Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC)

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PABackground: PDAC is a leading cause of cancer-related death worldwide, and most patients have incurable disease at diagnosis. Life expectancy is only 3-6 months post-diagnosis, ostensibly due to early dissemination to liver and other vital organs. Results: By transfecting a shRNA library into non-metastatic PDAC line S2-028 followed by experimental metastasis assay, ITIH5 was identified. Metastatic PDAC cell lines (e.g., S2-007, MIAPaCa-2, Panc-1) had significantly lower ITIH5 protein expression compared to immortalized pancreatic ductal epithelial cells and non-/poorly-metastatic PDAC cell lines (e.g., S2-028 and BxPC3). By manipulating expression in different PDAC cell lines (over-expression in S2-007 and MIAPaCa-2, knockdown in non-metastatic S2-028 with two different shRNA) functional and selective regulation of metastasis was observed. Orthotopic tumor growth of PDAC cells was not blocked. Thus ITIH5 qualifies as a metastasis suppressor. Overexpression of ITIH5 significantly inhibited invasion and migration, while down-regulation increased these cellular properties. Immunohistochemistry of a human PDAC tissue microarray (n = 81) revealed that negative expression of ITIH5 showed significantly higher incidence of liver metastasis (P = 0.0482) corresponding with worse prognosis after surgery (P = 0.0299). Conclusions: ITIH5 is a potent metastasis suppressor with suggestive prognostic value in PDAC. Future studies will continue to characterize biochemical properties of ITIH5, identify interaction partners, and investigate the molecular mechanism(s) of action. Support: National Foundation for Cancer Research, Steiner Family Fund and CA168524.Citation Format: Ken Sasaki, Hiroshi Kurahara, S Natsugoe, Tomoo Iwakuma, Danny R. Welch. Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3264. doi:10.1158/1538-7445.AM2015-3264