Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Sternness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades
Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Sternness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades
复制标题
DOI：
10.3390/cancers11060813
复制
发表时间：
2019-06-01
期刊：
影响因子：
5.2
通讯作者：
Chan, Karen K. L.
中科院分区：
文献类型：
--
作者：
Siu, Michelle K. Y.;Jiang, Yu-Xin;Chan, Karen K. L.
代谢重编程是癌症中的常见现象。因此，糖酵解酶可用于在癌症治疗中选择性靶向癌细胞。己糖激酶2（HK2）将葡萄糖转化为葡萄糖-6-磷酸，这是葡萄糖代谢的第一个关键步骤。在这里，我们证明了HK2在卵巢癌中过表达，并且在腹水和转移灶中显示出显著更高的表达。HK2表达与晚期和高级别癌症显著相关，并且是独立的预后因素。在功能上，卵巢癌细胞系和腹水源性肿瘤细胞中HK 2的敲低阻碍了乳酸产生、细胞迁移和侵袭以及细胞干细胞特性，沿着FAK/ERK 1/2活化以及转移和干细胞相关基因的减少。2-DG是一种糖酵解抑制剂，可延缓细胞迁移和侵袭，降低干细胞特性。相反，HK2的过表达通过FAK/ERK 1/2/MMP 9途径促进细胞迁移和侵袭，并通过FAK/ERK 1/2/NANOG/SOX 9级联增强干细胞特性。HK2废除阻碍体内肿瘤生长和扩散。值得注意的是，卵巢癌相关的成纤维细胞衍生的IL-6有助于其上调。总之，受肿瘤微环境调节的HK2控制乳酸产生，并通过FAK/ERK 1/2信号通路介导的MMP 9/NANOG/SOX 9表达促进卵巢癌转移和干性调节。HK2可能是卵巢癌的一个潜在的预后标志物和治疗靶点。
Metabolic reprogramming is a common phenomenon in cancers. Thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in glucose metabolism. Here, we demonstrated that HK2 was overexpressed in ovarian cancer and displayed significantly higher expression in ascites and metastatic foci. HK2 expression was significantly associated with advanced stage and high-grade cancers, and was an independent prognostic factor. Functionally, knockdown of HK2 in ovarian cancer cell lines and ascites-derived tumor cells hindered lactate production, cell migration and invasion, and cell stemness properties, along with reduced FAK/ERK1/2 activation and metastasis- and stemness-related genes. 2-DG, a glycolysis inhibitor, retarded cell migration and invasion and reduced stemness properties. Inversely, overexpression of HK2 promoted cell migration and invasion through the FAK/ERK1/2/MMP9 pathway, and enhanced stemness properties via the FAK/ERK1/2/NANOG/SOX9 cascade. HK2 abrogation impeded in vivo tumor growth and dissemination. Notably, ovarian cancer-associated fibroblast-derived IL-6 contributed to its up-regulation. In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression. HK2 could be a potential prognostic marker and therapeutic target for ovarian cancer.