title: Specific tumor-derived CCL2 mediated by pyruvate kinase M2 in colorectal cancer cells contributes to macrophage recruitment in tumor microenvironment.
abstract: Development of colorectal cancer has been considered as a result of imbalance of pro- and anti-inflammatory intestinal microenvironment accompanied by macrophage recruitment. Despite macrophages are implicated in remodeling tumor microenvironment, the mechanism of macrophage recruitment is not fully elucidated yet. In this study, we reported clinical association of highly expressed pyruvate kinase M2 in colorectal cancer with macrophage attraction. The conditioned medium from Caco-2 and HT-29 cells with depleted pyruvate kinase M2 dramatically reduced macrophage recruitment, which is reversed by addition of, a critical chemotaxis factor to macrophage migration, rCCL2. Silencing of endogenous pyruvate kinase M2 markedly decreased CCL2 expression and secretion by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Endogenous pyruvate kinase M2 interacted with p65 and mediated nuclear factor-κB signaling pathway and mainly regulated phosphorylation of Ser276 on p65 nuclear factor-κB. In addition, inhibition of macrophage recruitment caused by pyruvate kinase M2 silencing was rescued by ectopic expression of p65. Interestingly, pyruvate kinase M2 highly expressed in colorectal cancer tissue, which is correction with macrophage distribution. Taken together, we revealed a novel mechanism of pyruvate kinase M2 in promoting colorectal cancer progression by recruitment of macrophages through p65 nuclear factor-κB-mediated expression of CCL2.
authors.affiliation: 1 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.|2 Hainan General Hospital, Haikou, China.
authors.forename: Kejian
authors.initials: K
authors.lastname: Zou
authors.affiliation: 3 Traditional Chinese Medicine Hospital of Kunshan, Suzhou, China.
authors.forename: Yaodong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 2 Hainan General Hospital, Haikou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 4 Baotou Cancer Hospital, Baotou, China.
authors.forename: Liansheng
authors.initials: L
authors.lastname: Zheng
authors.affiliation: 5 Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
authors.forename: Wanfu
authors.initials: W
authors.lastname: Xu
authors.affiliation: 1 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Li
mesh_terms: D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; C498143:RELA protein, human; D051996:Transcription Factor RelA; D011770:Pyruvate Kinase
keywords: CCL2; Pyruvate kinase M2; colorectal cancer; macrophages