Differential Expression of RUNX Genes in Human Esophageal Squamous Cell Carcinoma: Downregulation of RUNX3 Worsens Patient Prognosis

Background: The RUNX proteins are a family of transcriptional factors that have essential functions during embryogenesis and development, whereas deregulation in expression of RUNXs is often linked to tumor formation. To date, there has been no study describing the precise expression, prognostic impact and methylation status of RUNXs in esophageal squamous cell carcinoma. Methods: Resected specimens from 61 patients with esophageal SCC were used to identify the expression of RUNX1, RUNX2 and RUNX3 by real-time RT-PCR. Localization of mRNA was done by in situ hybridization, expression of Smad4 was evaluated by immunohistochemistry, and the methylation status of RUNX3 was analyzed by methylation-specific PCR. Results: RUNX3 had a significant impact on patient prognosis with worse survival in the RUNX3-negative group. In early tumors (T1/T2), the prevalence of lymph vessel invasion and the number of metastatic lymph nodes were significantly higher in RUNX3-negative tumors. Furthermore, RUNX3 became a strong prognostic factor only in Smad4-positive tumors. Also, the methylation status of the RUNX3 promoter had a significant correlation with the loss of RUNX3 expression. Conclusion: Downregulation of RUNX3 may play a role in disease progression of esophageal SCC, and hypermethylation of the promoter region might be one of the crucial pathways to silence RUNX3 gene.