METTL3介导RNA m6A修饰在具核梭菌促结直肠癌转移中的作用和机制

肠道菌群和宿主细胞互作在结肠癌发生发展中扮演重要角色，但具核梭菌在结肠癌转移中的作用和机制尚不明确。我们前期发现，具核梭菌丰度与结肠癌患者淋巴结转移相关，且具核梭菌共培养可下调结肠癌细胞RNA m6A修饰水平和甲基转移酶METTL3表达，促进结肠癌细胞侵袭和远处转移。MeRIP-seq测序筛选并验证具核梭菌调控m6A修饰的靶基因KIF26B，且KIF26B可促进结肠癌细胞侵袭转移。由此我们提出“具核梭菌下调结肠癌细胞中METTL3介导的RNA m6A修饰水平，抑制YTHDF2调控的KIF26B mRNA降解，高表达的驱动蛋白KIF26B促进结肠癌细胞转移”的科学假说。我们将通过分子、细胞、动物、临床等系统研究，阐明具核梭菌调控结肠癌细胞RNA m6A修饰、促进结肠癌转移的机制。研究可丰富RNA m6A修饰的理论内涵，挖掘具核梭菌与结肠癌细胞互作的实验依据，提供结肠癌临床诊治的新分子靶标。

The interplay between gut microbiota and host cells plays critical role on the development and progression of colorectal cancer (CRC). However, the pathogenic role and its underlying mechanism of Fusobacterium Nucleatum (Fn) promoting CRC metastasis remain unclear. We have previously shown that the abundance of Fn was related to the lymph node metastasis in CRC patients. Co-culture with Fn could downregulate the level of RNA m6A modification and the expression level of methyltransferase METTL3, thus promote the cellular invasion and distant metastasis of CRC. In addition, overexpression of METTL3 could attenuate the pro-metastatic effect of Fn in CRC. KIF26B was screened and preliminary verified as a novel target of m6A modification by MeRIP-seq sequencing analysis. In vitro and in vivo studies observed that KIF26B could promote CRC cell invasion and liver metastasis. Therefore, we hypothesized that Fn could modulate METTL3-mediated RNA m6A modification of CRC cells, upregulating the target gene KIF26B, thereby promoting tumor metastasis. We will prove our idea by performing molecular and cellular experiments, animal modeling, and clinical samples analysis. Our study could enrich the theoretical connotation of RNA m6A modification, provide new insight into the interplay mechanism between Fn and CRC cells, and may shed light on the novel targeted therapy for metastatic CRC patients.