IGF2BP3通过转录后调控KRAS促进结直肠癌发生和演进的机制及其在抗EGFR单抗耐药中的作用

IGF2BP3 is a differential expression gene of colorectal cancer from our preliminary study through high-throughput transcriptome sequencing, our results showed that IGF2BP3 promoted CRC cells proliferation, invasion and metastasis, and was asociated with anti- EGFR monoclonal antibody resistance . In view of our preliminary analysis and study, we propose that IGF2BP3 promotes tumorigenesis, progression of colorectal cancer by regulating the expression of KRAS at post-transcriptional level, and which is related to anti-EGFR monoclonal antibody resistance. This subject intends to engineer orthotopic colon metastatic mouse models using IGF2BP3-overexpressing and knockout CRC cell lines, then observe the role of IGF2BP3 deregulation on proliferation, invasion and metastasis. Moveover, we will detect the binding between IGF2BP3 protein and KRAS mRNA through RIP, EMSA, and explor the underlying mechanism about regulating the activty of EGFR pathway signaling. Furthermore, we will investigate sensitivity and resistance of CRC cells to anti-EGFR monoclonal antibody after IGF2BP3 overexpress or knockout, We will also further analyze the association among the EGFR-targeted antibody resistance between IGF2BP3 and KRAS expression in a large cohort of CRC tissues. The project will provide important theoretical basis for revealing molecular mechanism of progression of CRC at post-transcriptional level and discovering the potential therapeutic targets for CRC.

IGF2BP3是本课题组通过转录组测序所筛选出的一个CRC相关差异表达基因，前期研究发现IGF2BP3表达上调促进CRC细胞增殖和迁移，并与抗EGFR单抗耐药有关，但其分子机制尚不清楚。鉴于前期的分析研究，我们初步提出“IGF2BP3通过靶向结合KRAS mRNA分子在转录后水平调节EGFR通路的活性，参与CRC的发生和演进及抗EGFR单抗耐药的产生”。本项目拟建立可视化原位移植瘤转移动物模型，进一步分析IGF2BP3对CRC细胞增殖、侵袭转移能力的影响；利用RIP、EMSA等实验检测IGF2BP3蛋白与KRAS mRNA的结合，探讨其作用机制；通过体内外实验，观察IGF2BP3过表达和敲除CRC细胞对抗EGFR单抗的敏感及耐药性；并在临床标本中验证IGF2BP3、KRAS表达与抗EGFR单抗耐药的相关性。本项目将为在转录后水平揭示CRC演进的分子机制及开发潜在治疗靶点的提供重要理论基础。

IGF2BP3是本课题组通过转录组测序所筛选出的一个CRC相关差异表达基因，前期研究发现IGF2BP3表达上调促进CRC细胞增殖和迁移，并与抗EGFR单抗耐药有关，但其分子机制尚不清楚。本研究发现IGF2BP3在结直肠癌组织中表达显著上调，并且其表达与结直肠癌的恶性进展及与不良预后密切相关；IGF2BP3蛋白通过结合EGFR mRNA分子，维持其稳定性，转录后持续激活EGFR信号通路，进而促进结直肠癌的发生和演进，并通过转录后调节EGFR信号通路的活性，增强了结直肠癌细胞对EGFR单抗药物西妥昔单抗药物的耐药。本研究成果有望为结直肠癌的靶向治疗及耐药逆转等方面提供重要的分子靶点。