FAT10调节HKII增强细胞糖酵解促进膀胱癌增殖的机制研究

Hexokinase II (HKII)-mediated glycolysis plays an important role in the proliferation of bladder cancer (BC), and its specific mechanism still remains unclear. Our study had demonstrated that FAT10 stabilized the substrate to promote cell proliferation in BC (oncotarget, 2016). Our previous studies have shown as follow: FAT10 and HKII were significantly high expression in BC, and the relationship of them was positive correlation for each other. Knockdown of FAT10 could decrease the expression of HKII in BC, and the result of Co-IP had showed the interaction between FAT10 and HKII. In addition, down-regulation of FAT10 significantly decreased LDH activity in BC cells and decreased lactic acid concentration in cell supernatant. In summary, we hypothesized that FAT10 enhances cell glycolysis by stabilizing HKII to promote cell proliferation in BC. In this study, we firstly analyze the expressions of FAT10 and HKII in BC and its correlation with clinicopathological features. Secondly, it is studied the effect of FAT10 on the cell proliferation by regulating HKII-mediated glycolysis in BC in vitro and in vivo. Finally, it is explored the molecular mechanism of FAT10 regulating HKII by in vitro ubiquitination assay. These will provide a new theoretical basis for the prevention and treatment of BC.

己糖激酶II（HKII）介导的糖酵解在膀胱癌增殖中发挥着重要的作用，但其具体机制仍不清楚。我们研究证实FAT10通过稳定底物蛋白促进膀胱癌增殖（Oncotarget，2016）。预实验结果显示：膀胱癌组织中FAT10及HKII蛋白均高表达，且呈正相关；降低膀胱癌细胞中FAT10表达可下调HKII，且免疫共沉淀等实验证实FAT10与HKII相互结合；另外，下调FAT10导致膀胱癌细胞胞液LDH活性明显减弱，细胞上清液乳酸浓度明显下降。综上，我们推测FAT10通过稳定HKII增强膀胱癌细胞糖酵解从而促进膀胱癌的细胞增殖。本研究拟先分析膀胱癌中FAT10和HKII的表达及其与临床病理特征的关联；再通过体内外实验研究FAT10通过调控HKII介导膀胱癌糖酵解进而促进膀胱癌增殖的作用；最后利用体外泛素化实验等技术探讨FAT10调控HKII的具体分子机制。本研究结果将为膀胱癌的防治提供新的理论依据。

类泛素蛋白FAT10和己糖激酶蛋白HK2在几个细胞过程中起着重要的调节作用。然而，这两种蛋白之间的关系及其在膀胱癌发病机制中的作用尚不清楚。在这里，我们发现膀胱癌组织中的FAT10和HK2蛋白水平明显高于正常邻近组织。此外，在体内和体外，RNA干扰介导的FAT10沉默导致HK2水平降低，并抑制膀胱癌的进展。我们的体内和体外实验结果显示，HK2对FAT10介导的膀胱癌进展至关重要。目前的研究表明，FAT10通过EGFR/AKT途径积极调节HK2，从而促进膀胱癌的进展。根据我们的发现，FAT10被认为通过调节其降解和泛素化来稳定EGFR的表达。目前的研究结果表明，FAT10和HK2在膀胱癌的进展中存在相关性。此外，我们还发现了一条可能参与调控HK2的新途径，这些发现暗示了FAT10、EGFR/AKT和HK2轴在膀胱癌进展中的起重要作用。