VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer
VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer
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DOI：
10.1002/ijc.32429
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发表时间：
2020-01-15
影响因子：
6.4
通讯作者：
Fang, Weiyi
中科院分区：
文献类型：
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作者：
Chen, Yiyu;Liu, Zhen;Fang, Weiyi
液泡蛋白分选33B （VPS33B）在结直肠癌（CRC）中的生物学作用尚未得到研究。我们报道了VPS33B在葡聚糖硫酸钠/偶氮氧甲烷（DSS/AOM）诱导的CRC小鼠模型和尼古丁处理的CRC细胞中通过PI3K/AKT/c-Jun通路下调。VPS33B降低是促进人类结直肠癌患者预后不良的不利因素。VPS33B过表达通过调节表皮生长因子受体(EGFR)/RAS/ERK/c-Myc/p53/miR-133a-3p反馈回路及下游细胞周期或emt相关因子，在体内外抑制结直肠癌增殖、肝内转移及顺铂（DDP）化疗耐药。此外，NESG1作为新发现的肿瘤抑制因子，通过在细胞质中共定位与VPS33B相互作用，并通过下调RAS/ERK/c- jun介导的转录而受到VPS33B的刺激。NESG1还通过RAS/ERK/c-Jun通路激活VPS33B的表达。抑制NESG1通过逆转vps33b -过表达细胞中的vps33b调节信号来增加细胞的生长、迁移和侵袭。综上所述，VPS33B作为肿瘤抑制因子容易被化学致癌物失调，并与NESG1相互作用，调节EGFR/RAS/ERK/c-Myc/p53/miR-133a-3p反馈回路，从而抑制CRC的恶性表型。
The biological role of vacuolar protein sorting 33B (VPS33B) has not been examined in colorectal cancer (CRC). We report that VPS33B was downregulated in dextran sulfate sodium/azoxymethane (DSS/AOM) -induced CRC mice models and nicotine-treated CRC cells via the PI3K/AKT/c-Jun pathway. Reduced VPS33B is an unfavorable factor promoting poor prognosis in human CRC patients. VPS33B overexpression suppressed CRC proliferation, intrahepatic metastasis and chemoresistance of cisplatin (DDP) in vivo and in vitro through modulating the epidermal growth factor receptor (EGFR)/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and the downstream cell cycle or EMT-related factors. Furthermore, NESG1 as a newly identified tumor suppressor interacted with VPS33B via colocalization in the cytoplasm, and it was stimulated by VPS33B through the downregulation of RAS/ERK/c-Jun-mediated transcription. NESG1 also activated VPS33B expression via the RAS/ERK/c-Jun pathway. Suppression of NESG1 increased cell growth, migration and invasion via the reversion of the VPS33B-modulating signal in VPS33B-overexpressed cells. Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and thus suppress the malignant phenotype of CRC.