Abstract
To develop a prognostic biomarker for esophageal squamous cell carcinoma (ESCC), we examined the proteomic profile of ESCC using two-dimensional difference gel electrophoresis (2D-DIGE), and identified proteins associated with prognosis by mass spectrometry. The prognostic performance of the identified proteins was examined by immunohistochemistry in additional cases. We identified 22 protein spots whose intensity was statistically different between ESCC cases with good (N = 9; survived more than 5 years without evidence of recurrence) and poor (N = 24; died within 2 years postsurgery) prognosis, within the patient group that had two or more lymph node metastases. Mass spectrometric protein identification resulted in 18 distinct gene products from the 22 protein spots. Transglutaminase 3 (TGM3) was inversely correlated with shorter patient survival. The prognostic performance of TGM3 was further examined by immunohistochemistry in 76 ESCC cases. The 5-year disease-specific survival rate was 64.5% and 32.1% for patients with TGM3-positive and TGM3-negative tumors, respectively (p = 0.0033). Univariate and multivariate analyses revealed that TGM3 expression was an independent prognostic factor among the clinicopathologic variables examined. It is noteworthy that the prognostic value of TGM3 was shown to be higher than those of the lymph node metastasis, intramural metastasis and vascular invasion status. These results establish TGM3 as a novel prognostic biomarker for ESCC for the first time. Examination of TGM3 expression may provide novel therapeutic strategies to prevent recurrence of ESCC.