Alterations of thyroid hormone receptor alpha gene: frequency and association with Nm23 protein expression and metastasis in gastric cancer.

Thyroid hormone receptor genes (c-erbA, or TR) have been implicated as tumor suppressor genes. We investigated whether two subtypes of TR genes (TRalpha and TRbeta) are altered in human gastric cancer, as well as the role of such alterations in tumor metastasis. As a preliminary survey (n=18), Southern blot analysis was conducted with full-length TRalpha or TRbeta cDNA probes, after digestion with restriction enzyme (EcoRI, BamHI, or HindIII). The survey showed the most frequent alteration was in TRalpha gene by a loss of two HindIII fragments (7.1 and 10.1 kb). Subsequent study focused at this TRalpha alteration by increasing patient number up to a total of 42. TRalpha alteration was noted in 19 (49%) of the 39 patients with informative results. The TRalpha alteration was associated with the development of distant (hematogenous) metastasis (P=0.0084) and high expression level of Nm23 protein (P=0.020). These findings suggest that TRalpha might be involved in tumorigenesis, and that interactions between the TRalpha and nm23 genes might take part in hematogenous metastasis of gastric cancer.