Bharadwaj Alamelu G, Rector Katherine, Simpson Melanie A
Department of Biochemistry, University of Nebraska, 1901 Vine Street, Lincoln, NE 68588-0664, USA.
J Biol Chem. 2007 Jul 13;282(28):20561-72. doi: 10.1074/jbc.M702964200. Epub 2007 May 14.
Prostate cancer progression can be predicted in human tumor biopsies by abundant hyaluronan (HA) and its processing enzyme, the hyaluronidase HYAL1. Accumulation of HA is dictated by the balance between expression levels of HA synthases, the enzymes that produce HA polymers, and hyaluronidases, which process polymers to oligosaccharides. Aggressive prostate tumor cells express 20-fold higher levels of the hyaluronan synthase HAS3, but the mechanistic relevance of this correlation has not been determined. We stably overexpressed HAS3 in prostate tumor cells. Adhesion to extracellular matrix and cellular growth kinetics in vitro were significantly reduced. Slow growth in culture was restored either by exogenous addition of hyaluronidase or by stable HYAL1 coexpression. Coexpression did not improve comparably slow growth in mice, however, suggesting that excess hyaluronan production by HAS3 may alter the balance required for induced tumor growth. To address this, we used a tetracycline-inducible HAS3 expression system in which hyaluronan production could be experimentally controlled. Adjusting temporal parameters of hyaluronan production directly affected growth rate of the cells. Relief from growth suppression in vitro but not in vivo by enzymatic removal of HA effectively uncoupled the respective roles of hyaluronan in growth and angiogenesis, suggesting that growth mediation is less critical to establishment of the tumor than early vascular development. Collectively results also imply that HA processing by elevated HYAL1 expression in invasive prostate cancer is a requirement for progression.
在人类肿瘤活检中，前列腺癌的进展可通过大量透明质酸（HA）及其加工酶——透明质酸酶HYAL1来预测。HA的积累取决于HA合成酶（产生HA聚合物的酶）和透明质酸酶（将聚合物加工成寡糖的酶）表达水平之间的平衡。侵袭性前列腺肿瘤细胞中透明质酸合成酶HAS3的表达水平高出20倍，但这种相关性的机制尚未确定。我们在前列腺肿瘤细胞中稳定过表达HAS3。细胞对细胞外基质的黏附以及体外细胞生长动力学显著降低。通过外源添加透明质酸酶或稳定共表达HYAL1可恢复培养中的缓慢生长。然而，共表达并未同等程度地改善小鼠体内的缓慢生长，这表明HAS3过量产生透明质酸可能会改变诱导肿瘤生长所需的平衡。为解决这一问题，我们使用了四环素诱导型HAS3表达系统，通过该系统可对透明质酸的产生进行实验控制。调整透明质酸产生的时间参数直接影响细胞的生长速率。通过酶促去除HA可在体外而非体内缓解生长抑制，这有效地分离了透明质酸在生长和血管生成中的各自作用，表明生长调节对肿瘤形成的重要性低于早期血管发育。总体结果还表明，侵袭性前列腺癌中通过提高HYAL1表达来加工HA是肿瘤进展的必要条件。
