Inflammatory Molecule, PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NFκB Signaling.

P-selectin glycoprotein ligand 1 (SELPLG/PSGL-1) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. Apc^Min/+ mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a Apc^Min/+;PSGL-1^-/- genotype. The incidence and pathologic features of the intestinal tumors were compared between the Apc^Min/+ mice and Apc^Min/+;PSGL-1^-/- mice. Importantly, PSGL-1-deficient mice showed increased susceptibility to develop intestinal tumors and accelerated tumor growth. Mechanistically, increased production of the mouse chemokine ligand 9 (CCL9/MIP-1γ) was found in the PSGL-1-deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1γ). Studies in vitro demonstrated that macrophage-derived MIP-1γ promoted colorectal cancer tumor cell growth through activating NFκB signaling. Conversely, restoration of the PSGL-1 signaling via bone marrow transplantation reduced MIP-1γ production and attenuated the ability of Apc^Min/+;PSGL-1^-/- mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence of PSGL-1-positive cells was associated with a favorable tumor-node-metastasis staging and decreased lymph node metastasis.Implications:PSGL-1 deficiency and inflammation render intestinal tissue more vulnerable to develop colorectal tumors through a MIP-1γ/NFκB signaling axis. Mol Cancer Res; 15(4); 467-77. ©2017 AACR. ©2017 American Association for Cancer Research.

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