The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment.
The three mammalian receptors UNC5H1, UNC5H2, and UNC5H3 (also named UNC5A, UNC5B, and UNC5C in human) that belong to the family of the netrin-1 receptors, UNC5H, were initially proposed as mediators of the chemorepulsive effect of netrin-1 on specific axons. However, they were also recently shown to act as dependence receptors. Such receptors induce apoptosis when unbound to their ligand. We show here that the expression of the human UNC5A, UNC5B, or UNC5C is down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers. In colorectal tumors, this down-regulation is associated with loss of heterozygosity occurring within UNC5A, UNC5B, and UNC5C genes but may also be partially related to epigenetic processes because histone deacetylase inhibitor increased UNC5C expression in various cancer cell lines. Moreover, sequencing of UNC5C gene in patients with colorectal tumors revealed the presence of missense mutations. The lossreduction of expression may be a crucial mechanism for tumorigenicity because the expression of UNC5H1, UNC5H2, or UNC5H3 inhibits tumor cell anchorage-independent growth and invasion. Moreover, these hallmarks of malignant transformation can be restored by netrin-1 addition or apoptosis inhibition. Hence, UNC5H1, UNC5H2, and UNC5H3 receptors may represent tumor suppressors that inhibit tumor extension outside the region of netrin-1 availability by inducing apoptosis.
Thiebault
Karine
K
ApoptosisDifferentiation Laboratory, Equipe Labellisée la Ligue, Molecular and Cellular Genetic Center, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5534, University of Lyon, 69622 Villeurbanne, France.
Mazelin
Laetitia
L
Pays
Laurent
L
Llambi
Fabien
F
Joly
Marie-Odile
MO
Scoazec
Jean-Yves
JY
Saurin
Jean-Christophe
JC
Romeo
Giovanni
G
Mehlen
Patrick
P
D016475:3T3 Cells; D000818:Animals; D001369:Axons / Q000502:physiology; D016923:Cell Death / Q000235:genetics*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface / Q000235:genetics*; D012004:Rectal Neoplasms / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C000603585:UNC5A protein, human; C000617308:Unc5A protein, mouse; C000617307:Unc5b protein, mouse