FRAS1-related extracellular matrix protein 2 drives the progression and poor prognosis of IL-1β-associated esophageal squamous cell carcinoma

Abstract

Background Chronic inflammation generates a tumor-supporting microenvironment, but it remains unclear whether and how the persistent inflammation drives genetic abnormalities leading to the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Methods By global RNA-sequncing, we screened genes related to ESCC with stimulation of the pro-inflammatory factor, interleukin (IL)-1β, and identified FRAS1-related extracellular matrix protein (FREM)2 as a oncogene. Flow cytometry was used to detect the expression of IL-1β and its receptor IL-1R1 in fresh ESCC specimens. The interaction between FREM2 and IL-1β signal was examined in vitro and in vivo. Levels of FREM2 and IL-1R1 were determined in ESCC tissue arrays derived from 299 patients, and their correlation with clinical outcomes was analyzed. Results Multiple genes-related to ESCC occurrence and recurrence were elevated when exposed to the persistent stimulation of IL-1β. Among them, FRAS1-related extracellular matrix protein 2 (FREM2) was identified as a new oncogene in ESCC. IL-1β and its receptor IL-1R1 highly expressed in ESCC, especially in tumor cells. FREM2 was induced by IL-1β, and in turn bound to and stabilized IL-1R1, facilitating IL-1β signal transduction. The activation of downstream NK-κB and JNK signals mediated the tumor-promoting effect, while the reduction of FoxP1 was responsible for IL-1β-induced FREM2 transcription. High levels of FREM2 and IL-1R1 synergistically indicated the shorter survival time in patients. Conclusion These results suggest FREM2 is an IL-1β-stimulated oncogene, which as a cofactor of IL1R1 promotes IL-1β-induced ESCC progression. Therapeutic strategies targeting FREM2 is likely to prolong the survival of ESCC patients.