Department of Microbiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Int J Biol Sci. 2022 Jan 1;18(1):112-123. doi: 10.7150/ijbs.63388. eCollection 2022.
Persistent infection with high-risk human papillomavirus (HPV) is the main risk factor for cervical cancer. Our mass spectrometry data showed that the Ras-associated binding protein Rab31 was upregulated by HPV; however, little is known regarding the role of Rab31 in the metastasis of cervical cancer cells. In this study, we showed that Rab31 was highly expressed in cervical cancer tissues and cells, and both HPV E6 and E7 promoted the expression of Rab31. Rab31 knockdown inhibited while Rab31 overexpression promoted the migration and invasion capabilities of cervical cancer cells. Additionally, Rab31 knockdown inhibited the epithelial-mesenchymal transition (EMT) and cytoskeletal rearrangement in cervical cancer cells. Furthermore, Rab31 interacted with mitogen-activated protein kinase 6 (MAPK6), and Rab31 knockdown inhibited the expression of MAPK6, which was mainly localized in the cytoplasm. More importantly, Rab31 knockdown promoted and Rab31 overexpression inhibited MAPK6 degradation. Accordingly, MAPK6 overexpression restored the decreased migration potential caused by Rab31 knockdown. Finally, a xenograft mouse model showed that Rab31 knockdown in cervical cancer cells led to reduced tumor growth and impaired lung and liver metastasis . In conclusion, Rab31 plays a crucial role in cervical cancer metastasis by inhibiting MAPK6 degradation. Thus, Rab31 may serve as a novel therapeutic target to manage cervical cancer.
持续性感染高危型人乳头瘤病毒（HPV）是宫颈癌的主要危险因素。我们的质谱数据显示 HPV 上调了 Ras 相关结合蛋白 Rab31；然而，Rab31 在宫颈癌转移中的作用知之甚少。在这项研究中，我们表明 Rab31 在宫颈癌组织和细胞中高表达，HPV E6 和 E7 均促进 Rab31 的表达。Rab31 敲低抑制而 Rab31 过表达促进宫颈癌细胞的迁移和侵袭能力。此外，Rab31 敲低抑制宫颈癌细胞中的上皮-间充质转化（EMT）和细胞骨架重排。此外，Rab31 与丝裂原活化蛋白激酶 6（MAPK6）相互作用，Rab31 敲低抑制 MAPK6 的表达，MAPK6 主要定位于细胞质中。更重要的是，Rab31 敲低促进而 Rab31 过表达抑制 MAPK6 降解。因此，MAPK6 过表达恢复了 Rab31 敲低引起的迁移潜力降低。最后，异种移植小鼠模型表明 Rab31 敲低可导致宫颈癌细胞中肿瘤生长减少，并损害肺和肝转移。总之，Rab31 通过抑制 MAPK6 降解在宫颈癌转移中发挥关键作用。因此，Rab31 可能成为管理宫颈癌的新治疗靶点。
