ABSTRACT

Rhophilin Rho GTPase binding protein 2 (P76RBE) belongs to rhophilin family of Rho-GTPase-binding proteins and is found to contribute to the development of diverse cancers. Data in Oncomine and Kaplan–Meier Plotter databases showed that P76RBE was upregulated in ovarian cancer tissues compared with normal tissues, and patients with high P76RBE expression had worse overall survival, which indicated P76RBE may be associated with the pathogenesis of ovarian cancer. This study aimed to investigate the role of P76RBE in ovarian cancer and to reveal the possible underlying mechanisms. The results demonstrated that P76RBE was highly expressed in ovarian cancer tissues and ovarian cancer cell lines. Functionally, silencing of P76RBE suppressed the proliferation, induced cell cycle arrest, and inhibited migration and invasion in OVCAR-3 and OV-90 cells, while overexpression of P76RBE showed opposite effects on A2780 cells. Mechanically, P76RBE silencing resulted in downregulation of integrin β1, accompanying the reduced NF-κB p65 phosphorylation and nuclear translocation. Importantly, integrin β1 knockdown effectively rescued the effects of P76RBE overexpression on ovarian cancer cells with suppressed proliferation, migration, and invasion. Additionally, in the xenograft tumors derived from OVCAR-3 and OV-90 cell lines, P76RBE knockdown inhibited tumor growth. Meanwhile, the expression of integrin β1 and NF-κB p65 phosphorylation was decreased. In summary, our findings indicate that P76RBE contributes to the progression of ovarian cancer through regulating the integrin β1/NF-κB signaling, and it may be a promising target for ovarian cancer therapy.

摘要

Rhophilin Rho GTPase 结合蛋白 2 (P76RBE) 属于 Rho-GTPase 结合蛋白的 rhophilin 家族，被发现有助于多种癌症的发展。Oncomine 和 Kaplan-Meier Plotter 数据库中的数据显示，与正常组织相比，P76RBE 在卵巢癌组织中表达上调，P76RBE 高表达的患者总生存期较差，提示 P76RBE 可能与卵巢癌的发病机制有关。本研究旨在探讨 P76RBE 在卵巢癌中的作用并揭示可能的潜在机制。结果表明，P76RBE在卵巢癌组织和卵巢癌细胞系中高表达。在功能上，P76RBE 的沉默抑制了 OVCAR-3 和 OV-90 细胞的增殖，诱导细胞周期停滞，并抑制了迁移和侵袭，而 P76RBE 的过表达对 A2780 细胞表现出相反的作用。机械地，P76RBE 沉默导致整合素 β1 的下调，伴随着减少的 NF-κB p65 磷酸化和核转位。重要的是，整合素 β1 敲低有效地挽救了 P76RBE 过表达对卵巢癌细胞增殖、迁移和侵袭的抑制作用。此外，在源自 OVCAR-3 和 OV-90 细胞系的异种移植肿瘤中，P76RBE 敲低抑制了肿瘤生长。同时，整合素β1和NF-κB p65磷酸化的表达降低。总之，我们的研究结果表明，P76RBE 通过调节整合素 β1/NF-κB 信号传导促进卵巢癌的进展，它可能是卵巢癌治疗的一个有希望的靶点。