Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China.
Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China.
Cell Death Dis. 2023 Feb 27;14(2):167. doi: 10.1038/s41419-023-05644-z.
Metastasis is the leading cause of treatment failure and tumor-related death in colorectal cancer (CRC). Our previous studies report that CEMIP functionally promotes CRC metastasis and is closely related to poor outcomes. However, the molecular network of CEMIP promoting CRC metastasis is still not fully understood. In the current study, we identify CEMIP interacting with GRAF1, and the combination of high-CEMIP and low-GRAF1 predicts poor survival of patients. Mechanistically, we elucidate that CEMIP interacts with the SH3 domain of GRAF1 through the 295-819aa domain, and negatively regulates the stability of GRAF1. Moreover, we identify MIB1 to be an E3 ubiquitin ligase for GRAF1. Importantly, we uncover that CEMIP acts as a scaffold protein in bridging MIB1 and GRAF1, which is critical to GRAF1 degradation and CEMIP-mediated CRC metastasis. Furthermore, we found that CEMIP activates CDC42/MAPK pathway-regulated EMT by enhancing the degradation of GRAF1, which is indispensable to CEMIP-mediated migration and invasion of CRC cells. Subsequently, we prove that CDC42 inhibitor suppresses CEMIP-mediated CRC metastasis in vitro and in vivo. Collectively, our results reveal that CEMIP promotes CRC metastasis through GRAF1/CDC42/MAPK pathway-regulated EMT, and suggest that CDC42 inhibitor could be a novel therapeutic strategy for CEMIP-mediated CRC metastasis.
转移是结直肠癌（CRC）治疗失败和肿瘤相关死亡的主要原因。我们之前的研究报告称，CEMIP 可发挥功能性作用促进 CRC 转移，并且与不良预后密切相关。然而，CEMIP 促进 CRC 转移的分子网络仍未被完全理解。在本研究中，我们鉴定到 CEMIP 与 GRAF1 相互作用，并且高 CEMIP 和低 GRAF1 的组合预测患者的生存不良。在机制上，我们阐明 CEMIP 通过 295-819aa 结构域与 GRAF1 的 SH3 结构域相互作用，并负调控 GRAF1 的稳定性。此外，我们鉴定到 MIB1 是 GRAF1 的 E3 泛素连接酶。重要的是，我们揭示了 CEMIP 作为衔接蛋白在桥接 MIB1 和 GRAF1 中发挥作用，这对于 GRAF1 降解和 CEMIP 介导的 CRC 转移至关重要。此外，我们发现 CEMIP 通过增强 GRAF1 的降解来激活 CDC42/MAPK 通路调控的 EMT，这对于 CEMIP 介导的 CRC 细胞迁移和侵袭是不可或缺的。随后，我们证明了 CDC42 抑制剂可在体外和体内抑制 CEMIP 介导的 CRC 转移。总之，我们的研究结果揭示了 CEMIP 通过 GRAF1/CDC42/MAPK 通路调控的 EMT 促进 CRC 转移，并提示 CDC42 抑制剂可能是针对 CEMIP 介导的 CRC 转移的新型治疗策略。
