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Involvement of TSLC1 in Progression of Esophageal Squamous Cell Carcinoma¹

Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507 [T. I., Y. S., Y. H., J. K., T. K., G. W., M. I.], and Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045 [Y. M.], Japan

Frequent allelic losses of 11q23 in esophageal squamous cell carcinoma (ESCC) have been reported previously, but no tumor suppressor genes in this region have been identified in ESCC. TSLC1 was identified on chromosome 11q23.2 as a tumor suppressor gene in non-small cell lung cancer by functional complementation of a lung adenocarcinoma cell line. The purpose of this study is to evaluate the role of TSLC1 in ESCC. Loss of TSLC1 expression was observed by reverse transcription-PCR in 75% of the cell lines (27 of 36) and 50% of the primary tumors from ESCC patients (28 of 56). In a clinicopathological analysis, loss of TSLC1 expression correlated significantly with depth of invasion (pT) and status of metastasis (pM; P = 0.012 and 0.036, respectively). Patients with tumors lacking TSLC1 expression tended to have a poorer prognosis than those with tumors expressing TSLC1. (P = 0.079). Moreover, TSLC1 expression was an independent prognostic factor in a multivariate analysis (P = 0.049). Methylation analyses revealed that TSLC1 expression or loss correlated with the promoter methylation status, as determined by bisulfite sequencing, and that TSLC1 expression could be restored by a demethylating agent in certain cell lines. The growth of TSLC1-transfected ESCC cells was significantly suppressed both in vitro and in vivo (P < 0.01), possibly by a G₁ cell cycle arrest. TSLC1 expression also suppressed motility and invasion of ESCC cells in vitro significantly (P < 0.01). These findings suggest that loss of TSLC1 expression has an important role in tumor growth, cell motility, and invasion and is associated with aggressive tumor behavior in ESCC.

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