Abstract 3465: The effect of ephrin-A1 on the resistance of photodynamic therapy in esophageal cancer cells
Authors: Peiwen Yang, Ching-Yueh Hsieh, Mien-Chie Hung, Fang-Tzu Kuo, Yu-Ting Huang, Jang-Ming Lee
Journal: Cancer Research (2012)

Abstract Photodynamic therapy (PDT) has been demonstrated as an effective minimally invasive treatment modality for early esophageal cancer. However, the molecular action in esophageal cancer during PDT is hardly known. To know better about the mechanisms of the resistance to PDT in esophageal cancer cells, we selected the PDT-resistant sub-cell lines and investigated the global gene modulations in the resistant cells by whole-genome microarray. Photofrin is a most frequently used photosentizer in PDT. We have selected two Photofrin-PDT resistant sub-cell lines, PDTR4-4 and PDTR4-6, derived from CE48T/VGH (CE48T) esophageal cancer cell line. At least 700 genes reached to over 1.5 fold changes in both subcell lines compared to parental cell line. Among the candidate genes, TNF and EFNA1 genes were notably up-regulated in both resistant cell lines and down-regulated in Photofrin-PDT treated cells compared to untreated cells by microarray analysis. It revealed that TNF and EFNA1 encoded proteins may play some roles to promote the resistance to Photofrin-PDT. EFNA1 encodes ephrin-A1, a ligand belongs to a receptor tyrosine kinase. It has been found associated with tumor formation and up-regulated in various cancer types. TNF encodes tumor necrosis factor-alpha (TNF-alpha)cytokine. Because TNF-alpha can induce ephrin-A1 expression in endothelial cells, we suggest TNF-alpha may activate the expression of ephrin-A1 and induce the resistance to Photofrin-PDT in esophageal cancer cells. Currently, we investigated whether TNF-alpha can activate the expression of ephrin-A1 in esophageal cancer cells. We clearly observed recombinant TNF- alpha can activate the gene expression of EFNA1 in transcription level. To further demonstrate Photofrin-PDT inhibit the gene expression of TNF and EFNA1 in esophageal cancer cells, we detected the mRNA expression of both TNF and EFNA1 in CE48T cells upon Photofrin-PDT treatment by quantitative PCR. We clearly observed Photofrin-PDT can inhibit the expression of the transcripts encoded by both TNF and EFNA1. The protein expression of ephrin-A1 was also suppressed by Photofrin- PDT. Meanwhile, we determined the background expression levels of both TNF and EFNA1 in PDTR4-6 and another more resistant sub-cell line PDTR5-8. Compared to parental cells, both PDTR4-6 and PDTR5-8 displayed significant over-expression of TNF and EFNA1 in transcription levels. Finally, we investigated whether exogenous ephrin-A1 can enhance the resistance to Photofrin-PDT in esophageal cancer cells. We preliminarily observed the CE48T cells which incubated in the medium containing 10 and 25 ng/ml of recombinant ephrin-A1 were more resistant to Photofrin-PDT induced cell death by around 20 % versus untreated cells. Based on our findings, we suggest TNF-alpha -induced ephrin-A1 expression may contribute to Photofrin-PDT resistance in esophageal cancer cells. 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 3465. doi:1538-7445.AM2012-3465