Department of Obstetrics and Gynecology, Bao'an Maternity and Child Health Hospital, Jinan University, Shenzhen, 518100, China.
Maternal-Fetal Medicine Institute, Bao'an Maternity and Child Health Hospital, Jinan University, Shenzhen, 518100, China.
Exp Mol Med. 2019 Apr 19;51(4):1-12. doi: 10.1038/s12276-019-0236-0.
Rho GTPase-activating protein 26 (ARHGAP26) is a negative regulator of the Rho family that converts the small GTP-binding protein RhoA (GTP-RhoA) to its inactive GDP-bound form and is a putative tumor suppressor gene associated with cell growth and migration. Here, the involvement of ARHGAP26 in ovarian cancer cell proliferation and migration was investigated. In this study, low ARHGAP26 expression was observed in ovarian cancer tissues and was associated with a poor overall survival and higher β-catenin expression in patients with ovarian cancer. A2780 and HEY cells with ARHGAP26 upregulation showed decreased cell proliferation, migration, and invasion, along with decreased GTP-RhoA, β-catenin, VEGF, MMP2, and MMP7 expression. ARHGAP26 upregulation in A2780 cells also inhibited lung metastasis in vivo. SKOV3 cells with ARHGAP26 downregulation demonstrated an inverse effect, which was inhibited by ARHGAP26 overexpression or DKK1, an antagonist of the β-catenin pathway. SMURF1, an E3 ubiquitin ligase, interacted with and induced ubiquitination of ARHGAP26. ARHGAP26 upregulation in SKOV3 cells significantly inhibited SMURF1 upregulation-induced cell migration and invasion. Overall, SMURF1-mediated ubiquitination of ARHGAP26 may promote invasion and migration of ovarian cancer cells via the β-catenin pathway.
Rho GTPase 激活蛋白 26（ARHGAP26）是 Rho 家族的负调控因子，可将小分子 GTP 结合蛋白 RhoA（GTP-RhoA）转化为其无活性的 GDP 结合形式，是一种与细胞生长和迁移相关的潜在肿瘤抑制基因。在此，研究了 ARHGAP26 在卵巢癌细胞增殖和迁移中的作用。在这项研究中，观察到卵巢癌组织中 ARHGAP26 表达水平较低，与患者总生存期较差和β-连环蛋白表达水平较高相关。ARHGAP26 上调的 A2780 和 HEY 细胞表现出细胞增殖、迁移和侵袭能力降低，同时 GTP-RhoA、β-连环蛋白、VEGF、MMP2 和 MMP7 的表达降低。A2780 细胞中 ARHGAP26 的上调也抑制了体内的肺转移。下调 ARHGAP26 的 SKOV3 细胞表现出相反的效果，这种效果可被 ARHGAP26 过表达或β-连环蛋白通路的拮抗剂 DKK1 抑制。E3 泛素连接酶 SMURF1 与 ARHGAP26 相互作用并诱导其泛素化。ARHGAP26 在 SKOV3 细胞中的上调显著抑制了 SMURF1 上调诱导的细胞迁移和侵袭。总体而言，SMURF1 介导的 ARHGAP26 泛素化可能通过β-连环蛋白通路促进卵巢癌细胞的侵袭和迁移。
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