文章：

HMGA蛋白在癌症中的作用

Roles of HMGA proteins in cancer

原文发布日期：2007-12-01

DOI: 10.1038/nrc2271

类型: Review Article

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要点：

1. The high mobility group A (HMGA) family is composed of four proteins, HMGA1a, HMGA1b, HMGA1c and HMGA2, encoded by two distinct genes. HMGA1 proteins are products of the same gene, generated through alternative splicing. They are non-histone nuclear proteins known as 'architectural transcriptional factors'.
2. HMGA gene rearrangements, due to chromosomal translocations, are a feature of human benign tumours of mesenchymal origin. In most of the cases the breakpoint occurs in the third intron of the HMGA2 gene, resulting in deregulation of its expression, truncation or, more frequently, in the generation of fusion genes encoding chimeric transcripts containing the first three exons of HMGA2 and ectopic sequences from other genes.
3. HMGA protein overexpression is a constant feature of human malignant neoplasias. It represents a poor prognostic index as their overexpression often correlates with the presence of metastasis and with a reduced survival.
4. HMGA proteins have a crucial role in cell transformation. They show oncogenic activities in vitro and in vivo, and blockage of their synthesis suppresses the malignant phenotype.
5. The appearance of a neoplastic phenotype in Hmga1^−/− and Hmga1^+/− mice revealed that HMGA proteins also have a tumour suppressor function.
6. HMGA proteins exert their oncogenic activity through several mechanisms: induction of E2F1 and AP1 activity, induction of cyclin A expression, inactivation of p53-induced apoptosis, impairment of DNA repair, enhancement of the expression of proteins involved in inflammation, and modulation of the expression of microRNAs and genes involved in epithelial–mesenchymal transition.
7. Blocking HMGA function could be an excellent tool for cancer treatment because of the specificity, low toxicity and wide range of applications of such therapy.

要点翻译：

1. 高迁移率族A（HMGA）蛋白家族包含四种成员：HMGA1a、HMGA1b、HMGA1c和HMGA2，由两个独立基因编码。HMGA1蛋白源自同一基因的不同剪接变体，属于非组蛋白核蛋白，被称为“结构转录因子”。
2. HMGA基因重排是间叶源性人类良性肿瘤的典型特征，由染色体易位导致。多数情况下断裂点位于HMGA2基因的第三内含子区域，导致其表达失调、蛋白截断，或更常见地形成融合基因——该嵌合转录本包含HMGA2的前三个外显子及其他基因的异位序列。
3. HMGA蛋白过表达是人类恶性肿瘤的恒定特征。这种过表达常与转移灶存在和生存率降低相关，因而是预后不良的指标。
4. HMGA蛋白在细胞转化过程中起关键作用。它们在体外和体内均表现出致癌活性，而阻断其合成可抑制恶性表型。
5. 在Hmga1−/−和Hmga1+/−小鼠中观察到的肿瘤表型表明，HMGA蛋白同时具有肿瘤抑制功能。
6. HMGA蛋白通过多种机制发挥致癌作用：诱导E2F1和AP1活性、促进细胞周期蛋白A表达、灭活p53诱导的细胞凋亡、削弱DNA修复能力、增强炎症相关蛋白表达，以及调控上皮-间质转化相关microRNAs和基因的表达。
7. 鉴于其作用特异性、低毒性及广泛适用性，阻断HMGA功能可能成为癌症治疗的理想策略。

英文摘要：

The high mobility group A (HMGA) non-histone chromatin proteins alter chromatin structure and thereby regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias. Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumours. Conversely, unrearranged HMGA overexpression is a feature of malignant tumours and is also causally related to neoplastic cell transformation. Here, we focus on the role of the HMGA proteins in human neoplastic diseases, the mechanisms by which they contribute to carcinogenesis, and therapeutic strategies based on targeting HMGA proteins.

摘要翻译： 

高迁移率族A（HMGA）非组蛋白染色质蛋白通过改变染色质结构，从而增强或抑制转录因子，调控多个基因的转录。该蛋白家族通过不同机制参与良性和恶性赘生物的发生。HMGA基因重排是大多数良性人类间叶肿瘤的特征；相反，未重排的HMGA过表达则是恶性肿瘤的特征，并与肿瘤细胞转化存在因果关系。本文重点阐述HMGA蛋白在人类肿瘤性疾病中的作用、其参与致癌的机制，以及以HMGA蛋白为靶点的治疗策略。

原文链接：

Roles of HMGA proteins in cancer