Abstract 244: Characterization of a Candidate Tumor Suppressor Gene DIRAS1 in Esophageal Squamous Cell Carcinoma

Abstract Loss of 19p is one of the most frequent alterations in many malignancies including esophageal squamous cell carcinoma (ESCC), suggesting the existence of a tumor suppressor gene (TSG) within the frequently deleted region. In this study we describe the identification and characterization of one candidate TSG, DIRAS family, GTP-binding RAS-like 1 (DIRAS1), at 19p13.3. DIRAS1 downregulation occurred in 34 of 75 (43.33%) primary ESCCs and 5/9 (55.6%) of the ESCC cell lines. Immunohistochemistry detection demonstrated that the down-regulation DIRAS1 expression was an independent prognostic factor of ESCC and associated with poor survival in ESCC. Functional studies showed that Ectopic expression of DIRAS1 in ESCC cells inhibited cell proliferation, foci formation, and tumor formation in nude mice. The tumor-suppressive mechanism of DIRAS1 was associated with its proapoptotic role in a mitochondrial-dependent manner by down-regulation of phosphorylated BAD and activating caspase-9, caspase3 and PARP via ERK- and p38-dependent signaling pathway. In addition, down-regulation of DIRAS1 protein was significantly correlated with ESCC lymph node metastasis (P = 0.003), which was associated with its function in inhibiting cell migration and invasion by down-regulation of MMP-2 and MMP-9 via ERK- and p38-dependent signaling pathway. In conclusion, our findings suggest that DIRAS1 plays an important suppressive role in the development and progression of ESCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 244. doi:1538-7445.AM2012-244