The tropomyosin-related kinase (Trk) family of neurotrophin receptors, TrkA TrkB and TrkC, has been implicated in the growth and survival of human cancers. Here we report that Trks are frequently overexpressed in hepatocellular carcinoma (HCC) from patients and human liver cancer cell lines. To unravel the underlying molecular mechanism(s) for this phenomenon, DNA methylation patterns of CpG islands in TrkA, TrkB, and TrkC genes were examined in normal and cancer cell lines derived from liver. A good correlation was observed between promoter hypermethylation and lower expression of TrkA. TrkB, and TrkC genes, which was supported by the data that inhibiting DNA methylation with 5-azacytidine restored expression of those genes in normal liver cell lines. Furthermore. Irks promoted the proliferation of HepG2 and induced expression of the metastatic regulator, Twist. These results suggest that Irks may contribute to growth and metastasis of liver cancer. (C) 2011 Elsevier Inc. All rights reserved.