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

Yanxin Luo,William M Grady,Piri Welsch,Samornmas Kanngurn,Andrew M Kaz,Shelli M Morris,James D Lutterbaugh,Jianping Wang,Sanford D Markowitz,Hamish S Scott

doi:10.1371/journal.pgen.1003552

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.

Highlights

Colorectal cancer (CRC) arises through the accumulation of gene mutations and epigenetic alterations that result in the transformation of normal colon epithelial cells into adenocarcinomas [1]
neurotrophin tyrosine kinase receptor 3 (NTRK3) has been previously shown to be an oncogene in breast cancer and possibly hepatocellular carcinoma
Through a genomewide methylation screen, we unexpectedly found that NTRK3 is commonly methylated in colorectal cancers but not in normal colon samples, which led us to assess whether NTRK3 could be a tumor suppressor gene in the colon

Summary

Introduction

Colorectal cancer (CRC) arises through the accumulation of gene mutations and epigenetic alterations that result in the transformation of normal colon epithelial cells into adenocarcinomas [1]. Aberrant CpG island methylation is associated with gene silencing and can inactivate tumor suppressor genes in the colon, which promotes tumor formation through the deregulation of various cellular processes including proliferation and apoptosis, among others [1,2]. In order to identify methylated tumor suppressor genes that play a role in the formation of CRC, we conducted a genome-wide screen for methylated genes in colorectal cancers and matched normal colon epithelium tissue samples. Through this screen, we found a set of novel methylated genes, which included neurotrophin tyrosine kinase receptor 3 (NTRK3), a gene that has been found to be hypermethylated in esophageal adenocarcinoma [3]. Our findings raised the question of whether NTRK3 acts as an oncogene or tumor suppressor gene in the pathogenesis of CRC

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