Abstract 5146: ATP-binding cassette transporter, ABCG2, activation is responsible for chemo-resistant, SIK3 low expressed ovarian cancer

Abstract

Abstract Background: Epithelial ovarian cancer (EOC) has a high tumor-associated mortality rate among the gynecological cancers because of chemo-resistant development. Materials and Method: The human EOC cell lines, SKOV3, OVRCA4, were obtained from the American Type Culture Collection (ATCC). For determine ATP-binding cassette transporters and SIK3 expression, Western blot and Quantitative real-time polymerase chain reaction (qRT-PCR) were used. We used a lentiviral small-hairpin RNA (shRNA) system to knock down SIK3 in the ovarian cancer cell lines. Microarray data derived from SKOV3, OVRCA4 cells expressing sh-luc, sh-SIK3 (01), and sh-SIK3 (63) were analyzed by MetaCore and Ingenuity Pathways Analysis (IPA). Top 10 up-and down-regulated genes and other metastasis-related genes and 5 most highly enriched networks were identified. For determining cell viability when cells treated with cisplatin and Taxol, WST-1 assay was used. Immunohistochemistry and quantification of ABCG2 and SIK3 were performed in EOC tissues. Statistical analysis of OS and PFS were performed using SPSS statistical software (Version 22.0; IBM Corp, Armonk, NY). Survival curves were generated using the Kaplan-Meier method, and differences in survival were assessed using the log-rank test. Results: Knockdown SIK3 expression upregulates ABCG2 expression, activity as well as resistance to chemotherapeutic agents. The ABCG2 and SIK3 expression levels in 204 EOC patient were mutually reversed. In all stages of the disease, high expression of SIK3 (SIK3-H) was associated with a significant better OS, PFS, compared with low expression of SIK3 (SIK3-L) (127.0 vs 46.0 months, 66.0 months vs 26.0 months respectively). Patients with SIK3-L and ABCG2-H carried the worst prognosis. Conclusion: (1) High expression of SIK3 indicates a better prognosis in primary ovarian cancer and serous type disease, especially in advanced serous disease. (2) Ovarian cancer patients with SIK3-L and ABCG2-H expression carried the worst prognosis due to chemoresistance Citation Format: Keng-Fu Hsu, Yu-Ling Liang, Chin-Han Wu, Neng-Yao Shih. ATP-binding cassette transporter, ABCG2, activation is responsible for chemo-resistant, SIK3 low expressed ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5146.