Nat Commun:WSX1:肝细胞癌的新型肿瘤抑制因子

2021-06-14 xiaozeng MedSci原创

肝细胞癌(HCC)作为全球最常见的恶性肿瘤之一,在癌症相关死亡率中排第五。

肝细胞癌(HCC)作为全球最常见的恶性肿瘤之一,在癌症相关死亡率中排第五。HCC的发生发展是一个多因素过程,其中调节基因的遗传和表观遗传改变会导致致癌基因的激活和抑癌基因的失活。

与大多数的其他恶性肿瘤不同的是,HCC是一种与炎症和免疫相关的疾病,其几乎都出现在发炎的肝纤维化或肝硬化环境中。值得注意的是,检测和消除转化细胞的严格控制的免疫网络在HCC中经常失调。而迄今为止,HCC细胞诱导免疫耐受和逃避宿主稳态免疫监视的机制仍不清楚。

PD-L1(程序性死亡配体-1)是一种关键的免疫检查点蛋白,其能够与T细胞上的PD-1(程序性死亡1受体)结合并激活共抑制信号,最终抑制效应T细胞的功能。尽管如此,PD-L1表达的稳态调控及其在癌症中的失调的相关机制仍知之甚少,而了解PD-L1的相关调控机制将有助于开发更有效的治疗策略。


WSX1是IL-27的受体亚基,在免疫细胞中广泛表达且与免疫反应密切相关,但其在非免疫细胞中的功能尚不清楚。

WSX1在HCC中下调且与患者预后不良相关

在该研究中,研究人员发现,WSX1在人肝细胞中高表达,但在HCC细胞中其表达水平下调。在NRAS/AKT衍生的原发性HCC小鼠模型中,研究人员揭示了WSX1的独立于IL-27的肿瘤抑制作用,该作用主要依赖于CD8+T细胞的免疫监视,即通过减少肿瘤性PD-L1的表达和相关CD8+ T 细胞耗竭。


机制研究显示,WSX1通过转录下调PI3K同工型PI3Kδ的表达水平,失活AKT并减少AKT诱导的GSK3β抑制作用。激活的GSK3β会进一步的促进PD-L1的降解,最终引起PD-L1的减少。

相关示意图

总而言之,该研究结果揭示,WSX1是一种肿瘤抑制因子,其可通过阻断PI3Kδ/AKT/GSK3β/PD-L1通路来增强肝脏的免疫监视作用。该研究结果也会深入了解宿主免疫反应的稳态调控提供了一定的见解,并有助于相关癌症免疫疗法的开发。


原始出处:

Wu, M., Xia, X., Hu, J. et al. WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression. Nat Commun 12, 3500 (09 June 2021).

 

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    2021-11-02 liuli5079
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    2022-03-14 xjy02
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    2022-03-16 liye789132251
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