circNRIP1抑制POFUT1/Notch通路调控结直肠癌发生发展的分子机制和临床意义研究

结直肠癌（CRC）是全球高发恶性肿瘤，早期诊断困难和转移是主要致死原因。我们前期利用CRC组织环状RNA（circRNA）芯片和数据库筛选发现：circNRIP1在CRC组织和血浆外泌体异常表达；上调其表达显著抑制CRC细胞增殖和转移能力；机制研究表明，circNRIP1通过吸附IGF2BP1，抑制POFUT1/Notch通路活性。我们据此提出科学假说：CRC通过外泌体清除circNRIP1，激活IGF2BP1/POFUT1/Notch通路，促进自身恶性进展。本项目将承前启后，通过一系列体内外实验，并结合大量临床组织和血液样本，明确circNRIP1/IGF2BP1/POFUT1/Notch轴调控CRC发生发展的分子功能和机制，探讨组织和血浆外泌体circNRIP1作为CRC早期诊断和疗效监测标志物的临床肿瘤学意义。项目完成将为揭示CRC发生发展的分子机制、开发新的诊疗标志物提供实验依据。

The incidence of colorectal cancer (CRC) is very high worldwide. Clinically, difficulty in early diagnosis and metastasis are primary causes of death due to CRC. Studies have demonstrated that circular RNA (circRNA) took part in carcinogenesis and development of cancers including CRC, while the molecular mechanism remains unclear. In our preliminary experiments, we identified a circRNA, hsa_circ_0004771, i.e., circNRIP1, by circRNA array and verified by Real-time quantitative PCR (RT-qPCR), was significantly downregulated in CRC tissue and upregulated in plasma exosomes of CRC patients. Overexpression of circNRIP1 could substantially suppress the proliferation and metastasis of CRC cells both in vitro and in vivo. Molecular mechanical study revealed that circNRIP1 could sponge IGF2BP1, thus reducing the mRNA stability and protein level of POFUT1, resulting in suppressed Notch pathway. Based on these findings, we came up with the scientific hypothesis that in CRC cells, HNRNPM mediated exosomal assemble and downregulation of circNRIP1, activating IGF2BP1/POFUT1/Notch pathway, resulting in CRC progression. Therefore, in the present project, by using a series of in vitro and in vivo studies, we aim to further confirm the biological functions and molecular mechanisms of circNRIP1 in CRC, and furthermore, to explore the clinical significance of plasma exosomal circNRIP1 in CRC patients. We believe that the results of our study will provide experimental evidences to elucidate the exact molecular mechanisms for carcinogenesis and development of CRC, and might identify new molecular biomarkers in CRC diagnosis and/or treatment.