PNAS：癌症侵袭、复发与蛋白

　　

生物通报道：Johns Hopkins大学的科学家进行了一项旨在分析前列腺癌细胞生长和侵袭性机制的研究，发现一种特殊蛋白的减少与前列腺癌的侵袭性有关，并且是癌症复发的危险信号。该文章发表在八月二十七日的美国国家科学院院刊，Proceedings of the National Academy of Sciences杂志上。

美国癌症协会的调查显示，在美国今年约有240,000人被诊断为前列腺癌，其中大多数年龄都超过65岁。前列腺癌是美国男性中第二大致命癌症，今年美国约有28,000人死于这一疾病。然而这种疾病的侵袭性差异很大，低级别的前列腺癌并无大碍，但高级别的前列腺癌死亡率很高。高级别前列腺癌患者的差异也很大，超过65%的患者在初次治疗后会发生癌症复发。识别面临癌症复发风险的患者，阐明引起癌症复发的分子机制是非常很重要的。

Johns Hopkins大学的研究者们针对SPARC（富含半胱氨酸的酸性分泌蛋白）家族中的SPARCL1基因进行了研究。在胚胎的前列腺发育中该基因对于细胞迁移非常重要，而在前列腺癌发展过程中该基因又会重新活跃起来。研究发现，在前列腺发育和再生中，SPARC富含半胱氨酸的酸性分泌蛋白家族的Sparcl1表达量下调。而在前列腺癌中也存在类似的现象，在高级别侵袭性前列腺癌中SPARCL1的表达量降低。一般来说，良性和恶性前列腺癌细胞都会表达高水平的SPARCL1基因，当癌细胞开始转移时这一基因的表达水平会降低。该研究团队将SPARCL1基因表达量的下调与前列腺癌的侵袭性关联起来。

进一步研究显示，SPARCL的表达下降通过Ras同源基因家族中的RHOC起作用，提高了前列腺癌的转移和侵袭性。研究人员结合了临床病理学参数对治疗后前列腺癌的复发进行了预测，证明SPARCL1表达下降是独立预示疾病发展的重要指标。研究人员还发现，在许多其他疾病中SPARCL1基因也能够作为预测肿瘤复发的标志，包括膀胱癌、乳腺癌、结肠癌、直肠癌、舌癌、肺癌、皮肤癌和卵巢癌等。

“我们的发现不仅可以使医生识别哪些患者手术后面临着癌症复发的风险，也为癌症治疗提供了潜在的新选择，”Johns Hopkins大学医学院的泌尿学、肿瘤学和病理学副教授Edward Schaeffer博士说。

文章总结道，SPARCL1是潜在的细胞迁移/侵袭调节子，并且其表达量的减少与前列腺癌复发有关。“我们的研究有助于识别癌症复发风险高的患者，而我们的终极目标是开发新的治疗手段阻止癌症复发。”Schaeffer说。

目前，该研究团队正在解码SPARCL1基因的调控机制，尝试通过治疗手段使SPARCL1回到正常水平，以期防止患者癌症复发。文章第一作者Paula Hurley博士也在进一步寻找预示着致死性前列腺癌且与癌转移有关的新基因。

（生物通编辑：叶予）

生物通推荐原文摘要：

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome

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.