Abstract 3801: Rhomboid domain containing 2 (RHBDD2) over-expression is associated to colorectal cancer progression and drug sensitivity to 5-FU treatment
Authors: Ezequiel Lacunza, Maria V. Croce, Ariel Zwenger, Amada Segal-Eiras, Martín C. Abba
Journal: Cancer Research (2011)

Abstract Colorectal carcinoma (CRC) is the second leading cause of death among malignancies in the world. Postoperative chemotherapy is widely accepted as the standard modality for the treatment of this disease; however 50% of patients within an oncology protocol will develop tumor metastatic dissemination. The drug 5-fluorouracil (5-FU) is one of the most commonly used agents for the treatment of CRC at early and advanced tumor stages, but clinical resistance is a major limitation. The identification of novel predictive biomarkers of resistance to 5-FU treatment would allow developing new therapies and improving the quality of life for CRC patients. The aim of this study was to evaluate the role of RHBDD2 gene expression in human colorectal carcinogenesis and its effect on treatment with chemotherapeutic agent 5-FU. Firstly, we analyzed a dataset of 430 colorectal samples (32 healthy control, 355 primary CRC and 43 metastatic CRC) derived from two independent public available gene expression studies: Bittner et al., 2005 (GEO Acc.#GSE2109), and Sabates-Bellver et al., 2007 (GEO Acc.#GSE8671). A statistical significant increase in RHBDD2 expression was detected between normal colorectal samples and CRC specimens with and without metastasis (p&amp;lt;0.001). In order to validate these data, we performed an immunohistochemical analysis on 140 colorectal tissue samples (5 normal tissues, 20 benign lesions and 115 colorectal carcinomas). We detected high RHBDD2 protein expression in tumor samples compared with normal and benign lesions (p&amp;lt;0.005). Interestingly, a subset of 33 CRC specimens which were obtained from patients treated with 5-FU prior to surgery, showed a higher intensity of reaction compared with the other CRC samples (p&amp;lt;0.001). To analyze this finding, RHBDD2 5-FU sensitivity was evaluated by Real Time quantitative RT-PCR in the colon carcinoma cell lines Colo205 and Caco-2. Cells were incubated with 5-FU (50 to 200 µM) for 48 and 72Hs. We detected a dramatic up-regulation of RHBDD2 mRNA levels in both cell lines after being exposed to 5-FU (p&amp;lt;0.001). Furthermore, we analyzed the phenotypic effects of silencing RHBDD2 gene expression with and without 5-FU treatment in both cell lines over cell proliferation and apoptosis. In conclusion, our findings suggest that RHBDD2 over-expression might play a role in colorectal neoplastic progression, modulating the response of colon cancer cells to 5-FU treatment. Further studies are needed to evaluate the relevance of RHBDD2 gene expression as a predictive biomarker as well as a therapeutic target to enhance drug efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3801. doi:10.1158/1538-7445.AM2011-3801