Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome
Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome
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DOI：
10.1073/pnas.1203525109
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发表时间：
2012-09-11
影响因子：
11.1
通讯作者：
Schaeffer, Edward M.
中科院分区：
文献类型：
--
作者：
Hurley, Paula J.;Marchionni, Luigi;Schaeffer, Edward M.
前列腺癌是美国男性癌症死亡的第二大原因。然而，疾病的侵袭性是多种多样的，低度疾病通常是惰性的，而高度癌症是死亡密度最大的疾病。高级别前列腺癌患者的结局也各不相同，超过65%的患者即使在初级治疗后也会复发。识别有复发风险的男性并阐明驱动其疾病的分子过程至关重要，因为这些男性最有可能从多模式治疗中受益。我们以前的研究表明，雄激素诱导的前列腺发育表达谱在侵袭性前列腺癌中被重新激活。在此，我们报告了一个这样的基因，Sparcl 1，分泌的蛋白质，酸性和富含半胱氨酸（Cys）家族的基质细胞蛋白，在前列腺发育和再生的侵入性阶段的下调。我们进一步证明了前列腺癌中的平行过程，SPARCL 1在高级别/转移性前列腺癌中的表达降低。从机制上讲，我们证明了SPARCL 1丢失通过Ras同源基因家族成员C（RHOC）（一种已知的转移进展介质）增加前列腺癌细胞的迁移和侵袭特性。通过使用结合临床病理参数的模型来预测前列腺癌治疗后的复发，我们发现SPARCL 1丢失是疾病进展的一个重要的、独立的预后标志物。因此，SPARCL 1是细胞迁移/侵袭的有效调节因子，其丢失与前列腺癌复发独立相关。
Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matri-cellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/meta-static prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.