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Mol Cell:揭示明星分子RB在肿瘤中的新功能

2018-12-07 生物君 iNature

程序性死亡配体-1(PD-L1)在肿瘤细胞中的异常表达通过抑制癌症免疫来促进癌症进展。视网膜母细胞瘤蛋白RB是已知调节细胞周期,DNA损伤反应和分化的肿瘤抑制因子。2018年12月7日,华中科技大学Wu Heshui,江苏大学附属医院Zhu Runzhi及美国梅奥诊所黄浩杰共同通讯在Mol Cell在线发表题为“Phosphorylated RB Promotes Cancer Immunity

程序性死亡配体-1(PD-L1)在肿瘤细胞中的异常表达通过抑制癌症免疫来促进癌症进展。视网膜母细胞瘤蛋白RB是已知调节细胞周期,DNA损伤反应和分化的肿瘤抑制因子。2018年12月7日,华中科技大学Wu Heshui,江苏大学附属医院Zhu Runzhi及美国梅奥诊所黄浩杰共同通讯在Mol Cell在线发表题为“Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression”的研究论文,该论文证明RB与核因子κB(NF-κB)蛋白p65相互作用,并且它们的相互作用主要依赖于CDK4 / 6介导的RB的丝氨酸-249 /苏氨酸-252(S249 / T252)磷酸化。研究结果揭示了先前未被认识到的过度磷酸化RB抑制NF-κB活性和PD-L1表达的肿瘤抑制功能,并表明RB-NF-κB轴可用于克服由常规或靶向治疗引发的癌症免疫逃避。

逃避免疫监视是人类癌症的标志。虽然癌细胞产生的新抗原可能被免疫系统识别,但肿瘤通常可以通过不同的机制逃避免疫攻击,包括终止免疫反应的免疫检查点的异常激活。

程序性死亡-1(PD-1)及其配体PD-L1(也称为B7-H1)是两种主要的免疫检查点分子。在癌细胞中表达的PD-L1在活化的T细胞中与其受体PD-1结合,从而引发T细胞凋亡,细胞毒性T细胞功能丧失和癌症免疫逃避。基于抗PD-1和抗PD-L1抗体的免疫检查点阻断疗法已被批准用于治疗不同的癌症类型。虽然PD-1 / PD-L1阻断可以改善患者无进展生存期,但所有患者的反应率仍然相对较低,这通常与患者样本中PD-L1的低表达率相关。这些研究强调需要进一步研究以更好地了解PD-L1表达的分子机制,以改善患者对临床免疫治疗的反应。

视网膜母细胞瘤蛋白RB是充分研究的肿瘤抑制因子。它是一种多功能蛋白质,可调节许多重要的细胞活动,包括细胞周期进程,DNA损伤反应和检查点激活以及分化。 RB蛋白主要以三种状态存在:未磷酸化,低磷酸化(也称为低磷酸化或部分磷酸化)和高磷酸化。未磷酸化或低磷酸化的RB与E2F转录因子相互作用并抑制E2F靶基因表达和G1 / S细胞周期转变。然而,在有丝分裂原刺激或G1晚期,RB在多个位点通过细胞周期蛋白/ CDK复合物如CYCLIN D / CDK4 / 6过度磷酸化,导致E2F因子从RB隔离和细胞周期的进展中释放。

NF-κB是一种与癌症高度相关的转录因子。在促炎性细胞因子如TNF-α的刺激下,NF-κB可被MAP3K7-IKK信号轴激活。除了调节经典促生存基因之外,已知NF-κB在各种癌症类型中调节PD-L1(也称为CD274)基因的mRNA表达。最近的基于CRISPR / Cas9的筛选将NF-κB途径鉴定为促进癌细胞逃避T细胞免疫攻击的关键机制之一。在本研究中,研究人员发现过度磷酸化的RB是NF-κB活性和PD-L1转录的主要抑制因子。

总之,该研究确定了先前未表征的过度磷酸化RB的肿瘤抑制功能,其通过抑制NF-κB转录活性和PD-L1表达来促进肿瘤免疫。 研究结果还表明,RB的这种活性可用于克服与当前治疗相关的癌症免疫耐受性,包括放射和化学疗法以及靶向疗法,例如CDK4 / 6小分子抑制剂。

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