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Macrophages are major inflammatory cells in the tumor microenvironment that can contribute to tumor progression.Tumor-associated macrophages (TAMs) in established tumors generally have an M2 phenotype with tumor-promoting activity, but the mechanisms regulating the TAM phenotype remain elusive.Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens.Here, we investigated the role of CARD9 in the tumor microenvironment in tumor metastasis.Knockout of CARD9 in colon cancer cells severely impaired their hepatic metastatic ability.CARD9 was expressed in TAMs, which exhibited an M2-like functional profile in mouse liver tumor.However, knockout of CARD9 did not affect infiltration of inflammatory cells into rumors.Macrophage polarization was mediated by CARD9, and this process relied substantially on activation of nuclear factor-kappa B (NF-B) and inhibition of Statl signaling.Analysis of lymph node metastases in human colon carcinoma demonstrated CARD9 expression negatively associated with tumor differentiation grade.CARD9 has a central role in regulating the M2 phenotype of TAMs in promoting hepatic metastasis of colon cancer through NF-B and Stat1 signaling.CARD9 might be a novel marker for cancer prognosis and offer therapeutic opportunities for anticancer treatment.