Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Oncogene. 2019 Feb;38(7):935-949. doi: 10.1038/s41388-018-0493-8. Epub 2018 Sep 10.
Tumor metastasis is the main cause of death in advanced colorectal cancer. Our previous research showed that upregulation of KIAA1199 predicted poorer outcomes, and promoted cell motility and tumor metastasis in colorectal cancer, with the mechanisms not being fully elucidated. Here, we demonstrate that silencing of KIAA1199 results in reduced tumor metastasis in the orthotopic transplantation tumor model of colorectal cancer. Importantly, we find that KIAA1199 interacts with protein phosphatase 2A (PP2A) through the C-terminal domain and increases phosphatase activity of PP2A, which is essential for KIAA1199-mediated cell motility. Moreover, we identify stathmin, a microtubule-destabilizing protein, as a downstream of KIAA1199-PP2A complex. KIAA1199-induced dephosphorylation of stathmin results in microtubule destabilization and leads to enhanced cell motility. Furthermore, a microtubule-stabilizing drug paclitaxel could prevent KIAA1199-induced microtubule destabilization, and inhibit cell migration and invasion in vitro and tumor metastasis in vivo in colorectal cancer. Collectively, our study reveals that KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway, and suggests that KIAA1199 may be a promising target for preventing metastasis in colorectal cancer.
肿瘤转移是晚期结直肠癌患者死亡的主要原因。我们之前的研究表明，KIAA1199 的上调预示着更差的预后，并促进了结直肠癌的细胞迁移和肿瘤转移，但其机制尚未完全阐明。在这里，我们证明沉默 KIAA1199 可减少结直肠癌细胞原位移植肿瘤模型中的肿瘤转移。重要的是，我们发现 KIAA1199 通过 C 端结构域与蛋白磷酸酶 2A（PP2A）相互作用，并增加 PP2A 的磷酸酶活性，这对于 KIAA1199 介导的细胞迁移是必不可少的。此外，我们鉴定了微管不稳定蛋白 stathmin 是 KIAA1199-PP2A 复合物的下游靶点。KIAA1199 诱导的 stathmin 去磷酸化导致微管不稳定，从而增强细胞迁移。此外，微管稳定剂紫杉醇可预防 KIAA1199 诱导的微管去稳定，并抑制结直肠癌细胞在体外的迁移和侵袭以及体内的肿瘤转移。综上所述，我们的研究揭示了 KIAA1199 通过 PP2A/stathmin 通路调控微管稳定性促进结直肠癌细胞转移，并表明 KIAA1199 可能是预防结直肠癌转移的有前途的靶点。
