Interaction between oncogenic FREM2 with IL-1ß signaling contributes to esophageal squamous cell carcinoma progression

Inflammatory signals can promote tumorigenesis. The pro-inflammatory cytokine interleukin (IL)-1ß is overexpressed in many types of tumor; however, it is unclear whether it directly interacted with oncogenes in esophageal squamous cell carcinoma. In this study, we performed RNA sequencing to identify tumorgenesis and recurrence-related factors in ESCC and identified FRAS1-related extracellular matrix protein (FREM)2 as a candidate oncogene. IL-1ß and IL-1R1 were upregulated in ESCC tissue, which was accompanied by elevated Frem2 expression. FREM2 formed complex with IL-1R1 at the cell surface and promoted ESCC cell proliferation and migration via activation of nuclear factor-?B–p65/mitogen-activated protein kinase–c-Jun N-terminal kinase signaling. IL-1ß stimulation resulted in the upregulation of FREM2 in ESCC cells through inhibition of Forkhead box P1. Increased FREM2 and IL-1R1 levels were correlated with shorter survival time in ESCC patients. Overall design: RNA profiles of tumor tissues and paired normal tissues from 4 ESCC patients were generated by sequencing