蛋白质circPETH-147aa调节肝细胞癌细胞中的代谢重编程,以重塑免疫抑制微环境
Tian Lan1,2,3, Fengwei Gao4,5,6, Yunshi Cai4,5,6
1Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. blue_sky_land@163.com.
与瘤相关的巨细胞释放circPETH,这是一个循环RNA,推动肝细胞癌 (HCC) 糖分和转移. 一个小分子,诺拉西,抑制circPETH,增强抗瘤免疫力和提高免疫疗法的疗效.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 代谢重编程对于癌症转移和免疫逃避至关重要.
- 循环RNAs (circRNAs) 越来越多地被认为是癌症的关键调节者.
- 瘤相关巨细胞 (TAMs) 影响瘤微环境 (TME) 和癌症进展.
研究的目的:
- 为了研究circPETH的作用,一个TAM衍生的circRNA,在肝细胞癌 (HCC) 的进展和转移.
- 阐明circPETH影响HCC细胞代谢和免疫逃避的分子机制.
- 为了确定潜在的治疗策略,针对circPETH治疗HCC.
主要方法:
- 描述circPETH表达及其通过细胞外囊泡 (EV) 从TAM到HCC细胞的传输.
- 涉及m6A修饰,蛋白相互作用 (PKM2,ALDOA) 和mRNA稳定性 (SLC43A2) 的机制研究.
- 作为circPETH抑制剂的小分子诺拉西的体外和体内评估,评估其对HCC表型,T细胞功能和免疫治疗反应的影响.
主要成果:
- 由TAMs的EVs运输的circPETH通过circPETH-147aa.通过增强ALDOA酸化促进HCC细胞中的糖解和转移.
- circPETH-147aa通过增加SLC43A2mRNA稳定性来降低抗HCC免疫力,从而导致CD8+T细胞中的甲氨酸和白氨酸缺乏.
- 小分子Norathyriol有效地准circPETH-147aa,逆转HCC的代谢和转移表型,并提高抗PD1疗法的疗效.
结论:
- 在HCC中,circPETH是代谢重编程,转移和免疫抑制的关键媒介.
- 诺拉西里醇通过向circPETH和克服对免疫检查点抑制剂 (ICI) 的耐药性,显示出作为抗HCC治疗剂的巨大潜力.
- 这项研究强调了针对EV介导的circRNA通信在先进的HCC中具有治疗价值.
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