic target for MM.

DOI: 10.1038/s41401-025-01529-3

Source: https://www.nature.com/articles/s41401-025-01529-3