Concordant Promoter Methylation of Transforming Growth Factor-Beta Receptor Types I and II Occurs Early in Esophageal Squamous Cell Carcinoma

Introduction: Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor with multiple functions through its type I (TGFBR1) and type II (TGFBR2) receptors. A reduction or loss of expression of TGFBRs enables cancer cells to escape the growth inhibitory effect of TGF-beta and to gain a growth advantage. Objective: The promoter methylation status and expression of TGFBR1, TGFBR2 and Smad4 gene were investigated in esophageal squamous cell carcinoma (ESCC). Design: Methylation-specific polymerase chain reaction approach was used to detect the methylation status. Immunohistochemistry and reverse transcription-polymerase chain reaction method were used to examine the protein and messenger RNA expression, respectively. Results: Both the ESCC and the high-grade dysplastic tissues showed hypermethylation of TGFBR1 and TGFBR2, and the hyper-methylation of TGFBR1 and TGFBR2 in ESCC tissues was significantly associated with decreased messenger RNA and protein expression (P < 0.05). When stratified for tumor lymph node metastasis stages, TGFBR1 and TGFBR2 gene methylation was more frequent in stage III and stage IV tumor tissues than that in stage I and stage II tumor tissues (P, 0.05). Simultaneous methylation of the 2 receptors was progressively increased along with the increasing of tumor lymph node metastasis stage and decreasing of histological differentiation. Smad4 hypermethylation was only detected in 7 ESCC tumor tissues and associated with the loss of Smad4 expression. The decreased protein expression of TGFBR1, TGFBR2 and Smad4 was correlated with increased expression of TGF-beta 1 in ESCC. Conclusions: These data suggest that promoter methylation of TGFBR1 and TGFBR2 may exist in the early stage of ESCC and play important roles in TGFBR1 and TGFBR2 gene silencing.