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.