Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
Cancer Sci. 2023 Aug;114(8):3114-3127. doi: 10.1111/cas.15839. Epub 2023 May 26.
Colorectal cancer (CRC) is related to gut microbiota dysbiosis, especially butyrate-producing bacteria reduction. Our previous study suggested that administration of Clostridium butyricum, a butyrate-producing bacterium, exerts a crucial effect against CRC, however the potential mechanism is not clear. We first found that methyltransferase-like 3 (METTL3) showed a positive correlation with proliferation, epithelial-mesenchymal transition (EMT), DNA repair, metastasis, and invasion in a database analysis. The expression of METTL3 gradually increased from human normal colon tissue, to adenoma, and carcinoma, and was positively correlated with E-cadherin and CD34 levels. Overexpression of METTL3 promoted the proliferation, migration, and invasion of CRC cells and induced vasculogenic mimicry (VM) formation. Clostridium butyricum could downregulate METTL3 expression in CRC cells and decrease the expression of vimentin and vascular endothelial growth factor receptor 2 to reduce EMT and VM formation. Clostridium butyricum alleviated the pro-oncogenic effect of METTL3 overexpressing plasmid in CRC cells. The anti-EMT effect on METTL3 reduction of C. butyricum could be blunted by knocking down G-protein coupled receptor 43. Moreover, C. butyricum prevented EMT and VM and inhibited tumor metastasis in nude mice. Accordingly, C. butyricum could inhibit EMT and VM formation of intestinal carcinogenesis through downregulating METTL3. These findings broaden our understanding of probiotics supplement in CRC prevention and treatment.
结直肠癌（CRC）与肠道微生物失调有关，尤其是丁酸盐产生菌减少。我们之前的研究表明，丁酸盐产生菌丁酸梭菌的给药对 CRC 具有重要作用，但潜在的机制尚不清楚。我们首先发现，甲基转移酶样 3（METTL3）在数据库分析中与增殖、上皮-间充质转化（EMT）、DNA 修复、转移和侵袭呈正相关。METTL3 的表达从人正常结肠组织逐渐增加，到腺瘤和癌，与 E-钙黏蛋白和 CD34 水平呈正相关。METTL3 的过表达促进 CRC 细胞的增殖、迁移和侵袭，并诱导血管生成拟态（VM）形成。丁酸梭菌可下调 CRC 细胞中的 METTL3 表达，并降低波形蛋白和血管内皮生长因子受体 2 的表达，从而减少 EMT 和 VM 形成。丁酸梭菌减轻了 CRC 细胞中 METTL3 过表达质粒的促癌作用。G 蛋白偶联受体 43 敲低可削弱丁酸梭菌对 METTL3 减少的抗 EMT 作用。此外，丁酸梭菌可预防 EMT 和 VM，并抑制裸鼠肿瘤转移。因此，丁酸梭菌可通过下调 METTL3 抑制肠道癌变中的 EMT 和 VM 形成。这些发现拓宽了我们对益生菌补充在 CRC 预防和治疗中的理解。
