RAI16负调控肿瘤相关巨噬细胞c/EBPβ-TGF-β1通路抑制结直肠癌的机制研究

结直肠癌（CRC）严重威胁人类健康，GEO数据库显示维甲酸诱导蛋白16（RAI16）在CRC患者肿瘤组织中明显下调，并与肿瘤转移高度相关。申请人长期专注于RAI16的功能研究，发现RAI16基因敲除可显著促进AOM/DSS诱导小鼠的CRC发病进程。并发现，与从野生型CRC小鼠分离的肿瘤相关巨噬细胞（TAMs）相比，从RAI16基因敲除CRC小鼠分离的TAMs在体外可显著促进CRC细胞增殖、迁移、侵袭及上皮间质转化，TGF-β1及其上游转录因子c/EBPβ表达显著升高，而TGF-β1中和抗体抑制其对CRC细胞恶性转化的促进作用，提示RAI16通过负调控TAMs中TGF-β1的表达而抑制CRC进展。本课题将利用体内外实验进一步研究RAI16负调控TAMs中c/EBPβ-TGF-β1通路，抑制TGF-β1表达，从而抑制CRC细胞恶性转化的分子机制，为CRC治疗提供新的有效靶点和理论依据。

Colorectal cancer (CRC) is a great threat to human health. The GEO database shows that retinoic acid-induced protein 16 (RAI16) is significantly down-regulated in tumor tissues of CRC patients and is highly related to tumor metastasis. We have focused on the functional study of RAI16 for a long period of time. Our previous study revealed that RAI16 gene knockout promoted the progression of CRC in AOM/DSS-induced CRC mice model. Further study disclosed that compared with tumor-associated macrophages (TAMs) isolated from wild type CRC mice, TAMs isolated from RAI16 gene knockout CRC mice significantly promoted the proliferation, migration, invasion and epithelial-mesenchyme transformation of CRC cells in vitro; The expression of TGF-β1 and c/EBPβ, a transcription factor of TGF-β1, was increased significantly; And, the neutralizing antibody of TGF-β1 could inhibit the effect of TAMs derived from RAI16 gene knockout CRC mice, that promoting the malignant transformation of CRC cells. The above results indicated that RAI16 inhibited the progression of CRC by inhibiting the expression of TGF-β1 of TAMs. In this study, the molecular mechanism of RAI16 negatively regulating the c/EBPβ-TGF-β1 pathway to inhibit the expression of TGF-β1 of TAMs, then inhibiting the malignant transformation of CRC cells, will be explored in vitro and in vivo. A new treatment target and the theoretical basis will be provided for clinical CRC therapy.