MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6.
MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6.
复制标题
DOI：
10.18632/oncotarget.14681
复制
发表时间：
2017-02-21
期刊：
影响因子：
--
通讯作者：
Takahashi C
中科院分区：
文献类型：
--
作者：
Yoshida A;Kitajima S;Li F;Cheng C;Takegami Y;Kohno S;Wan YS;Hayashi N;Muranaka H;Nishimoto Y;Nagatani N;Nishiuchi T;Thai TC;Suzuki S;Nakao S;Tanaka T;Hirose O;Barbie DA;Takahashi C
我们建立了体外细胞培养系统来确定视网膜母细胞瘤 (Rb) 蛋白在肿瘤进展过程中的新活性。 p53缺失小鼠来源的软组织肉瘤细胞中Rb的消耗诱导了球形表型。从 Rb 耗尽的球体中回收的细胞表现出较慢的增殖和较低的 BrdU 掺入效率，但具有更高的成球活性和攻击行为。我们发现了 6 个 miRNA，包括 mmu-miR-18a、-25、-29b、-140、-337 和 -1839，其表达水平与 Rb 状态和球形活性密切相关。其中，mmu-miR-140 似乎受到 Rb 的正控制，并拮抗 Rb 消耗对球形生成和肿瘤发生的影响。此外，在mmu-miR-140可能靶向的基因中，Il-6因Rb耗尽而上调，并因mmu-mir-140过表达而下调。总而言之，我们证明了 mmu-mir-140 通过靶向其 3'-非翻译区介导 Rb 功能下调 Il-6 的可能性。最后，我们在人乳腺癌细胞系 MCF-7 中检测到 RB、hsa-miR-140 和 IL-6 之间存在相同的关系。由于 IL-6 是癌细胞恶性特征的关键调节剂，并且 RB 通路在大多数癌症中受损，因此 hsa-miR-140 可能是一种有前途的治疗工具，可以破坏肿瘤抑制因子失活和促炎细胞因子反应之间的联系。
We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3′-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.