Inflammatory cytokine IL-6 regulates ADAMTS14 expression through MAPK and PI3K signaling in colorectal cancer

Abstract

Extracellular matrix (ECM) remodeling is a critical component of colorectal cancer (CRC) progression and tumor microenvironment organization. Members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) metalloproteinase family are known regulators of ECM structure; however, the transcriptional regulation of ADAMTS14 and its potential role in inflammation-associated ECM remodeling remain poorly understood. In this study, we investigated whether inflammatory signaling regulates ADAMTS14 expression and explored its association with ECM organization in CRC. Interleukin-6 (IL-6) stimulation significantly increased ADAMTS14 expression at both mRNA and protein levels in CRC cells. Promoter deletion analyses identified a critical IL-6-responsive region between -145 and -43 bp upstream of the transcription start site, suggesting transcriptional responsiveness of ADAMTS14 to inflammatory signaling. Inhibition experiments demonstrated that Extracellular Signal-Regulated Kinase, c-Jun N-terminal Kinase, Phosphatidylinositol 3-Kinase, and Nuclear Factor Kappa B pathways were associated with IL-6-induced ADAMTS14 expression. Transcriptomic analyses of The Cancer Genome Atlas CRC datasets revealed that ADAMTS14 expression is elevated in tumors and is associated with inflammatory signaling, stromal activation, fibroblast-related gene expression, and ECM organization pathways. Functional enrichment analyses indicated that ADAMTS14-correlated genes are primarily involved in ECM organization, collagen fibril organization, and connective tissue development. Together, these findings identify ADAMTS14 as an inflammation-responsive ECM-associated metalloproteinase and suggest that IL-6 signaling may be associated with ECM-related transcriptional programs through regulation of ADAMTS14 expression. Our findings further suggest that ADAMTS14 expression may be associated with inflammatory and stromal-related transcriptional programs in CRC.