Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies.
OBJECTIVE
The UNC5H netrin-1 receptors (UNC5H1-3 also called UNC5A-C) belong to the functional dependence receptors family, which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer a tumor-suppressor activity. Indeed, cells harboring these receptors are thought to be dependent on ligand availability for their survival, thereby inhibiting uncontrolled tumor cell proliferation. We investigate here whether UNC5C acts as a tumor suppressor in colorectal malignancies.


METHODS
The level of UNC5C was analyzed in a panel of 86 primary sporadic colorectal carcinomas. Loss of heterozygosity in the UNC5C locus and epigenetic alterations in the UNC5C promoter were also analyzed. Intestinal tumor progression was monitored in mice bearing both UNC5C and APC1638N mutations, and apoptosis was measured in intestinal tumors developed in UNC5C/APC1638N mutant mice.


RESULTS
We show here that UNC5C expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, in mice, inactivation of UNC5C is associated with increased intestinal tumor progression and a decrease in tumor cell apoptosis.


CONCLUSIONS
The loss of UNC5C expression observed in human colorectal cancer is a selective advantage for tumor progression, in agreement with the dependence receptor hypothesis. Thus, the UNC5C dependence receptor is a tumor suppressor that regulates sporadic colorectal cancer.
Bernet
Agnès
A
Apoptosis, Cancer and Development Laboratory-Equipe labellisée La Ligue, Centre National de la Recherche Scientifique, CNRS UMR5238, University of Lyon, Centre Léon Bérard, Lyon, France.
Mazelin
Laetitia
L
Coissieux
Marie-May
MM
Gadot
Nicolas
N
Ackerman
Susan L
SL
Scoazec
Jean-Yves
JY
Mehlen
Patrick
P
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D018450:Disease Progression; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008745:Methylation; D051379:Mice; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism
D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C115727:UNC5C protein, human