miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/β-catenin/BCL9 pathway.
miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/β-catenin/BCL9 pathway.
复制标题
DOI：
10.1158/0008-5472.can-13-3311-t
复制
发表时间：
2014-03-15
期刊：
影响因子：
11.2
通讯作者：
Carrasco R
中科院分区：
文献类型：
--
作者：
Zhao JJ;Lin J;Zhu D;Wang X;Brooks D;Chen M;Chu ZB;Takada K;Ciccarelli B;Admin S;Tao J;Tai YT;Treon S;Pinkus G;Kuo WP;Hideshima T;Bouxsein M;Munshi N;Anderson K;Carrasco R
Wnt/β-连环蛋白信号转导是多种人类癌症的发病机制的基础，包括致命的浆细胞癌多发性骨髓瘤（MM）。在这项研究中，我们报告了肿瘤抑制microRNA miR-30- 5 p的下调是MM中常见的致病事件。有证据表明，miR-30- 5 p的下调是MM细胞和骨髓基质细胞之间相互作用的结果，这反过来又增强了BCL 9的表达，BCL 9是Wnt信号通路的转录共激活因子，已知可促进MM细胞增殖，存活，迁移，耐药性和MM癌症干细胞的形成。在人MM的三种鼠异种移植模型中，miR-30 c和miR-30 mix能够降低体内肿瘤负荷和转移潜力，而不会对相关骨疾病产生不利影响，这进一步促进了将重新表达miR-30- 5 p的策略作为治疗方法的临床转化潜力。总之，我们的研究结果提供了一个临床前理论基础，以探索miR-30- 5 p递送作为体内根除MM细胞的有效治疗策略。
Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma (MM). In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in MM. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between MM cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional co-activator of the Wnt signaling pathway known to promote MM cell proliferation, survival, migration, drug resistance and formation of MM 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-30mix to reduce tumor burden and metastatic potential in vivo, in three murine xenograft models of human MM, 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 MM cells in vivo.