Division of Hematology and Medical Oncology, Department of Medicine.
Blood. 2014 Jan 2;123(1):86-93. doi: 10.1182/blood-2013-07-515254. Epub 2013 Oct 17.
MicroRNA-155 (miR-155) plays pleiotropic roles in the biology of normal and malignant B lymphocytes, including the modulation of the transforming growth factor β (TGF-β) pathway via the targeting of SMAD5. However, the extent of the miR-155-mediated disruption of the TGF-β1/SMAD5 axis remains to be elucidated. To address this issue, we used the miR-155 knockout (KO) mouse and diffuse large B-cell lymphoma (DLBCL) cell lines ectopically expressing miR-155. In the DLBCL models, expression of miR-155 blocked TGF-β1-mediated activation of the retinoblastoma protein (RB), decreasing the abundance of the inhibitory pRB-E2F1 complex and limiting G0/G1 arrest. Genetic knockdown of SMAD5, p15, or p21 recapitulated these effects, establishing a circuitry whereby the targeting of SMAD5 by miR-155 blunts the TGF-β1-induced transcription of p15 and p21, thus sustaining RB phosphorylation and inactivity. Next, we demonstrated that SMAD5 levels are elevated in mature B lymphocytes from the miR-155 KO mice, which display a heightened sensitivity to TGF-β1 characterized by suppression of RB phosphorylation and more pronounced G0/G1 cell cycle arrest. Our findings suggest that a miR-155-mediated perturbation of the RB/E2F axis may play a role in DLBCL pathogenesis, and contribute to the reduced number of germinal center B cells and impaired T cell-dependent antibody response found in the miR-155 KO mice.
miR-155（微小 RNA-155）在正常和恶性 B 淋巴细胞的生物学中发挥着多效作用，包括通过靶向 SMAD5 调节转化生长因子β（TGF-β）途径。然而，miR-155 介导的 TGF-β1/SMAD5 轴的破坏程度仍有待阐明。为了解决这个问题，我们使用了 miR-155 敲除（KO）小鼠和过表达 miR-155 的弥漫性大 B 细胞淋巴瘤（DLBCL）细胞系。在 DLBCL 模型中，miR-155 的表达阻断了 TGF-β1 介导的视网膜母细胞瘤蛋白（RB）的激活，减少了抑制性 pRB-E2F1 复合物的丰度，并限制了 G0/G1 期停滞。SMAD5、p15 或 p21 的基因敲低重现了这些效应，建立了一个电路，其中 miR-155 靶向 SMAD5 削弱了 TGF-β1 诱导的 p15 和 p21 的转录，从而维持 RB 磷酸化和失活。接下来，我们证明了 miR-155 KO 小鼠成熟 B 淋巴细胞中的 SMAD5 水平升高，这些细胞对 TGF-β1 更为敏感，表现为 RB 磷酸化抑制和更明显的 G0/G1 细胞周期停滞。我们的发现表明，miR-155 介导的 RB/E2F 轴的扰动可能在 DLBCL 发病机制中发挥作用，并导致 miR-155 KO 小鼠中发现的生发中心 B 细胞数量减少和 T 细胞依赖性抗体反应受损。
