乙酰肝素酶在乳腺癌侵袭转移中的作用及调控机制

The Role of Heparanase in the Invasion and Metastasis of Breast Carcinoma and Its Regulation Mechanism

乙酰肝素酶(Heparanase,HPSE)是目前发现的哺乳动物细胞中唯一能降解细胞外基质和基底膜中硫酸肝素蛋白多糖侧链—硫酸乙酰肝素的内源性糖苷酶,是目前抗肿瘤转移的理想靶点。HPSE在乳腺癌中常有高表达,并与肿瘤大小和淋巴结转移等密切相关。体外研究表明,乳腺癌细胞中HPSE启动子活性增高,转染HPSE的乳腺癌细胞在体内成瘤后,其肿瘤体积、重量、微血管密度以及癌细胞存活时间均明显高于阴性对照组。应用反义核酸技术或RNA干扰技术封闭或沉默HPSE基因表达后,乳腺癌细胞黏附和侵袭能力显著降低,表明HPSE在乳腺癌侵袭转移中发挥极其重要的作用。HPSE在乳腺癌侵袭转移中受多种机制调控,主要有:雌激素与其受体结合后作用于HPSE基因特定区域,从而提高HPSE转录活性,增强其基因和蛋白的表达:HPSE可使破骨细胞刺激因子产生增加,从而导致骨质溶解破坏,为乳腺癌骨转移奠定基础;HPSE诱导循环淋巴细胞产生刺激因子,从而促进乳腺癌的侵袭转移。此外,HPSE基因还受p53基因、ETS基因、EGR1基因、PI-88因子、COX-2等的调控。本文就HPSE在乳腺癌中的表达状况、在侵袭转移中的作用及调控机制进行综述。

Heparanase is the only one endogenous glucuronidase found in mammalian cells up to now, and can degrade the heparan sulfate which is the side chain of heparin sulfate proteoglycans existing in the extracellular matrix and basement membrane. Heparanase is considered as an ideal target for the treatment of cancer metastasis. High expression of heparanase gene was found in breast cancer, and was closely associated with tumor size and lymph node metastasis. In vitro, high level of heparanase promoter activity was found in breast cancer cells. In vivo, compared with negative control group, breast cancer cells transfected with heparanase could generate higher tumor volume, tumor weight, microvessel density and longer survival time of cancer cells. Blockage or silencing of heparanase gene expression through antisense technology or RNA interference technology could reduce the ability of adhesion and invasion of breast cancer cells, indicating that heparanase played important roles in the invasion and metastasis of breast cancer. Mechanisms involved in the regulation of heparanase in the invasion and metastasis of breast cancer are as following. Estrogen could bind to its receptor and then affect the specific region of heparanase gene which could activate heparanase transcription and the expression of heparanase mRNA and protein. Heparanase could increase the secretion of osteoclast-stimulating factor which could cause the osteolytic lesions in the absence of detectable bone metastasis. Heparanase could also induce circulating lymphocytes to produce stimulating factors which might promote the invasion and metastasis of breast cancer. Furthermore, p53 gene, ETS gene, EGR1 gene, PI-88 factor, and Cox-2 could also regulate the expression of heparanase gene. This article reviewed the role of heparanase in the invasion and metastasis of breast cancer and summarized the corresponding regulation mechanisms.