《Cancer Cell》两项华裔科学家研究组癌症成果

　　

生物通报道：8月17日出版的著名癌症研究期刊《Cancer Cell》公布了两个华裔研究组癌症研究的最新成果：HER2抗体抗肿瘤效应的最新免疫机制，以及致癌基因MDM2的调控基因。

芝加哥大学和生物物理研究所的研究人员发现了HER2抗体抗肿瘤效应的最新免疫机制，为在临床上更加合理有效地联合使用HER2抗体和化疗药物进行肿瘤治疗，提供了新的理论基础。

乳腺癌是严重影响女性健康的重要疾病之一，抗人类表皮生长因子受体-2(HER2)的抗体，已被用于临床乳腺癌病人的治疗。传统认为抗HER2抗体阻断HER2受体信号导致肿瘤细胞死亡，而越来越多的研究显示免疫在抗HER2抗体抗肿瘤作用中具有重要作用，但具体机制还很不清楚。

该研究以源于HER2转基因小鼠的TUBO乳腺肿瘤细胞为模型，利用可以阻止TUBO上HER2信号的HER2抗体，真实模拟了临床上HER2抗体的肿瘤治疗作用。HER2抗体可以消除野生型小鼠肿瘤，而对免疫缺陷小鼠则几乎丧失抗肿瘤作用，这一结果直接证明了HER2抗体所介导的抗瘤效应依赖于适应性免疫反应。进一步研究发现，HER2抗体可以增强肿瘤特异性CD8+ T细胞的功能和肿瘤特异的记忆性T细胞反应；HER2抗体抗瘤效应需要释放大量危险信号HMGB-1，来活化天然性免疫反应MyD88信号，进而启动适应性免疫反应。此外，研究发现化疗药物和HER2抗体联合应用时，治疗顺序不同会导致相反的记忆性抗肿瘤反应，这为临床优化HER2抗体的联合应用提供了重要的理论依据。

另外来自哈佛大学的魏文意（Wenyi Wei，音译）博士研究组发现了调控着致癌基因MDM2的基因，这一上游基因的新发现涉及了p53细胞信号传导路径，该发现可能指出了帮助杀死肿瘤的新的药物靶标。这项发现还指出了可能的癌症风险生物标记，有朝一日它们可能有助于患者采取针对癌症的预防措施。

研究人员发现当DNA受到破坏之后，MDM2后退，允许p53暂停细胞并进行修复，而当MDM2重新出现后，p53消失，细胞周期恢复正常。然而，已知MDM2 也是一种致癌基因，因为MDM2过多会完全制止p53，因此也就削弱了它的预防癌症的能力。

MDM2并非简单地逐渐消失，而是通过一对酶的联合作用而积极地降解。其中一个酶称为酪蛋白激酶I（CKI），当细胞探测到DNA损伤的时候它会被激活，尽管这种激活的细节尚不很清楚。它的工作是让MDM2磷酸化，这会引发MDM2被另一种酶beta-TRCP1破坏。beta-TRCP1通过用一种称为遍在蛋白的小蛋白质标记MDM2从而起作用，这就像给一件不想要的家具贴上“垃圾”的标签。26S蛋白酶体然后就像垃圾收集者一样清扫掉了MDM2，释放出了p53的DNA修复工作。

这项新的研究定义了DNA损伤之后MDM2如何被蛋白质降解所调控。尽管长久以来人们知道p53被激活了，这种情况发生的机制远远不那么清楚，这些类型的实验可能最终实现用治疗来干预这一发生机制的方法。

原文摘要：

Phosphorylation by Casein Kinase I Promotes the Turnover of the Mdm2 Oncoprotein via the SCFβ-TRCP Ubiquitin Ligase

Highlights
Multisite-phosphorylation by CKI triggers Mdm2 destruction via SCFβ-TRCP 4 SCFβ-TRCP controls Mdm2 stability independently of its auto-ubiquitination process
Inactivation of β-TRCP results in elevated resistance to DNA damage-induced apoptosis
Mdm2 turnover by SCFβ-TRCP controls p53 activity in response to genotoxic stress
Summary
Mdm2 is the major negative regulator of the p53 pathway. Here, we report that Mdm2 is rapidly degraded after DNA damage and that phosphorylation of Mdm2 by casein kinase I (CKI) at multiple sites triggers its interaction with, and subsequent ubiquitination and destruction, by SCFβ-TRCP. Inactivation of either β-TRCP or CKI results in accumulation of Mdm2 and decreased p53 activity, and resistance to apoptosis induced by DNA damaging agents. Moreover, SCFβ-TRCP-dependent Mdm2 turnover also contributes to the control of repeated p53 pulses in response to persistent DNA damage. Our results provide insight into the signaling pathways controlling Mdm2 destruction and further suggest that compromised regulation of Mdm2 results in attenuated p53 activity, thereby facilitating tumor progression.
 

The Therapeutic Effect of Anti-HER2/neu Antibody Depends on Both Innate and Adaptive Immunity

Highlights
The tumor regression by anti-HER2/neu antibody is T cell-dependent
FcR-dependent stress by antibody is required to prime adaptive immune cells
Some chemotherapy drugs could abrogate antibody-mediated immunity
A selected immunotherapy could further enhance antibody-mediated immunity
Summary
Anti-HER2/neu antibody therapy is reported to mediate tumor regression by interrupting oncogenic signals and/or inducing FcR-mediated cytotoxicity. Here, we demonstrate that the mechanisms of tumor regression by this therapy also require the adaptive immune response. Activation of innate immunity and T cells, initiated by antibody treatment, was necessary. Intriguingly, the addition of chemotherapeutic drugs, although capable of enhancing the reduction of tumor burden, could abrogate antibody-initiated immunity leading to decreased resistance to rechallenge or earlier relapse. Increased influx of both innate and adaptive immune cells into the tumor microenvironment by a selected immunotherapy further enhanced subsequent antibody-induced immunity, leading to increased tumor eradication and resistance to rechallenge. This study proposes a model and strategy for anti-HER2/neu antibody-mediated tumor clearance.