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首页> 外文期刊>Journal of experimental & clinical cancer research : >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-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA

机译：RNA结合蛋白IMP3是通过稳定MEKK1 mRNA的结肠直肠癌进展的MEK1 / ERK信号通路的新型调节器

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MEK1/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. To 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. We 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. Our 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.
机译：MEK1 / ERK信号通路在大多数肿瘤进展中起重要作用，包括结肠直肠癌（CRC），然而，MEK1靶向治疗在治疗CRC患者方面几乎没有有效，表明可能存在激活MEK1 / ERK信号通路的复杂机制以外RAS激活机制。为了调查IMP3的临床意义，我们分析了上海复旦大学癌症中心的公共数据集和样本中的表达水平。通过体外和体内实验确定了IMP3对增殖，迁移和侵袭的影响。为了研究Imp3在结肠癌中的作用，产生有条件的IMP3敲除C57BL / 6小鼠。通过RNA测序，RNA免疫沉淀，荧光素酶报告称和Western印迹测定，筛选和验证CRC中的IMP3 / MEKK1 / MEK / ERK信号轴。我们发现RNA结合蛋白IMP3直接与MEKK1 mRNA 3'-UTR结合，调节其稳定性，促进MEKK1表达并顺序激活MEK1 / ERK信号传导。在功能上，IMP3通过MEKK1 / MEK1 / ERK信号通路在体外和体内促进CRC细胞的恶性生物过程，而且IMP3？/？与氮氧基甲烷/葡聚糖钠硫酸钠处理后，比例表明，与野生型小鼠相比，MEKK1的表达和结肠直肠肿瘤相比。临床上，IMP3和MEKK1的表达是阳性相关的，并且CRC患者的转移伴随的IMP3和MEKK1蛋白质水平负相关。此外，Mek1抑制剂与ShRNA-Imp3组合的抑制剂在体外和体内具有协同作用。我们的研究表明，IMP3调节CRC中的MEKK1，从而激活了结直肠癌进展中的MEK1 / ERK信号传导，此外，这些结果对CRC的临床前试验中的其他靶疗法将MEK1抑制剂与其他靶疗法相结合的潜在应用提供了新的见解耐心。

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