Authors' Affiliations: Department of Medical Oncology; Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute; Harvard School of Public Health; Department of Pathology, Brigham & Women's Hospital; Department of Developmental Biology, Harvard School of Dental Medicine; Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and Experimental Therapies, H. Lee Moffitt Cancer Center, Florida; and Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
Cancer Res. 2014 Mar 15;74(6):1801-13. doi: 10.1158/0008-5472.CAN-13-3311-T. Epub 2014 Mar 5.
Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo.
Wnt/β-catenin 信号通路是广泛存在于人类癌症，包括致命的浆细胞瘤多发性骨髓瘤的发病机制基础。在这项研究中，我们报告了肿瘤抑制 microRNA miR-30-5p 的下调是多发性骨髓瘤的一种常见发病事件。有证据表明，miR-30-5p 的下调是多发性骨髓瘤细胞与骨髓基质细胞相互作用的结果，进而增强了 Wnt 信号通路转录共激活因子 BCL9 的表达，已知 BCL9 促进多发性骨髓瘤细胞的增殖、存活、迁移、耐药性和多发性骨髓瘤癌干细胞的形成。miR-30c 和 miR-30 混合物在三种人类多发性骨髓瘤的小鼠异种移植模型中具有减少肿瘤负担和转移潜力，而不影响相关的骨疾病，这进一步鼓励了将重新表达 miR-30-5p 作为治疗方法的策略用于临床转化的潜力。综上所述，我们的研究结果为探索 miR-30-5p 递送来作为一种有效的治疗策略以消除体内多发性骨髓瘤细胞提供了临床前依据。
