title: Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling.
abstract: Macrophage infiltration promotes tumorigenesis. However, the macrophage infiltration regulatory molecules have not been fully determined. Nerve injury-induced protein 1 (ninjurin1) is a homophilic cell surface adhesion molecule that plays an important role in cell migration and attachment. Although ninjurin1 is believed to play a role in several malignancies, it is unclear whether ninjurin1 expression contributes to cancer progression. We used transgenic mice (tg mice) that overexpressed ninjurin1 on macrophages. We subjected ninjurin1 tg mice to a well-known mouse model of colitis-associated colon cancer in which animals are treated with azoxymethane (AOM) and dextran sulfate sodium (DSS). After AOM and DSS treatment, ninjurin1 tg mice developed fewer and smaller tumors compared with wild-type (wt) mice. Ninjurin1 tg mice also showed reduced infiltration of macrophages and suppressed angiogenesis in the tumor mass. We therefore explored whether ninjurin1 decreases macrophage migration into the tumor sites. After adoptive transfer to tumor-bearing recipients, wild type and ninjurin1 tg mice's peritoneal macrophages were freshly isolated and labeled with carboxyfluorescein succinimidyl ester (CFSE). As expected, compared with that of wt type macrophages, tumor infiltration of ninjurin1-overexpressing macrophages was significantly decreased. We also found that ninjurin1 overexpression suppressed FAK activity. In addition, knockdown of ninjurin1 enhanced FAK activity and migration activity of RAW264.7 cells. Ninjurin1 overexpression on macrophage inhibits tumor growth by suppression of macrophage infiltration through repression of FAK signaling. Ninjurin1 is a key regulator molecule for macrophage migration and Tumor-associated macrophages (TAM) mediated tumorigenesis in vivo.
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.|College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jong Kyu
authors.initials: JK
authors.lastname: Woo
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Yeong-Su
authors.initials: YS
authors.lastname: Jang
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.|National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.affiliation: College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.affiliation: National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Life sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Sejin
authors.initials: S
authors.lastname: Jeon
authors.affiliation: Department of Life sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Oh
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D003092:Colitis / Q000150:complications; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000378:metabolism*; D000067996:RAW 264.7 Cells
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D009414:Nerve Growth Factors; C484439:Ninj1 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse
keywords: colitis-associated colon cancer model (CAC); colon cancer; focal adhesion kinase (FAK); macrophage; ninjurin1