抑癌因子ZNRF3异常表达是CRC发生发展的重要原因，但其内在调控机制不明。申请人前期发现lncRNA-miRNA间的调控范式可驱动病理基因表达参与疾病进程，因而通过生物信息学分析和细胞验证发现lncRNA GTF2IRD2P1可竞争性结合miR-146a/b调控ZNRF3表达。研究中还发现肿瘤微环境中的肿瘤相关成纤维细胞（CAFs）分泌的CXCL11可能是导致CRC中GTF2IRD2P1低表达的根本原因。因而提出CAFs分泌的CXCL11可抑制癌细胞中lncRNA GTF2IRD2P1表达，进而介导miR-146a/b/ZNRF3轴，促进肿瘤增殖和转移，加速CRC进程。本项目拟在临床组织检测各因子的表达；细胞实验验证各因子间的靶向关系；细胞和原位移植瘤模型中验证该通路在CAFs促癌表型中的功能作用，以期进一步阐明CRC的发生及演进机制，为该病的早期诊断或预后提供新的思路和实验基础。

Abnormal expression of the tumor suppressor factor ZNRF3 is an important cause of CRC development, but its intrinsic regulation mechanism is unknown. Applicants have previously discovered that the regulatory paradigm between lncRNA-miRNAs can drive the expression of pathological genes involved in disease progression. Therefore, bioinformatics analysis and cell validation revealed that lncRNA GTF2IRD2P1 can competitively bind to miR-146a/b to regulate ZNRF3 expression. The study also found that CXCL11 secreted by Cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be the underlying cause of low expression of GTF2IRD2P1 in CRC. Therefore, it is proposed that CXCL11 secreted by CAFs can inhibit the expression of lncRNA GTF2IRD2P1 in cancer cells, and then mediate miR-146a/b/ZNRF3 axis, promote tumor proliferation and metastasis, finally accelerate CRC progression. This project intends to detect the expression of various factors in clinical tissues; cell experiments verify the targeted regulation relationship between various factors in the pathway; verify the functional role of this pathway in CAFs promoting tumor proliferation and metastasis in cells and orthotopic transplanted tumors model. In order to further clarify the occurrence and evolution mechanism of CRC, it provides a new idea and experimental basis for the early diagnosis or prognosis of the disease.