Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
Cell Death Dis. 2022 Jan 10;13(1):44. doi: 10.1038/s41419-021-04493-y.
Transforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.
转化生长因子-β（TGF-β）在晚期乳腺癌中作为促转移因子发挥作用。E3 泛素连接酶 RNF12 通过与抑制性 SMAD7 结合并诱导其蛋白酶体降解来刺激 TGF-β信号通路。RNF12 活性如何被调节及其在癌症中的确切作用尚不完全清楚。在这里，我们报告 RNF12 在侵袭性乳腺癌中过度表达，其高表达与预后不良相关。RNF12 在斑马鱼和小鼠异种移植模型中促进乳腺癌细胞迁移、侵袭和实验性转移。RNF12 水平与磷酸化 AKT/蛋白激酶 B（PKB）水平呈正相关，并且在基底样亚型中均显示出比乳腺癌细胞中亮氨酸样亚型更高的水平。在机制上，AKT 介导的磷酸化诱导 RNF12 的核定位，维持其稳定性，并加速 RNF12 介导的 SMAD7 降解。此外，我们证明 RNF12 和 AKT 在乳腺癌细胞迁移中具有功能上的协同作用。值得注意的是，RNF12 表达与乳腺癌组织中磷酸化 AKT 和磷酸化 SMAD2 水平强烈相关。因此，我们的研究结果揭示了 RNF12 作为 TGF-β和 AKT 信号通路在乳腺癌进展过程中相互作用的一个重要决定因素。
