Abstract A48: Overexpression of Semaphorin-3E enhances pancreatic cancer cell proliferation ad is associated with patient poor survival

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the US with a 5-year survival rate of less than 6%. There is an urgent need for a better understanding of PDAC in order to find better therapeutic targets. Two recent large-scale genomic analyses of human PDAC have uncovered increased copy numbers of an axon-guidance gene SEMA3E that codes for Semaphorin-3E (Sema3E). Several recent reports have implicated Sema3E in metastasis of breast and colon cancers, particularly in promoting tumor cell migration and invasion, as well as inducing epithelial-to-mesenchymal transition (EMT). Here, we evaluated Sema3E expression levels in human pancreatic cancer tissue samples and correlation with patient survival; we further studied roles of Sema3E in pancreatic cancer cell proliferation. Materials and Methods: To determine expression levels of Sema3E in PDAC, qPCR analysis was performed on resected human PDAC samples and matched tissue controls, and immunohistochemical (IHC) analysis was performed on resected human PDAC tissues and tissues from a mouse model of PDAC. To generate Sema3E-overexpressing stable cells, human PDAC cell lines were transduced with Sema3E-expressing lentivirus or vector control. To generate Sema3E knock-down cell lines, CRISPR/Cas9 system was used to target Sema3E in the genome. MTT assay was performed on Sema3E-overexpressed cells to determine the effects of Sema3E on cell proliferation. Results: Using qPCR, Sema3E was found to be significantly upregulated in 46% of human PDAC samples (n=24), with an average fold-change of 9.54. IHC analyses of human and mouse PDAC revealed higher expression of Sema3E in tumor cells compared to normal cells (n=54). Interestingly, in human PDAC, Sema3E expression was concentrated in the nuclei of tumor cells while it has been reported to be a secreted protein. We found a positive correlation between high N/C ratio of Sema3E expression (i.e. expression in the nucleus relative to the cytoplasm) and poor survival. In addition, we also found overexpression of Sema3E is correlated with patient poor survival by analyzing a TCGA dataset (n=78). Overexpression of Sema3E in human PDAC cell lines enhanced cell proliferation and migration in vitro, while knocking-down Sema3E resulted in reduced cell proliferation. Conclusions: Our findings indicate that Sema3E is overexpressed in PDAC and is correlated with patient poor survival. Sema3E may play a pathogenic role in PDAC progression by enhancing tumor cell proliferation. These findings suggest that Sema3E could be an attractive novel therapeutic target for PDAC. Citation Format: Lin-Kin Yong, Syeling Lai, Zhengdong Liang, Dali Li, Ethan Poteet, William Fisher, Qianxin Mo, Changyi Chen, Qizhi Yao. Overexpression of Semaphorin-3E enhances pancreatic cancer cell proliferation ad is associated with patient poor survival. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A48.