Amodio Nicola, Gallo Cantafio Maria Eugenia, Botta Cirino, Agosti Valter, Federico Cinzia, Caracciolo Daniele, Ronchetti Domenica, Rossi Marco, Driessen Christoph, Neri Antonino, Tagliaferri Pierosandro, Tassone Pierfrancesco
Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy.
Department of Oncology and Hemato-oncology, University of Milan and Hematology, Fondazione Cà Granda IRCCS Policlinico, 20122 Milan, Italy.
Cancers (Basel). 2019 Feb 18;11(2):236. doi: 10.3390/cancers11020236.
Aberrant expression of microRNAs (miRNAs) has been associated to the pathogenesis of multiple myeloma (MM). While miR-155 is considered a therapeutic target in several malignancies, its role in MM is still unclear. The analysis of miR-155 expression indicates its down-regulation in MM patient-derived as compared to healthy plasma cells, thus pointing to a tumor suppressor role in this malignancy. On this finding, we investigated miR-155 replacement as a potential anti-tumor strategy in MM. The miR-155 enforced expression triggered anti-proliferative and pro-apoptotic effects in vitro. Given the lower miR-155 levels in bortezomib-resistant as compared to sensitive MM cells, we analyzed the possible involvement of miR-155 in bortezomib resistance. Importantly, miR-155 replacement enhanced bortezomib anti-tumor activity both in vitro and in vivo in a xenograft model of human MM. In primary MM cells, we observed an inverse correlation between miR-155 and the mRNA encoding the proteasome subunit gene PSMβ5, whose dysregulation has been largely implicated in bortezomib resistance, and we validated PSMβ5 3'UTR mRNA targeting, along with reduced proteasome activity, by miR-155. Collectively, our findings demonstrate that miR-155 elicits anti-MM activity, likely via proteasome inhibition, providing the framework for miR-155-based anti-MM therapeutic strategies.
微小RNA（miRNA）的异常表达与多发性骨髓瘤（MM）的发病机制相关。虽然miR-155在多种恶性肿瘤中被视为治疗靶点，但其在MM中的作用仍不清楚。对miR-155表达的分析表明，与健康浆细胞相比，其在MM患者来源的细胞中表达下调，因此表明其在这种恶性肿瘤中具有肿瘤抑制作用。基于这一发现，我们研究了miR-155替代作为MM潜在抗肿瘤策略的可能性。miR-155的强制表达在体外引发了抗增殖和促凋亡作用。鉴于与敏感MM细胞相比，硼替佐米耐药细胞中miR-155水平较低，我们分析了miR-155在硼替佐米耐药中的可能作用。重要的是，在人MM异种移植模型中，miR-155替代在体外和体内均增强了硼替佐米的抗肿瘤活性。在原发性MM细胞中，我们观察到miR-155与编码蛋白酶体亚基基因PSMβ5的mRNA呈负相关，该基因的失调在很大程度上与硼替佐米耐药有关，并且我们验证了miR-155对PSMβ5 3'UTR mRNA的靶向作用以及蛋白酶体活性的降低。总体而言，我们的研究结果表明，miR-155可能通过抑制蛋白酶体发挥抗MM活性，为基于miR-155的抗MM治疗策略提供了框架。
