Liu Zhen, Liu Jiahao, Li Yang, Wang Hao, Liang Zixi, Deng Xiaojie, Fu Qiaofen, Fang Weiyi, Xu Ping
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong Province, 510095, PR China.
Cancer Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, 510515, PR China.
Genes Dis. 2020 Jan 8;8(3):307-319. doi: 10.1016/j.gendis.2019.12.009. eCollection 2021 May.
The presence of VPS33B in tumors has rarely been reported. Downregulated VPS33B protein expression is an unfavorable factor that promotes the pathogenesis of lung adenocarcinoma (LUAD). Overexpressed VPS33B was shown to reduce the migration, invasion, metastasis, and chemoresistance of LUAD cells to cisplatin (DDP) and . Mechanistic analyses have indicated that VPS33B first suppresses epidermal growth factor receptor (EGFR) Ras/ERK signaling, which further reduces the expression of the oncogenic factor c-Myc. Downregulated c-Myc expression reduces the rate at which it binds the p53 promoter and weakens its transcription inhibition; therefore, decreased c-Myc stimulates p53 expression, leading to decreased epithelial-to-mesenchymal transition (EMT) signal. NESG1 has been shown to be an unfavorable indicator of non-small-cell lung cancer (NSCLC). Here, NESG1 was identified as an interactive protein of VPS33B. In addition, NESG1 was found to exhibit mutual stimulation with VPS33B via reduced RAS/ERK/c-Jun-mediated transcription repression. Knockdown of NESG1 activated EGFR/Ras/ERK/c-Myc signaling and further downregulated p53 expression, which thus activated EMT signaling and promoted LUAD migration and invasion. Finally, we observed that nicotine suppressed VPS33B expression by inducing PI3K/AKT/c-Jun-mediated transcription suppression. Our study demonstrates that VPS33B as a tumor suppressor is significantly involved in the pathogenesis of LUAD.
肿瘤中VPS33B的存在鲜有报道。VPS33B蛋白表达下调是促进肺腺癌（LUAD）发病的不利因素。过表达的VPS33B可降低LUAD细胞对顺铂（DDP）的迁移、侵袭、转移及化疗耐药性。机制分析表明，VPS33B首先抑制表皮生长因子受体（EGFR）Ras/ERK信号传导，进而降低致癌因子c-Myc的表达。c-Myc表达下调会降低其与p53启动子结合的速率并减弱其转录抑制作用；因此，c-Myc减少会刺激p53表达，导致上皮-间质转化（EMT）信号减弱。NESG1已被证明是非小细胞肺癌（NSCLC）的不良指标。在此，NESG1被鉴定为VPS33B的相互作用蛋白。此外，发现NESG1通过减少RAS/ERK/c-Jun介导的转录抑制与VPS33B相互刺激。敲低NESG1可激活EGFR/Ras/ERK/c-Myc信号传导并进一步下调p53表达，从而激活EMT信号传导并促进LUAD的迁移和侵袭。最后，我们观察到尼古丁通过诱导PI3K/AKT/c-Jun介导的转录抑制来抑制VPS33B表达。我们的研究表明，VPS33B作为一种肿瘤抑制因子，在LUAD发病机制中具有重要作用。
