NTRK3 Is a Potential Tumor Suppressor Gene Commonly Inactivated by Epigenetic Mechanisms in Colorectal Cancer

Abstract

NTRK3 is a member of the neurotrophin receptor family and regulates cell survival. It appears to be a dependence receptor, and thus has the potential to act as an oncogene or as a tumor suppressor gene. NTRK3 is a receptor for NT-3 and when bound to NT-3 it induces cell survival, but when NT-3 free, it induces apoptosis. We identified aberrantly methylated NTRK3 in colorectal cancers through a genome-wide screen for hypermethylated genes. This discovery led us to assess whether NTRK3 could be a tumor suppressor gene in the colon. NTRK3 is methylated in 60% of colon adenomas and 67% of colon adenocarcinomas. NTRK3 methylation suppresses NTRK3 expression. Reconstitution of NTRK3 induces apoptosis in colorectal cancers, if NT-3 is absent. Furthermore, the loss of NTRK3 expression associates with neoplastic transformation in vitro and in vivo. We also found that a naturally occurring mutant NTRK3 found in human colorectal cancer inhibits the tumor suppressor activity of NTRK3. In summary, our findings suggest NTRK3 is a conditional tumor suppressor gene that is commonly inactivated in colorectal cancer by both epigenetic and genetic mechanisms whose function in the pathogenesis of colorectal cancer depends on the expression status of its ligand, NT-3.

Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker

“…Our results showed that the overall mean of methylation level in either normal tumor free tissue or CRC tumor tissue samples was high in which there were just two samples with 0% methylation. Although our results are similar to those of Luo et al (41) and obviously NTRK3 promoter methylation is able to discriminate the tumoral samples from normal tumor free samples with acceptable sensitivity and specificity, however, its high level methylation in tumor adjacent tissue suggests that it may start methylation process far before the appearance of any pathological features in cancerous cells. However, this hypothesis should indeed be further analyzed with samples in very initial stages of carcinogenesis.…”

“…The NTRK3 gene has been recently demonstrated to become hypermethylated and silenced in CRC cell lines, which suggests its role as a tumor suppressor gene in colorectal cancer (41). The present study analyzed NTRK3 promoter methylation in order to determine whether it can act as a biomarker in diagnosis of CRC or not.…”

“…Considering the possibility of NTRK3 as a CRC tumor suppressor gene, based on the discovery of its mutant and methylated forms in CRC, Luo et al (41) conducted a study in order to define the effect of aberrant methylation on NTRK3 expression, and also to define whether NTRK3 has oncogenic or tumor suppressor functions in CRC cell lines. The authors concluded that aberrant methylation of NTRK3 is prevalent in CRC and adenomas that consequently silences its expression, which suggests its tumor suppressor role.…”

Dependence Receptors and Cancer: Addiction to Trophic Ligands

“…Interestingly, not only DCC, but also more recently other DRs such as UNC5H, TrkC, and CDON, have been shown to be negatively regulated in various cancer types (6,12,13); moreover, the inactivation of DCC, UNC5H, or CDON in mice is associated with tumor progression (6,10,12). The decreased expression of DRs in various tumor types occurs either through loss-of-heterozygosity (LOH), transcriptional or epigenetic regulation (12)(13)(14)(15)(16). CDON expression has recently been shown to be decreased in neuroblastoma and correlated with patient prognosis.…”

MethyLight droplet digital PCR for detection and absolute quantification of infrequently methylated alleles

“…The primer and probe sequences for methylated EVL (NP_057421) and methylated NTRK3 (NM_002530) were designed using ABI PrimerExpress software Version 5.0. 17 (Applied Biosystems, Life Technologies), and synthesized with a FAM reporter. We determined the relative amounts of each sample through a C-LESS-C1 assay, 18 which amplifies the total amount of DNA in a PCR reaction.…”