ERK调控NF90影响结直肠癌发生发展和代谢的研究

EGFR signal pathway has been reported to play key roles during Colorectal cancer (CRC) malignant progression. We previously identified that EGFR-Erk pathway activation can promote NF90 expression and knockdown of NF90 modulates tumor metabolism. However， the role of NF90 in CRC malignant progression is uncertain. Moreover, we found that NF90 is highly expressed in CRC and it can promote CRC malignant progression and modulate tumor metabolism. Thus, we hypothesized that “Erk regulated NF90 affects CRC malignant progression and tumor metabolism”. We plan to use large scale clinical samples to explore the relationships between CRC and NF90. With establishment of CRC orthotopic and subcutaneous mice models, we will measure the tumor growth and the antitumor effects of EGFR pathway inhibitors in the presence or absence of NF90. Furthermore, we plan to thoroughly study the tumor metabolism regulated by NF90 in cellular levels, including metabolism related genes and metabolic products. The project will systematic analyze the effect of NF90 during CRC progression and will provide rational therapeutic strategy in targeting EGFR pathway for treatment of CRC.

EGFR通路被发现在结直肠癌（CRC）发生发展中起到关键的作用且多种抑制剂已被开发用于癌症治疗。我们前期研究表明EGFR-Erk通路激活可以在CRC上调NF90，影响肿瘤代谢。然而，NF90在CRC恶性进展中的作用尚不明确。因此我们提出假设“ERK调控NF90影响CRC发生发展和肿瘤代谢”。本项目拟通过大规模临床调查探索NF90在CRC恶性进展中的作用。利用小鼠原位和异位肿瘤模型研究NF90在CRC发展中的作用以及NF90对EGFR通路抑制剂抗肿瘤效应的影响。在细胞水平对NF90调控肿瘤代谢进行深入研究，包括代谢相关基因与代谢产物的改变。本课题旨在从“临床-动物-细胞”多角度分析NF90在CRC发生发展中的作用及其上下游调控机制，为靶向EGFR通路治疗癌症提供新的思路。

丝氨酸甘氨酸一碳代谢通路(SGOC)在多种代谢过程重发挥重要作用。SGOC基因表达水平在肿瘤发生过程中表达异常，表明原癌基因参与了SGOC基因的调控。然而，具体调控机制仍不明确。在此，我们通过大规模临床分析鉴定发现白介素增强结合因子（ILF3，又名NF90）在原发结直肠癌中高表达，并且与肿瘤恶性预后相关。ILF3通过调节SGOC基因稳定性发挥这重要代谢调节作用，从而增加SGOC基因表达和促进肿瘤生长。机制研究表明，EGF-MEK-ERK通路介导ILF3的磷酸化，从而阻止E3连接酶SPOP街道的泛素化和ILF3的蛋白酶体降解。重要地，我们发现SGOC抑制剂可以阻止ERK-ILF3高表达的PDX生长。总之，EGF-ERK通路介导的ILF3的异常对丝氨酸代谢重编程具有重要作用，并且会导致结直肠癌的恶性进展。我们的发现表明通过抑制SGOC通路可能可以抑制ILF3高表达的结直肠癌的生长。