2. Academic Validation
  3. Enterococcus faecalis promotes the progression of colorectal cancer via its metabolite: biliverdin

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

  • J Transl Med. 2023 Feb 2;21(1):72. doi: 10.1186/s12967-023-03929-7.
Li Zhang # 1,  Jing Liu # 1,  Mingxia Deng 1,  Xiangliu Chen 2,  Lushun Jiang 1,  Jiajie Zhang 3,  Lisheng Tao 4,  Wei Yu 5,  Yunqing Qiu 6
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
  • 3 Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
  • 4 Department of Gastroenterology, The People's Hospital Affiliated to Jiangsu University, Zhenjiang, China.
  • 5 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. wyu@zju.edu.cn.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. qiuyq@zju.edu.cn.
  • # Contributed equally.
PMID: 36732757 DOI: 10.1186/s12967-023-03929-7
Abstract

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-regulation of proliferation and angiogenesis by BV were also confirmed in mice.

Conclusion: In conclusion, BV, as the tumor-stimulating metabolite of Efa, generates proliferative and angiogenic effects on CRC, which is mainly mediated by the activation of PI3K/Akt/mTOR.

Keywords

Angiogenesis; Colorectal cancer; Enterococcus faecalis; Interleukin-8; Vascular endothelial growth factor A.

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