Liu Shuang, Tian Shaoping, Lin Tianyu, He Xin, Eze Ideozu Justin, Wang Rui, Wang Yong, Yue Dan, Geng Hua
Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China.
Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
Front Genet. 2022 Oct 18;13:1034889. doi: 10.3389/fgene.2022.1034889. eCollection 2022.
Breast cancer is a leading cause of death and morbidity among female cancers. Several factors, including hormone levels, lifestyle, and dysregulated RNA-binding proteins, have been associated with the development of breast cancer. Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and protein kinase C, Zeta isoform (PKCζ) are oncogenes implicated in numerous cancers, including breast cancer. However, their interaction and role in promoting breast cancer proliferation and metastasis have not been well-characterized. In the present study, we demonstrated that G3BP1 expression was elevated in breast cancer and that knockdown of G3BP1 diminished the proliferation and metastasis of breast cancer cells. Mechanistically, we identified proliferation and a series of metastasis-related properties, including chemotaxis, migration, Golgi polarity localization, and actin polymerization, that were modulated by G3BP1 knockdown. We found that G3BP1 and PKCζ were co-localized and interacted intracellularly, and they co-underwent membrane translocation under EGF stimulation. Following the knockdown of G3BP1, we observed the membrane translocation and phosphorylation of PKCζ were significantly impaired, suggesting that G3BP1 regulates the activation of PKCζ. Our findings indicate that G3BP1 plays multiple roles in breast cancer cell proliferation and metastasis. The activation of PKCζ by G3BP1 may be the specific mechanism underlying the process.
乳腺癌是女性癌症中导致死亡和发病的主要原因。包括激素水平、生活方式和RNA结合蛋白失调在内的多种因素与乳腺癌的发生有关。Ras鸟苷三磷酸酶激活蛋白SH3结构域结合蛋白1（G3BP1）和蛋白激酶Cζ亚型（PKCζ）是涉及包括乳腺癌在内的多种癌症的癌基因。然而，它们在促进乳腺癌增殖和转移中的相互作用及作用尚未得到充分表征。在本研究中，我们证明G3BP1在乳腺癌中表达升高，并且敲低G3BP1可减少乳腺癌细胞的增殖和转移。从机制上讲，我们确定了增殖以及一系列与转移相关的特性，包括趋化性、迁移、高尔基体极性定位和肌动蛋白聚合，这些特性受G3BP1敲低的调节。我们发现G3BP1和PKCζ在细胞内共定位并相互作用，并且在表皮生长因子（EGF）刺激下它们共同发生膜转位。敲低G3BP1后，我们观察到PKCζ的膜转位和磷酸化明显受损，表明G3BP1调节PKCζ的激活。我们的研究结果表明G3BP1在乳腺癌细胞增殖和转移中起多种作用。G3BP1对PKCζ的激活可能是该过程的具体机制。
