Abstract
Abstract Cancer stem cells (CSCs) constitute a small proportion of tumor cells and can drive tumor growth, metastasis and recurrence. Identification of CSCs in ovarian cancer has been reported. However, the mechanisms regulating ovarian cancer CSCs remain unknown. High lactate production and low glucose oxidation, despite oxygen availability, termed as the Warburg effect, are commonly found in cancers. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in the Warburg effect. HK2 regulates tumorigenesis in different cancers. Yet, roles of HK2 and its underline mechanisms in ovarian cancer remain to be explored. In this study, we investigate the clinical significance, effects and mechanisms of HK2 on cell metastasis and CSCs regulation in ovarian cancer. HK2 was found to be up-regulated in ovarian cancer patients by immunohistochemistry when compared with benign ovarian cystadenomas. Significantly higher HK2 immunoreactivity was detected in metastatic foci than their corresponding primary tumors and associated with shorter disease-free survival. Decreased lactate production, impaired cell migration and invasion were detected in HK2 knockdown A2780CP cells using lactate assay, Transwell migration and invasion assays, respectively. Oppositely, ectopic expression of HK2 increased lactate production, cell migration and invasion in SKOV3 cells. We also found ectopic expression of HK2 in SKOV3 cells promoted anchorage-independent growth by soft agar assay. Then we further investigated the effect of HK2 on CSC load of ovarian cancer. Stable knockdown of HK2 in OVCAR3 cells led to impaired capacity to grow as multi-cellular spheroids in stem-condition culture system by sphere formation. Knockdown of HK2 in OVCAR3 cells down-regulated CD117 as measured by flow cytometry, which was accompanied by decreased mRNA/protein expression of Nanog, Bmi-1 and Klf-4, genes related to ovarian CSCs. Inversely, ectopic expression of HK2 in SKOV-3 cells promoted spheroids growth and increased CD117 proportion, which was accompanied by increased Nanog, Bmi-1 and Klf-4 mRNA/protein expression. Our data suggested that HK2 was associated with ovarian cancer progression, metastasis and stemness. HK2 could be a novel prognostic marker and potential therapeutic molecular target in ovarian cancer. Citation Format: Yuxin JIANG, Michelle KY Siu, Jingjing Wang, Thomas HY Leung, Annie NY Cheung, Hextan YS Ngan, Karen KL Chan. Hexokinase II (HK2) regulates stemness of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-270. doi:10.1158/1538-7445.AM2017-LB-270
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