title: Inflammation-induced S100A8 activates Id3 and promotes colorectal tumorigenesis.
abstract: The aberrant expression of S100A8 and S100A9 is linked to nonresolving inflammation and ultimately to carcinogenesis, whereas the underlying mechanism that allows inflammation to progress to specific cancer types remains unknown. Here, we report that S100A8 was induced by inflammation and then promoted colorectal tumorigenesis downstream by activating Id3 (inhibitor of differentiation 3). Using gene expression profiling and immunohistochemistry, we found that both S100A8 and S100A9 were upregulated in the chemically-induced colitis-associated cancer mouse model and in human colorectal cancer specimens. Furthermore, we showed that S100A8 and S100A9 acted as chemoattractant proteins by recruiting macrophages, promoting the proliferation and invasion of colon cancer cell, as well as spurring the cycle that culminates in the acceleration of cancer metastasis in a nude mouse model. S100A8 regulated colon cancer cell cycle and proliferation by inducing Id3 expression while inhibiting p21. Id3 expression was regulated by Smad5, which was directly phosphorylated by Akt1. Our study revealed a novel mechanism in which inflammation-induced S100A8 promoted colorectal tumorigenesis by acting upstream to activate the Akt1-Smad5-Id3 axis.
authors.affiliation: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.|Cancer Research Institute, Central South University, Changsha, China.|The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Ai
authors.affiliation: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Xiayu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: She
authors.affiliation: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Anliu
authors.initials: A
authors.lastname: Tang
authors.affiliation: Cancer Research Institute, Central South University, Changsha, China.|The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Zailong
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Cancer Research Institute, Central South University, Changsha, China.|The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.affiliation: Cancer Research Institute, Central South University, Changsha, China.|The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Shourong
authors.initials: S
authors.lastname: Shen
authors.affiliation: Cancer Research Institute, Central South University, Changsha, China.|The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.|Key Laboratory of Carcinogenesis, Ministry of Health; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D040501:Calgranulin A / Q000502:physiology*; D040502:Calgranulin B / Q000378:metabolism; D063646:Carcinogenesis / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D059467:Transcriptome
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D051796:Inhibitor of Differentiation Proteins; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; C067679:Idb3 protein, mouse
keywords: Id3; S100A8; S100A9; colorectal cancer; non-resolving inflammation