HYAL1 hyaluronidase in prostate cancer: A tumor promoter and suppressor
HYAL1 hyaluronidase in prostate cancer: A tumor promoter and suppressor
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DOI：
10.1158/0008-5472.can-05-1022
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发表时间：
2005-09-01
期刊：
影响因子：
11.2
通讯作者：
Lokeshwar, BL
中科院分区：
文献类型：
--
作者：
Lokeshwar, VB;Cerwinka, WH;Lokeshwar, BL
透明质酸酶降解透明质酸，促进转移。HYAL1型透明质酸酶是前列腺癌进展的独立预后指标，也是膀胱癌的生物标志物。然而，透明质酸酶（例如，HYAL1）是作为肿瘤启动子还是作为肿瘤抑制因子存在争议。我们稳定地转染了前列腺癌细胞DU145和PC-3 ML，用hyal1 -义（HYAL1-S）、hyal1 -反义（HYAL1-AS）或载体DNA。由于PC-3 ML表达的HYAL1很少，因此未产生HYAL1- as转染物。产生的透明质酸酶活性= 80毫单位（高生产者）。与载体转染相比，HYAL1-AS转染产生的透明质酸酶活性< 10%（18-24毫单位）。阻断HYAL1表达和高HYAL1产生均可导致前列腺癌细胞增殖减少4- 5倍。由于细胞周期蛋白B1、cdc25c和cdc2/p34的表达以及cdc2/p34激酶活性的降低，HYAL1-AS转染具有G(2)-M阻滞。与载体转染相比，高HYAL1产生者的凋亡活性和线粒体去极化增加了3倍，并表达了活化的促凋亡蛋白WOX1。阻断HYAL1表达可抑制肿瘤生长4- 7倍，而高HYAL1表达的转染物要么不形成肿瘤（DU145），要么生长速度慢3.5倍（pc - 3ml）。载体和中度HYAL1产生者产生肌肉和血管浸润性肿瘤，而HYAL1- as肿瘤是良性的，含有较小的毛细血管。高HYAL1产生者的标本99%无肿瘤细胞。本研究表明，根据浓度的不同，HYAL1具有肿瘤启动子和抑制子的功能，为抗透明质酸酶和高透明质酸酶治疗癌症提供了基础。
Hyaluronidases degrade hyaluronic acid, which promotes metastasis. HYAL1 type hyaluronidase is an independent prognostic indicator of prostate cancer progression and a biomarker for bladder cancer. However, it is controversial whether hyaluronidase (e.g., HYAL1) functions as a tumor promoter or as a suppressor. We stably transfected prostate cancer cells, DU145 and PC-3 ML, with HYAL1-sense (HYAL1-S), HYAL1-antisense (HYAL1-AS), or vector DNA. HYAL1-AS transfectants were not generated for PC-3 ML because it expresses little HYAL1. HYAL1-S transfectants produced = 80 milliunits hyaluronidase activity (high producers). HYAL1-AS transfectants produced < 10% hyaluronidase activity when compared with vector transfectants (18-24 milliunits). Both blocking HYAL1 expression and high HYAL1 production resulted in a 4- to 5-fold decrease in prostate cancer cell proliferation. HYAL1-AS transfectants had a G(2)-M block due to decreased cyclin B1, cdc25c, and cdc2/p34 expression and cdc2/p34 kinase activity. High HYAL1 producers had a 3-fold increase in apoptotic activity and mitochondrial depolarization when compared with vector transfectants and expressed activated proapoptotic protein WOX1. Blocking HYAL1 expression inhibited tumor growth by 4- to 7-fold, whereas high HYAL1 producing transfectants either did not form tumors (DU145) or grew 3.5-fold slower (PC-3 ML). Whereas vector and moderate HYAL1 producers generated muscle and blood vessel infiltrating tumors, HYAL1-AS tumors were benign and contained smaller capillaries. Specimens of high HYAL1 producers were 99% free of tumor cells. This study shows that, depending on the concentration, HYAL1 functions as a tumor promoter and as a suppressor and provides a basis for anti-hyaluronidase and high-hyaluronidase treatments for cancer.