Enterococcus faecalis promotes the progression of colorectal cancer via its metabolite: biliverdin

作者：Zhang Li, Jing Liu, Mingxia Deng, Xiangliu Chen, Lushun Jiang, Jiajie Zhang, Lisheng Tao, Wei Yu, Yunqing Qiu · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-03929-7 · 被引用次数：60 · 研究领域：Cancer Research and Treatments、Heme Oxygenase-1 and Carbon Monoxide、Drug Transport and Resistance Mechanisms

BACKGROUND: Enterococcus faecalis (Efa) has been shown to be a "driver bacteria" in the occurrence and development of colorectal cancer (CRC). This study aims to explore the effect of specific metabolites of Efa on CRC. METHODS: The pro-tumor effects of Efa were assessed in colonic epithelial cells. The tumor-stimulating molecule produced by Efa was identified using liquid chromatography mass spectrometry (LC-MS). The proliferative effect of metabolites on CRC cells in vitro was assayed as well. The concentration of vascular endothelial growth factor A (VEGFA) and interleukin-8 (IL-8) was determined using enzyme-linked immunosorbent assay (ELISA). Tubular formation assay of human umbilical vein endothelial cells (HUVEC) and cell migration assay were applied to study angiogenesis. Additionally, western blot analysis was used to investigate key regulatory proteins involved in the angiogenesis pathway. Tumor growth was assessed using mouse models with two CRC cells and human colon cancer organoid. RESULTS: Co-incubation with the conditioned medium of Efa increased the proliferation of cultured CRC cells. Biliverdin (BV) was determined as the key metabolite produced by Efa using LC-MS screening. BV promoted colony formation and cell proliferation and inhibited cell cycle arrest of cultured CRC cells. BV significantly increased the expression level of IL-8 and VEGFA by regulating the PI3K/AKT/mTOR signaling pathway, leading to the acceleration of angiogenesis in CRC. The up-regula...