糖皮质激素受体GR调控肝癌细胞的支链氨基酸分解代谢及其机制研究

Metabolic reprogramming is one of the hallmarks of cancer cells, however, the underlying mechanisms are still poorly understood. Glucocorticoid receptor (GR) has been found to be critical for glucose metabolism reprogramming of cancer cells in our previous study, but little is known about its role in cancer cell amino acid metabolism. We have also found that GR regulated expression levels of enzymes involved in branched-chain amino acid (BCAA) degradation, and more intriguingly, forced expression of BCAT2, the enzyme of first step of BCAA metabolism, in hepatocellular cancer cells could partially recover the retarded cell growth induced by shGR, suggesting the vital effect of GR-regulated BCAA metabolism on hepatocellular cancer cells. Based on this, we will study the potential role of GR in regulation of BCAA degradation and hepatocellular carcinoma progression in in vitro cultured tumor cells, and in vivo xenograft models and human hepatocellular carcinoma samples. Through this study, we may understand the mechanism of regulation of BCAA metabolism by GR and the crosstalk of aberrant BCAA metabolism and tumorigenesis.

代谢重编程是肿瘤细胞的十大生物学特征之一，但对于导致肿瘤细胞代谢异常的分子机制及其对肿瘤其它生物学行为的影响尚不清楚。我们前期研究发现，糖皮质激素受体（Glucocorticoid receptor，GR）是肿瘤细胞糖代谢重编程的重要调节因子，然而GR是否调节肝癌细胞氨基酸代谢却鲜有报道。我们尚未发表的研究结果显示，GR调节支链氨基酸(BCAA)相关代谢酶的表达，且BCAA代谢酶的过表达可以挽救GR敲低导致的细胞增殖阻滞。这提示GR很可能在调节肿瘤BCAA代谢中发挥重要作用，进而影响肿瘤的其它生物学行为。因此,本项目将利用GR过表达及敲低的细胞系，结合小鼠荷瘤模型和肝癌病人临床样本，鉴定GR在肿瘤BCAA代谢中的作用，阐释其作用的分子机制，从而建立肿瘤代谢异常和肿瘤其它生物学行为之间的crosstalk, 并探讨通过干预GR调节的BCAA代谢靶向治疗肝癌的可能性。

氨基酸代谢重编程是肿瘤代谢研究领域的热点问题，然而对于导致肿瘤细胞氨基酸代谢异常的分子机制及其对癌症进程的影响尚不清楚。有报道指出糖皮质激素受体（Glucocorticoid receptor，GR）调控肿瘤细胞糖和脂肪酸代谢，然而GR是否影响肝癌支链氨基酸（BCAA）代谢却未见报道。本项目研究发现GR在临床肝癌肿瘤组织中高表达，且与肝癌患者预后负相关；确证了GR促进肝癌细胞在BCAA匮乏条件下的生存生长，且BCAA饥饿处理也会改变GR的蛋白水平；解析了GR通过转录激活代谢酶BCKDHA促进BCAA分解代谢的机制；明确了抑制GR可以阻滞肝癌细胞体内外生存生长。为靶向氨基酸代谢酶的癌症治疗新策略的开发提供理论基础及潜在分子靶点。