Replacement of miR-155 Elicits Tumor Suppressive Activity and Antagonizes Bortezomib Resistance in Multiple Myeloma
Replacement of miR-155 Elicits Tumor Suppressive Activity and Antagonizes Bortezomib Resistance in Multiple Myeloma
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DOI：
10.3390/cancers11020236
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发表时间：
2019-02-01
期刊：
影响因子：
5.2
通讯作者：
Tassone, Pierfrancesco
中科院分区：
文献类型：
--
作者：
Amodio, Nicola;Cantafio, Maria Eugenia Gallo;Tassone, Pierfrancesco
microRNA（miRNAs）的异常表达与多发性骨髓瘤（MM）的发病机制有关。虽然miR-155被认为是几种恶性肿瘤的治疗靶点，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患者来源的浆细胞中下调，从而指出在这种恶性肿瘤中的肿瘤抑制作用。基于这一发现，我们研究了miR-155替代作为MM中潜在的抗肿瘤策略。miR-155强制表达在体外引发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MM细胞中的miR-155水平较低，我们分析了miR-155在硼替佐米耐药中的可能参与。重要的是，miR-155替代增强了人MM异种移植模型中的体外和体内硼替佐米抗肿瘤活性。在原代MM细胞中，我们观察到miR-155和编码蛋白酶体亚基基因PSM 5的mRNA之间呈负相关，PSM 5的失调在很大程度上与硼替佐米耐药性有关，我们验证了PSM 5 3 UTR mRNA靶向，沿着蛋白酶体活性降低，miR-155总的来说，我们的研究结果表明，miR-155增强抗MM活性，可能是通过蛋白酶体抑制，为基于miR-155的抗MM治疗策略提供了框架。
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 PSM5, whose dysregulation has been largely implicated in bortezomib resistance, and we validated PSM5 3UTR 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.