Department of Urology, The Johns Hopkins University, Baltimore, MD 21231, USA.
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14977-82. doi: 10.1073/pnas.1203525109. Epub 2012 Aug 27.
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 matricellular 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/metastatic 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.
前列腺癌是美国男性癌症死亡的第二大主要原因。然而，疾病侵袭性存在差异，低级别疾病通常较为惰性，而高级别癌症则导致最大密度的死亡。高级别前列腺癌患者的预后也存在差异，即使在初次治疗后，仍有多达 65%的患者出现疾病复发。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态治疗中获益。我们之前曾表明，雄激素诱导的前列腺发育中的表达谱在侵袭性前列腺癌中重新激活。在此，我们报告了在前列腺发育和再生的侵袭性阶段下调了一个这样的基因，即分泌蛋白、富含酸性半胱氨酸的 SPARC 家族基质细胞蛋白 1（Sparcl1）。我们进一步在高级别/转移性前列腺癌中证明了一个平行的过程，即 SPARCL1 在其中表达下调。从机制上讲，我们证明通过 Ras 同源基因家族成员 C（RHOC），即转移性进展的已知介质，Sparcl1 的缺失增加了前列腺癌细胞的迁移和侵袭特性。通过使用整合临床病理参数的模型来预测治疗后前列腺癌的复发，我们表明 Sparcl1 的缺失是疾病进展的一个显著的、独立的预后标志物。因此，Sparcl1 是细胞迁移/侵袭的有效调节剂，其缺失与前列腺癌的复发独立相关。
