NF-kappaB regulates netrin-1 expression and affects the conditional tumor suppressive activity of the netrin-1 receptors.
OBJECTIVE
Netrin-1 was recently proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. Because netrin-1 receptors belong to the family of dependence receptors, a selective advantage for a tumor is either to lose netrin-1 receptors or to gain autocrine expression of netrin-1. We have investigated whether netrin-1 is up-regulated in colorectal cancer and have searched for a link between NF-kappaB activation and netrin-1 up-regulation.


METHODS
The level of netrin-1, netrin-1 receptors, ie, DCC, UNC5H1, UNC5H2, UNC5H3, and the proinflammatory markers cyclooxygenase-2 and inhibitor of nuclear factor-kappaB (IkappaB) alpha were analyzed in a panel of 59 primary sporadic colorectal carcinomas. Netrin-1 expression was investigated in tumor cells and in mouse colonic crypts in response to NF-kappaB activation but also in a mouse model of inflammation-induced colorectal cancer. Binding of NF-kappaB to netrin-1 promoter and effect of NF-kappaB activation to the proapoptotic activity of UNC5H2 were also analyzed.


RESULTS
We show that colorectal tumors with a gain of netrin-1 are tumors that display increased activation of the NF-kappaB pathway. Moreover, netrin-1 up-regulation, which is associated with tumor formation in mice, is observed in mouse colonic crypts in response to NF-kappaB activation but also in a mouse model of inflammation-induced colorectal cancer. We demonstrate that the netrin-1 gene is a direct transcriptional target of NF-kappaB. We show that NF-kappaB-induced netrin-1 expression inhibits proapoptotic activity of the netrin-1 receptors.


CONCLUSIONS
We propose that NF-kappaB activation that occurs in response to inflammation confers a selective advantage for tumor development through NF-kappaB-mediated netrin-1 up-regulation.
Paradisi
Andrea
A
Apoptosis, Cancer and Development Laboratory-Equipe Labellisée La Ligue, CNRS UMR 5238, Université de Lyon, Centre Léon Bérard, Lyon, France.
Maisse
Carine
C
Bernet
Agnès
A
Coissieux
Marie-May
MM
Maccarrone
Mauro
M
Scoazec
Jean-Yves
JY
Mehlen
Patrick
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000075389:DCC Receptor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D000075389:DCC Receptor; D016328:NF-kappa B; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C501909:DCC protein, human; C000617351:NTN1 protein, human; C000617353:Ntn1 protein, mouse; C000617308:Unc5A protein, mouse; C105653:Unc5c protein, mouse; C000617307:Unc5b protein, mouse