Fusobacterium nucleatum Promotes the Growth and Metastasis of Colorectal Cancer by Activating E-Cadherin/Krüppel-Like Factor 4/Integrin α5 Signaling in a Calcium-Dependent Manner

Abstract

Gut microbiota and integrins are known to contribute to colorectal cancer (CRC), but whether they interact has been unclear. Here, we provided evidence that Fusobacterium nucleatum upregulated integrin α5 (ITGA5) in CRC in both human patients and murine models. Knocking down ITGA5 in CRC cells weakened the ability of F. nucleatum to stimulate their malignant characteristics. Fusobacterium nucleatum increased intracellular Ca2+ concentration, which in turn promoted interaction between E-cadherin and Krüppel-like factor 4 (KLF4), resulting in KLF4 phosphorylation and translocation in the nucleus, where it induced ITGA5 transcription and activated the downstream signaling. Knocking down E-cadherin or chelating Ca2+ with BAPTA-AM antagonized the impact of F. nucleatum on KLF4, whereas knocking down KLF4 or chelating Ca2+ antagonized the bacteria's oncogenic role. Knocking down KLF4 or ITGA5 attenuated F. nucleatum–induced growth of patient-derived organoids, subcutaneous xenografts, and orthotopic tumors, as well as liver metastasis in nude mice. Integrin α5 antibody antagonized the oncogenic role of F. nucleatum in vitro and in vivo. These findings suggest that F. nucleatum promotes the growth and metastasis of CRC by activating E-cadherin/KLF4/integrin α5 signaling in a Ca2+-dependent manner.