文章：

NFAT蛋白：在癌症进展中的新作用

NFAT proteins: emerging roles in cancer progression

原文发布日期：2009-11-01

DOI: 10.1038/nrc2735

类型: Review Article

开放获取: 否

要点：

1. Nuclear factor of activated T cells (NFAT) is a family of closely related transcription factors that are ubiquitously expressed in mammalian cells and tissues. NFAT1–4 are regulated by the calcium-sensitive phosphatase calcineurin, which induces nuclear translocation and transcriptional activation.
2. The transcriptional activity of NFATs is primarily regulated by phosphorylation that in turn determines subcellular localization. Maintenance kinases such as dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and casein kinase 1 phosphorylate cytoplasmic NFATs and prevent nuclear translocation, whereas export kinases such as DYRK1 and glycogen synthase kinase 3 phosphorylate nuclear NFATs and promote their export.
3. Overexpression and increased transcriptional activity of NFAT isoforms has been detected in various human solid tumours and cell lines, as well as haematological malignancies. This leads to the induction of genes that promote cellular phenotypes that are associated with tumour progression, such as proliferation, survival, migration and invasion phenotypes.
4. NFAT isoforms promote the migration and invasion of tumour cells, prerequisites for metastatic dissemination. These phenotypes are mediated by the transcriptional induction of NFAT target genes in tumour cells, such as prostaglandin E2 and lysophosphatidic acid.
5. NFATs are directly implicated in promoting tumour angiogenesis. In endothelial cells NFATs are activated by vascular endothelial growth factor A and promote vessel formation by inducing pro-angiogenic genes such as cyclooxygenase 2.
6. The activation of NFATs in tumour cells and the tumour microenvironment induces soluble factors that function through both paracrine and autocrine mechanisms to promote tumour progression.
7. Inactivation of NFATs decreases tumour formation. This is consistent with pathophysiological settings of increased expression of the calcineurin inhibitor Down syndrome candidate region 1, which attenuates the activation of NFATs and reduces tumour incidence.
8. Inhibition of NFAT activation using small-molecule inhibitors is predicted to suppress tumorigenesis. Paradoxically, patients receiving immunosuppressive therapy that blocks NFAT activity have a higher incidence of cancer.
9. Future cancer therapy targeting NFATs must take into account the cell type-specific phenotypes associated with deregulated the activation of NFATs.

要点翻译：

1. 活化T细胞核因子(NFAT)是一个在哺乳动物细胞和组织中广泛表达的转录因子家族，其成员结构高度相似。NFAT1-4受钙离子敏感性磷酸酶钙调神经磷酸酶的调控，该酶可诱导其核转位并激活转录功能。
2. NFATs的转录活性主要受磷酸化修饰调控，这一修饰决定其亚细胞定位。维持性激酶(如双特异性酪氨酸磷酸化调节激酶2和酪蛋白激酶1)可使胞质内的NFATs磷酸化从而阻止其核转位，而输出性激酶(如DYRK1和糖原合酶激酶3)则通过磷酸化核内的NFATs促进其出核。
3. 在多种人类实体瘤、细胞系及血液恶性肿瘤中均检测到NFAT亚型的过表达和转录活性增强。这诱导了促进肿瘤进展相关细胞表型的基因表达，包括增殖、存活、迁移和侵袭等表型。
4. NFAT亚型通过促进肿瘤细胞的迁移和侵袭能力，为转移扩散创造先决条件。这些表型由NFAT靶基因(如前列腺素E2和溶血磷脂酸)在肿瘤细胞中的转录诱导所介导。
5. NFATs直接参与促进肿瘤血管生成。在内皮细胞中，血管内皮生长因子A可激活NFATs，通过诱导环氧化酶2等促血管生成基因来促进血管形成。
6. 肿瘤细胞及肿瘤微环境中NFATs的激活可诱导分泌性因子，这些因子通过旁分泌和自分泌机制共同促进肿瘤进展。
7. NFATs的失活可抑制肿瘤形成。这一现象与钙调神经磷酸酶抑制剂唐氏综合征候选区域1表达增加的病理生理学背景相吻合，该抑制剂能减弱NFATs的激活并降低肿瘤发生率。
8. 理论预测使用小分子抑制剂阻断NFAT活化可抑制肿瘤发生。但矛盾的是，接受NFAT活性抑制免疫治疗的患者癌症发生率反而更高。
9. 未来针对NFATs的癌症治疗必须充分考虑其异常激活所引发的细胞类型特异性表型。

英文摘要：

The roles of nuclear factor of activated T cells (NFAT) transcription factors have been extensively studied in the immune system. However, ubiquitous expression of NFAT isoforms in mammalian tissues has recently been observed, and a role for these transcription factors in human cancer is emerging. Various NFAT isoforms are functional in tumour cells and multiple compartments in the tumour microenvironment, including fibroblasts, endothelial cells and infiltrating immune cells. How do NFAT isoforms regulate the complex interplay between these compartments during carcinoma progression? The answers lie with the multiple functions attributed to NFATs, including cell growth, survival, invasion and angiogenesis. In addition to elucidating the complex role of NFATs in cancer, we face the challenge of targeting this pathway therapeutically.

摘要翻译： 

活化T细胞核因子（NFAT）转录因子的作用已在免疫系统中被广泛研究。然而，近期发现NFAT亚型在哺乳动物组织中普遍表达，并且这些转录因子在人类癌症中的作用逐渐显现。多种NFAT亚型在肿瘤细胞以及肿瘤微环境中的多个组成部分（包括成纤维细胞、内皮细胞和浸润的免疫细胞）中发挥功能。NFAT亚型如何调控这些组成部分在癌症进展过程中的复杂相互作用？答案在于NFAT所具有的多种功能，包括细胞生长、存活、侵袭和血管生成。除了阐明NFAT在癌症中的复杂作用外，我们还面临如何将该通路作为治疗靶点的挑战。

原文链接：

NFAT proteins: emerging roles in cancer progression