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Interleukin-6 (IL-6) is a major regulator of matrix metalloproteinase (MMP) expression in cancers. A patient matched control study of human colorectal cancers revealed that levels of IL-6 expression correlated strongly with those of MMP-1 and MMP-3 . In human colon cancer cell lines, MMP-3 expression was increased by treatment with IL-6, and suppressed by interferon-gamma (IFN- γ ). Analysis of the MMP-1 and MMP-3 proximal promoters by gel shift and ChIP assays revealed noncanonical STAT binding elements (SBEs) which bound STAT-1 in a complex with AP-1/Fos constitutively and in an IL-6/PMA-inducible manner. STAT-3 was not observed to bind to these novel proximal promoter SBEs. Using northern blot analysis with a STAT-3 knockout colon cancer cell line confirmed that STAT-3 was not required for the IL-6 inducibility of MMP-1 and -3 expression. However, STAT-1 specific siRNA knockdown significantly inhibited induction, validating the requirement for STAT-1 in transcriptional activation. These results strengthen a role for STAT-1 in cytokine induction of malignancy-associated factors such as MMPs in colorectal cancer.