Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling

Woo, Jong Kyu; Jang, Yeong Su; Kang, Ju Hee; Hwang, Jong Ik; Seong, Je Kyung; Lee, Sang Jin; Jeon, Sejin; Oh, Goo Taeg; Lee, Ho‐Young; Oh, Seung Hyun

doi:10.18632/oncotarget.9020

Cited by 20 publications

(14 citation statements)

References 44 publications

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“…Interestingly, Yang et al reported that Ninj1 deficiency increases systemic inflammation and reduces the survival rate of mice with age, 60 implying that Ninj1 −/− mice exhibit higher levels of malfunctioning bacterial lysis in macrophages with age, leading to increased intestinal microbial imbalance and possibly contributing to the development of chronic colitis and colon cancer. Woo et al reported that Ninj1 overexpression on macrophages plays a negative role in the azoxymethane (AOM)/DSS model of colitis‐associated colon cancer (CAC) 35 . However, further studies are required to identify the precise mechanism underlying microbial imbalance caused by Ninj1 deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, both proteins have been associated with colon cancer. For instance, Ninj1 inhibits the development of colitis‐associated colon cancer by suppressing macrophage infiltration into tumors; while Ninj2 promotes human colorectal cancer cell growth 35,36 . However, its biological role in gut microbiota‐associated colitis has not yet been well characterized.…”

Section: Introductionmentioning

confidence: 99%

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Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

et al. 2020

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Disruption of colonic homeostasis caused by aberrant M1/M2 macrophage polarization and dysbiosis contributes to inflammatory bowel disease (IBD) pathogenesis. However, the molecular factors mediating colonic homeostasis are not well characterized. Here, we found that Ninjurin1 (Ninj1) limits colon inflammation by regulating macrophage polarization and microbiota composition under homeostatic conditions and during colitis development. Ninj1 deletion in mice induced hypersusceptibility to colitis, with increased prevalence of colitogenic Prevotellaceae strains and decreased immunoregulatory Lachnospiraceae strains. Upon co‐housing (CoH) with WT mice, Ninj1−/− mice showed increased Lachnospiraceae and decreased Prevotellaceae abundance, with subsequent improvement of colitis. Under homeostatic conditions, M1 macrophage frequency was higher in the Ninj1−/− mouse colons than wild‐type (WT) mouse colons, which may contribute to increased basal colonic inflammation and microbial imbalance. Following colitis induction, Ninj1 expression was increased in macrophages; meanwhile Ninj1−/− mice showed severe colitis development and impaired recovery, associated with decreased M2 macrophages and escalated microbial imbalance. In vitro, Ninj1 knockdown in mouse and human macrophages activated M1 polarization and restricted M2 polarization. Finally, the transfer of WT macrophages ameliorated severe colitis in Ninj1−/− mice. These findings suggest that Ninj1 mediates colonic homeostasis by modulating M1/M2 macrophage balance and preventing extensive dysbiosis, with implications for IBD prevention and therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

et al. 2020

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“…These results conflict a previous report dealing with the role of Ninj1 in colon cancer. During colon cancer development, overexpression of Ninj1 suppresses the migration of macrophages, resulting in the alleviation of cancer development [37]. Macrophages in tumor tissue directly facilitate the enhancement of growth and mobility of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Detrimental Role of Nerve Injury-Induced Protein 1 in Myeloid Cells under Intestinal Inflammatory Conditions

Jung

Kang

Pak

et al. 2020

IJMS

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Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell-surface adhesion molecule that regulates cell migration and attachment. This study demonstrates the increase in Ninj1 protein expression during development of intestinal inflammation. Ninj1-deficient mice exhibited significantly attenuated bodyweight loss, shortening of colon length, intestinal inflammation, and lesser pathological lesions than wild-type mice. Although more severe inflammation and serious lesions are observed in wild-type mice than Ninj1-deficient mice, there were no changes in the numbers of infiltrating macrophages in the inflamed tissues obtained from WT and Ninj1-deficient mice. Ninj1 expression results in activation of macrophages, and these activated macrophages secrete more cytokines and chemokines than Ninj1-deficient macrophages. Moreover, mice with conditional deletion of Ninj1 in myeloid cells (Ninj1fl/fl; Lyz-Cre+) alleviated experimental colitis compared with wild-type mice. In summary, we propose that the Ninj1 in myeloid cells play a pivotal function in intestinal inflammatory conditions.

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“…Additionally, inhibition of Ninj1 by a neutralizing Ninj1 antibody enhances penile angiogenesis and restores erectile function in streptozotocin-induced diabetic mice (20). Moreover, Ninj1 is capable of suppressing cancer cell invasion and migration in Ninj1-expressing cells and transgenic mice (21,22). Previously, we showed that Ninj1 is a target of p53 and in turn regulates p53 mRNA translation (23).…”

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confidence: 95%

Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner

Yang

Zhang

Yan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of -deficient mice and found that mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of altered the tumor susceptibility in both mutant and -null background. Specifically, in a mutant p53(R270H) background, deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a -null background, deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1-p53 loop may be targeted to manage inflammatory diseases and cancer.

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Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling

Cited by 20 publications

References 44 publications

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

Detrimental Role of Nerve Injury-Induced Protein 1 in Myeloid Cells under Intestinal Inflammatory Conditions

Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner

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