title: Inflammatory Molecule,PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NFκB Signaling.
abstract: 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 ofPSGL-1in tumor development remains unknown. Therefore, this study investigates the mechanistic role ofPSGL-1in the development of intestinal tumors in colorectal cancer. ApcMin/+mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a ApcMin/+;PSGL-1-/-genotype. The incidence and pathologic features of the intestinal tumors were compared between the ApcMin/+mice and ApcMin/+;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 thePSGL-1-deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1γ). Studiesin vitrodemonstrated that macrophage-derived MIP-1γ promoted colorectal cancer tumor cell growth through activating NFκB signaling. Conversely, restoration of thePSGL-1signaling via bone marrow transplantation reduced MIP-1γ production and attenuated the ability of ApcMin/+;PSGL-1-/-mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence ofPSGL-1-positive cells was associated with a favorable tumor-node-metastasis staging and decreased lymph node metastasis.Implications:PSGL-1deficiency 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.
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Jiangchao
authors.initials: J
authors.lastname: Li
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: He
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Cui-Ling
authors.initials: CL
authors.lastname: Qi
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: He
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Pharmaceutical University, Guangzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Chun-Kui
authors.initials: CK
authors.lastname: Shao
authors.affiliation: Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney at the Westmead, New South Wales, Australia.
authors.forename: Liang
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Vascular Biology Research Institute, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, China. wanglijing62@163.com.
authors.forename: Lijing
authors.initials: L
authors.lastname: Wang
mesh_terms: D000236:Adenoma / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019742:Chemokines, CC / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008262:Macrophage Activation; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D015398:Signal Transduction
chemical_list: D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C084882:P-selectin ligand protein