INSERM, U895, University of Nice-Sophia Antipolis, Nice, France.
Pigment Cell Melanoma Res. 2011 Feb;24(1):219-32. doi: 10.1111/j.1755-148X.2010.00790.x. Epub 2010 Nov 17.
Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, belongs to the family of matricellular proteins that modulate cell-matrix interactions and cellular functions. SPARC is highly expressed in melanoma, and we reported that SPARC promotes epithelial/mesenchymal-like changes and cell migration. Here, we used siRNA and conditional shRNA to investigate the contribution of tumor-derived SPARC to melanoma cell growth in vitro and in vivo. We found that depletion of SPARC induces G2/M cell cycle arrest and tumor growth inhibition with activation of p53 and induction of p21(Cip1/Waf1) acting as a checkpoint, preventing efficient mitotic progression. In addition, we demonstrate that reduced mesenchymal features and the invasive potential of SPARC-silenced cells are independent of p21(Cip1/Waf1) induction and cell cycle arrest. Importantly, overexpression of SPARC reduces p53 protein levels and leads to an increase in cell number during exponential growth. Our findings indicate that in addition to its well-known function as a mediator of melanoma cell migration and tumor-host interactions, SPARC regulates, in a cell-autonomous manner, cell cycle progression and proliferation through the p53/p21(Cip1/Waf1) pathway.
富含半胱氨酸的酸性分泌蛋白（SPARC），又名骨粘连蛋白，属于细胞基质蛋白家族，可调节细胞与基质的相互作用和细胞功能。SPARC 在黑色素瘤中高表达，我们曾报道过 SPARC 可促进上皮/间充质样改变和细胞迁移。在此，我们利用 siRNA 和条件性 shRNA 来研究肿瘤来源的 SPARC 对黑色素瘤细胞体外和体内生长的作用。我们发现，SPARC 耗竭可诱导 G2/M 细胞周期阻滞和肿瘤生长抑制，同时激活 p53 并诱导 p21（Cip1/Waf1）作为检验点，阻止有丝分裂的有效进行。此外，我们证实 SPARC 沉默细胞的间充质特征和侵袭潜能的降低与 p21（Cip1/Waf1）诱导和细胞周期阻滞无关。重要的是，SPARC 的过表达降低了 p53 蛋白水平，并导致指数生长期细胞数量增加。我们的研究结果表明，SPARC 除了作为黑色素瘤细胞迁移和肿瘤-宿主相互作用的中介的已知功能外，还通过 p53/p21（Cip1/Waf1）通路以细胞自主的方式调节细胞周期进程和增殖。
