Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
Mol Ther. 2018 Sep 5;26(9):2255-2266. doi: 10.1016/j.ymthe.2018.06.016. Epub 2018 Jun 22.
Transforming growth factor β1 (TGF-β1) plays a promoting role in tumor growth via a mechanism associated with hyperactive Smad3 and suppressed Smad7 signaling in the tumor microenvironment. We report that retrieving the balance between Smad3 and Smad7 signaling with asiatic acid (AA, a Smad7 inducer) and naringenin (NG, a Smad3 inhibitor) effectively inhibited tumor progression in mouse models of invasive melanoma (B16F10) and lung carcinoma (LLC) by promoting natural killer (NK) cell development and cytotoxicity against cancer. Mechanistically, we found that Smad3 physically bound Id2 and IRF2 to suppress NK cell production and NK cell-mediated cytotoxicity against cancer. Treatment with AA and NG greatly inhibited Smad3 translation and phosphorylation while it restored Smad7 expression, and, therefore, it largely promoted NK cell differentiation, maturation, and cytotoxicity against cancer via Id2/IRF2-associated mechanisms. In contrast, silencing Id2 or IRF2 blunted the protective effects of AA and NG on NK cell-dependent anti-cancer activities. Thus, treatment with AA and NG produced an additive effect on inactivating TGF-β1/Smad3 signaling, and, therefore, it suppressed melanoma and lung carcinoma growth by promoting NK cell immunity against cancer via a mechanism associated with Id2 and IRF2.
转化生长因子β1（TGF-β1）通过与肿瘤微环境中过度活跃的 Smad3 和受抑制的 Smad7 信号相关的机制，在肿瘤生长中发挥促进作用。我们报告说，用熊果酸（AA，一种 Smad7 诱导剂）和柚皮素（NG，一种 Smad3 抑制剂）恢复 Smad3 和 Smad7 信号之间的平衡，通过促进自然杀伤（NK）细胞的发育和对癌细胞的细胞毒性，有效地抑制了侵袭性黑色素瘤（B16F10）和肺癌（LLC）小鼠模型中的肿瘤进展。在机制上，我们发现 Smad3 与 Id2 和 IRF2 结合，抑制 NK 细胞的产生和 NK 细胞对癌细胞的细胞毒性。用 AA 和 NG 处理可显著抑制 Smad3 的翻译和磷酸化，同时恢复 Smad7 的表达，因此，通过 Id2/IRF2 相关机制，它在很大程度上促进了 NK 细胞的分化、成熟和对癌细胞的细胞毒性。相比之下，沉默 Id2 或 IRF2 削弱了 AA 和 NG 对 NK 细胞依赖性抗癌活性的保护作用。因此，用 AA 和 NG 治疗对 TGF-β1/Smad3 信号的失活产生了附加作用，因此，通过与 Id2 和 IRF2 相关的机制，它通过促进 NK 细胞对癌症的免疫来抑制黑色素瘤和肺癌的生长。
