RNA-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA.
RNA-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA.
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RNA结合蛋白IMP3是MEK1/ERK信号通路的新型调节剂，通过稳定MEKK1 mRNA来调节结直肠癌的进展
DOI：
10.1186/s13046-021-01994-8
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发表时间：
2021-06-21
期刊：
影响因子：
--
通讯作者：
Wei P
中科院分区：
文献类型：
--
作者：
Zhang M;Zhao S;Tan C;Gu Y;He X;Du X;Li D;Wei P
背景MEK 1/ERK信号通路在包括结直肠癌（CRC）在内的大多数肿瘤的进展中起重要作用，然而靶向MEK 1的治疗对CRC患者的治疗效果不佳，提示除了RAS激活机制外，MEK 1/ERK信号通路的激活可能还有复杂的机制。我们分析了其在公开数据集和复旦大学上海肿瘤防治中心样本中的表达水平。通过体外和体内实验确定IMP3对增殖、迁移和侵袭的影响。为了研究IMP 3在结肠癌发生中的作用，产生条件性IMP 3敲除C57 BL/6小鼠。结果发现IMP3与MEKK 1 mRNA 3′-UTR直接结合，调节MEKK 1 mRNA的稳定性，促进MEKK 1的表达，进而激活MEK 1/ERK信号通路。在功能上，IMP3通过MEKK 1/MEK 1/ERK信号通路在体外和体内促进CRC细胞的恶性生物学过程。此外，与野生型小鼠相比，用氧化偶氮甲烷/葡聚糖硫酸钠处理后，IMP3−/−小鼠显示MEKK 1表达降低以及结直肠肿瘤。在临床上，IMP3和MEKK 1的表达呈正相关，并且IMP3和MEKK 1蛋白水平与CRC患者的转移呈负相关。此外，MEK 1抑制剂与shRNA-IMP3联合应用在体内外均具有协同效应。结论我们的研究表明，IMP3在结直肠癌中调节MEK 1，从而激活MEK 1/ERK信号通路，促进结直肠癌的进展。
BackgroundMEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), however, MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism.MethodsTo investigate the clinical significance of IMP3, we analyzed its expression levels in publicly available dataset and samples from Fudan University Shanghai Cancer Center. The effects of IMP3 on proliferation, migration, and invasion were determined by in vitro and in vivo experiments. To investigate the role of IMP3 in colon carcinogenesis, conditional IMP3 knockout C57BL/6 mice was generated. The IMP3/MEKK1/MEK/ERK signaling axis in CRC was screened and validated by RNA-sequencing, RNA immunoprecipitation, luciferase reporter and western blot assays.ResultsWe find RNA binding protein IMP3 directly bind to MEKK1 mRNA 3′-UTR, which regulates its stability, promote MEKK1 expression and sequentially activates MEK1/ERK signaling. Functionally, IMP3 promote the malignant biological process of CRC cells via MEKK1/MEK1/ERK signaling pathway both in vitro and in vivo, Moreover,IMP3−/−mice show decreased the expression of MEKK1 as well as colorectal tumors compared with wild-type mice after treatment with azoxymethane/dextran sodium sulfate. Clinically, the expression of IMP3 and MEKK1 are positive correlated, and concomitant IMP3 and MEKK1 protein levels negatively correlate with metastasis in CRC patients. In addition, MEK1 inhibitor in combination with shRNA-IMP3 have a synergistic effect both in vitro and in vivo.ConclusionOur study demonstrates that IMP3 regulates MEKK1 in CRC, thus activating the MEK1/ERK signaling in the progression of colorectal cancer, Furthermore, these results provide new insights into potential applications for combining MEK1 inhibitors with other target therapy such as IMP3 in preclinical trials for CRC patients.
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