干扰素γ抑制的长链非编码RNA MAFG-DT通过招募PRC2调节CXCL9表达影响结直肠癌免疫浸润和转移的研究

The tumor immune microenvironment and its role in tumorigenesis and development has gradually attracted people attention. The roles of lncRNA in tumor immune microenvironment has rarely been reported. Our previous studies have found that there are many changes in the expression of lncRNA in colorectal cancer cells induced by interferon gamma, and MAFG-DT decreased the most. MAFG-DT can negatively regulate the increase of Th1 chemokine CXCL9 induced by interferon gamma; We also found that the expression of MAFG-DT was abnormally elevated in colorectal cancer. After knocking down MAFG-DT, the expression of CXCL9 was elevated in colorectal cancer cells. Bioinformatics analysis showed that the expression of MAFG-DT in colorectal cancer was negatively correlated with immune infiltration and MAFG-DT might bind to PRC2. In addition, it has been reported that PRC2-mediated histone H3K27me3 enrichment causes low expression of CXCL9 in cancer cells. Therefore, according to the previous experimental results and related literature, we speculate that MAFG-DT can inhibit the expression of CXCL9 by recruiting PRC2, and that the overexpression of MAFG-DT in colorectal cancer tissue can reduce the immune infiltration of tumor tissue, increase angiogenesis of tumor tissue, and promote the occurrence and development of colorectal cancer by inhibiting the expression of CXCL9. This study will provide a novel target for the diagnosis and treatment of colorectal cancer.

肿瘤免疫微环境逐渐引起人们的重视，长链非编码RNA在肿瘤免疫微环境中的作用目前鲜有报道。我们前期研究发现干扰素γ诱导结直肠癌细胞的过程中许多lncRNA的表达发生改变，其中MAFG-DT下降最明显，并且其可负向调控干扰素γ诱导Th1型趋化因子CXCL9的升高；我们还发现MAFG-DT在结直肠癌中表达显著升高，敲减MAFG-DT促进CXCL9表达，生物信息学分析显示结直肠癌中MAFG-DT的表达与肿瘤组织免疫细胞浸润呈负相关，并且MAFG-DT可能和PRC2结合。文献报道称，肿瘤中PRC2介导的组蛋白H3K27me3富集导致了肿瘤细胞CXCL9低表达。因此，我们推测MAFG-DT可以通过招募PRC2抑制CXCL9表达，结直肠癌组织中MAFG-DT通过抑制CXCL9表达减少肿瘤组织免疫细胞浸润、增加肿瘤血管生成，促进结直肠癌的进展。本研究将为结直肠癌的诊治提供新的思路和靶标。

长链非编码RNA在肿瘤的发生发展中发挥重要作用，本项目研究发现结直肠癌中存在大量异常表达的长链非编码RNA，其中MAFG-DT在结直肠癌组织中表达显著升高，且表达水平越高患者预后越差。此外，我们还发现MAFG-DT表达与结直肠癌组织中免疫细胞浸润相关，敲降MAFG-DT后结直肠癌细胞表达更高的CXCL9。并且，体外和体内表型实验结果表明，敲降MAFG-DT后结直肠癌细胞的增殖和转移能力显著降低。机制方面，我们发现MAFG-DT通过招募WDR5影响MAFG启动子区域的H3K4me3的富集，顺式调控MAFG的转录，进而影响MAFG下游靶基因的表达。回补实验表明结直肠癌中高表达的MAFG-DT依赖于对MAFG的调控作用促进结直肠癌的恶性进展。本项目为结直肠癌的分子机制研究提供了新的理论，证明了MAFG-DT是结直肠癌的潜在诊治靶点。