Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling
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Jong Kyu Woo1,2,*, Yeong-Su Jang1,*, Ju-Hee Kang1,3, Jong-Ik Hwang4, Je Kyung Seong2, Sang-Jin Lee3, Sejin Jeon5, Goo Taeg Oh5, Ho-Young Lee6,*, Seung Hyun Oh1,*
1College of Pharmacy, Gachon University, Incheon, Republic of Korea
2College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
3National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
4Graduate School of Medicine, Korea University, Seoul, Republic of Korea
5Department of Life sciences, Ewha Womans University, Seoul, Republic of Korea
6College of Pharmacy, Seoul National University, Seoul, Republic of Korea
*These authors contributed equally to this work
Keywords: macrophage, ninjurin1, colon cancer, colitis-associated colon cancer model (CAC), focal adhesion kinase (FAK)
Received: August 26, 2015 Accepted: March 29, 2016 Published: April 26, 2016
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.
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