文章：

粘蛋白在癌症中的作用、预后和治疗

Mucins in cancer: function, prognosis and therapy

原文发布日期：2009-12-01

DOI: 10.1038/nrc2761

类型: Review Article

开放获取: 否

要点：

1. Epithelial cells form a layer in which an apical surface is exposed to the external environment and to other forms of stress in ducts in specialized organs. As such, epithelial cells require robust defence mechanisms to avoid sustaining damage.
2. Secreted mucins are highly glycosylated proteins that form a physical barrier, which protects epithelial cells from stress-induced damage. Transmembrane mucins also contribute to the physical barrier and transmit growth and survival signals to the interior of the cell.
3. Deregulation of secreted mucin 2 (MUC2) production has provided an important link between inflammation and cancer. Expression of the transmembrane mucin MUC1 is upregulated in response to chronic inflammation.
4. Aberrant overexpression of transmembrane mucins is associated with diverse human carcinomas and, somewhat paradoxically, certain haematological malignancies. Human cancers have exploited the function of these mucins in promoting growth and survival.
5. Overexpression of transmembrane mucins contributes to oncogenesis by promoting receptor tyrosine kinase signalling, loss of epithelial cell polarity, constitutive activation of growth and survival pathways (for example, the Wnt–β-catenin and nuclear factor-κB pathways), and downregulation of stress-induced death pathways.
6. Gene expression profiling and analysis of protein levels have demonstrated that overexpression of transmembrane mucins is associated with a poor prognosis in several different types of carcinomas. Circulating levels of the transmembrane mucins MUC1 and MUC16 are used to monitor the clinical course of patients with breast and ovarian cancer, respectively.
7. Overexpression of the transmembrane mucins in human cancers has made them highly attractive targets for the development of vaccines, antibodies and drug inhibitors. Recent work has demonstrated that the MUC1 cytoplasmic domain is a direct drug target and that inhibition of MUC1 function blocks survival and tumorigenicity of human breast and prostate cancers in preclinical models.

要点翻译：

1. 上皮细胞形成一层结构，其顶面暴露于外界环境及特殊器官导管内的各种应激源。因此，上皮细胞需要强大的防御机制来避免损伤。
2. 分泌型黏蛋白是高度糖基化的蛋白质，能形成物理屏障保护上皮细胞免受应激损伤。跨膜黏蛋白不仅参与构成物理屏障，还能向细胞内部传递生长和存活信号。
3. 分泌型黏蛋白MUC2的调控失常揭示了炎症与癌症之间的重要关联。跨膜黏蛋白MUC1的表达会因慢性炎症反应而上调。
4. 跨膜黏蛋白的异常过表达与多种人类癌瘤相关，矛盾的是，还与某些血液系统恶性肿瘤有关。人类癌症利用了这些黏蛋白促进生长和存活的功能。
5. 跨膜黏蛋白过表达通过以下机制促进肿瘤发生：增强受体酪氨酸激酶信号传导、破坏上皮细胞极性、持续激活生长和存活通路（如Wnt-β-连环蛋白和核因子κB通路），以及抑制应激诱导的死亡通路。
6. 基因表达谱分析和蛋白水平检测表明，跨膜黏蛋白过表达与多种癌症的不良预后相关。跨膜黏蛋白MUC1和MUC16的循环水平分别用于监测乳腺癌和卵巢癌患者的临床进程。
7. 跨膜黏蛋白在人类癌症中的过表达使其成为疫苗、抗体和药物抑制剂开发的极佳靶点。最新研究表明MUC1胞质结构域可直接作为药物靶点，在临床前模型中抑制MUC1功能可阻断人类乳腺癌和前列腺癌的存活及成瘤能力。

英文摘要：

Epithelia are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are largely unrecognized as effectors of carcinogenesis. However, both types of mucins are intimately involved in inflammation and cancer. Moreover, diverse human malignancies overexpress transmembrane mucins to exploit their role in signalling cell growth and survival. Mucins have thus been identified as markers of adverse prognosis and as attractive therapeutic targets. Notably, the findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models.

摘要翻译： 

上皮组织通过黏液屏障抵御不良环境。构成黏液屏障的分泌型与跨膜黏蛋白在致癌过程中的作用长期被忽视。然而，两类黏蛋白均深度参与炎症与癌症的发生发展。多种人类恶性肿瘤通过过表达跨膜黏蛋白，利用其调控细胞生长与存活的信号功能。因此，黏蛋白已被确认为不良预后标志物及极具吸引力的治疗靶点。尤为重要的是，特定跨膜黏蛋白可诱导细胞转化并促进肿瘤进展的发现，为证实其功能抑制剂在临床前模型中作为抗肿瘤药物的有效性提供了实验依据。

原文链接：

Mucins in cancer: function, prognosis and therapy