Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Cell Death Dis. 2017 Sep 7;8(9):e3036. doi: 10.1038/cddis.2017.434.
CDP138, a CDK5 binding partner, regulates cell proliferation and migration. However, the mechanisms by which CDP138 functions in these processes remain unclear. In this study, we show that CDP138 is frequently overexpressed and that high levels of CDP138 are correlated with lymph node metastasis in lung cancer. Furthermore, we provide evidence that CDP138-depleted lung cancer cells exhibit enhanced radiosensitivity as well as reduced migration and invasion. Mechanistically, we identify GDF15, a member of the TGF-β superfamily, as a key downstream effector of CDP138. CDP138 silencing attenuates TGF-β/Smad signaling activation at least in part through the downregulation of GDF15. More importantly, the observed phenotypes caused by CDP138 knockdown are partially dependent on GDF15 inhibition. Together, our findings demonstrate that CDP138 positively modulates the TGF-β/Smad signaling pathway via GDF15 to promote radioresistance and metastasis, suggesting CDP138 as a potential oncogenic biomarker and a promising therapeutic target in the treatment of lung cancer.
CDP138 是 CDK5 的结合伴侣，调节细胞增殖和迁移。然而，CDP138 在这些过程中发挥作用的机制尚不清楚。在这项研究中，我们表明 CDP138 经常过表达，并且高水平的 CDP138 与肺癌中的淋巴结转移相关。此外，我们提供的证据表明，CDP138 耗尽的肺癌细胞表现出增强的放射敏感性以及减少的迁移和侵袭。在机制上，我们确定了 GDF15，TGF-β 超家族的一个成员，作为 CDP138 的关键下游效应子。CDP138 沉默至少部分通过下调 GDF15 来减弱 TGF-β/Smad 信号激活。更重要的是，CDP138 敲低引起的观察到的表型部分依赖于 GDF15 抑制。总之，我们的研究结果表明，CDP138 通过 GDF15 正向调节 TGF-β/Smad 信号通路，促进放射抗性和转移，提示 CDP138 作为一种潜在的致癌生物标志物和治疗肺癌的有前途的治疗靶点。
