Department of Gynecology, the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Cancer Sci. 2021 May;112(5):1785-1797. doi: 10.1111/cas.14864. Epub 2021 Mar 31.
The pathogenesis and cisplatin chemoresistance of ovarian cancer (OC) are still unclear. Vacuolar protein sorting-associated 33B (VPS33B) has not been reported in OC to date. In this study, immunohistochemistry was used to detect VPS33B protein expression between OC and ovarian tissues. MTT, EdU, colony formation, cell cycle, in vivo tumorigenesis, western blot, ChIP, EMSA, co-immunoprecipitation (CoIP), qRT-PCR, and microconfocal microscopy were used to explore the function and molecular mechanisms of VPS33B in OC cells. The results of the present study demonstrated that VPS33B protein expression was obviously reduced in OC compared with that in ovarian tissues. Overexpressed VPS33B suppressed cell cycle transition, cell growth, and chemoresistance to cisplatin in vitro and in vivo. Analysis of the mechanism indicated that overexpressed VPS33B regulated the epidermal growth factor receptor (EGFR)/PI3K/AKT/c-Myc/p53/miR-133a-3p feedback loop and reduced the expression of the cell cycle factor CDK4. Nasopharyngeal epithelium-specific protein 1 (NESG1) as a tumor suppressor not only interacted with VPS33B, but was also induced by VPS33B by the attenuation of PI3K/AKT/c-Jun-mediated transcription inhibition. Overexpressed NESG1 further suppressed cell growth by mediating VPS33B-modulated signals in VPS33B-overexpressing OC cells. Finally, NESG1 induced VPS33B expression by reducing the inhibition of PI3K/AKT/c-Jun-mediated transcription. Our study is the first to demonstrate that VPS33B serves as a tumor suppressor, and VPS33B can interact with NESG1 to suppress cell growth and promote cisplatin sensitivity by regulating the EGFR/PI3K/AKT/c-Myc/p53/miR-133a-3p feedback loop in OC cells.
卵巢癌（OC）的发病机制和顺铂化疗耐药性尚不清楚。到目前为止，在 OC 中尚未报道有空泡分选相关 33B（VPS33B）。在本研究中，通过免疫组织化学检测 OC 和卵巢组织之间 VPS33B 蛋白的表达。使用 MTT、EdU、集落形成、细胞周期、体内肿瘤发生、western blot、ChIP、EMSA、共免疫沉淀（CoIP）、qRT-PCR 和微共聚焦显微镜来探索 VPS33B 在 OC 细胞中的功能和分子机制。本研究结果表明，与卵巢组织相比，OC 中 VPS33B 蛋白表达明显降低。过表达 VPS33B 抑制 OC 细胞体外和体内的细胞周期转换、细胞生长和对顺铂的化疗耐药性。机制分析表明，过表达 VPS33B 调节表皮生长因子受体（EGFR）/PI3K/AKT/c-Myc/p53/miR-133a-3p 反馈环，降低细胞周期因子 CDK4 的表达。鼻咽癌特异性蛋白 1（NESG1）作为一种肿瘤抑制因子，不仅与 VPS33B 相互作用，而且还通过 VPS33B 减弱 PI3K/AKT/c-Jun 介导的转录抑制来诱导 NESG1 的表达。过表达 NESG1 通过介导 VPS33B 过表达 OC 细胞中调节的信号进一步抑制细胞生长。最后，NESG1 通过减少 PI3K/AKT/c-Jun 介导的转录抑制来诱导 VPS33B 的表达。我们的研究首次表明 VPS33B 作为一种肿瘤抑制因子，VPS33B 可以与 NESG1 相互作用，通过调节 OC 细胞中的 EGFR/PI3K/AKT/c-Myc/p53/miR-133a-3p 反馈环来抑制细胞生长并促进顺铂敏感性。
