Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, the Chinese University of Hong Kong, China.
Haematologica. 2013 Feb;98(2):288-95. doi: 10.3324/haematol.2012.065607. Epub 2012 Aug 28.
Platelet factor 4 (PF4) is an angiostatic chemokine that suppresses tumor growth and metastasis. We previously revealed frequent transcriptional silencing of PF4 in multiple myeloma, but the functional roles of this chemokine are still unknown. We studied the apoptotic effects of PF4 on myeloma cell lines and primary myeloma in vitro, and investigated the involved signaling pathway. The in vivo effects were also studied using a mouse model. PF4 not only suppressed myeloma-associated angiogenesis, but also inhibited growth and induced apoptosis in myeloma cells. We found that PF4 negatively regulated STAT3 and concordantly inhibited constitutive and interleukin-6-induced phosphorylation of STAT3, and down-regulated the expression of STAT3 target genes (Mcl-1, survivin and VEGF). Overexpression of constitutively activated STAT3 could rescue PF4-induced apoptotic effects. Furthermore, we found that PF4 induced the expression of SOCS3, a STAT3 inhibitor, and gene silencing of SOCS3 abolished its ability to inhibit STAT3 activation, suggesting a critical role of SOCS3 in PF4-induced STAT3 inhibition. Knockdown of LRP1, a putative PF4 receptor, could also abolish PF4-induced apoptosis and STAT3 inhibition. Finally, the tumor growth inhibitory effect of PF4 was confirmed by in vivo mouse models. Immunostaining of rabbit bone xenografts from PF4-treated mice showed induction of apoptosis of myeloma cells and inhibition of angiogenesis, which was associated with suppression of STAT3 activity. Together, our preclinical data indicate that PF4 may be a potential new targeting agent for the treatment of myeloma.
血小板因子 4（PF4）是一种血管生成抑制趋化因子，可抑制肿瘤生长和转移。我们之前发现多发性骨髓瘤中 PF4 频繁转录沉默，但这种趋化因子的功能作用仍不清楚。我们研究了 PF4 在骨髓瘤细胞系和原代骨髓瘤中的体外凋亡作用，并研究了涉及的信号通路。还使用小鼠模型研究了体内效应。PF4 不仅抑制骨髓瘤相关的血管生成，还抑制骨髓瘤细胞的生长并诱导其凋亡。我们发现 PF4 负调控 STAT3，并一致抑制 STAT3 的组成性和白细胞介素-6 诱导的磷酸化，下调 STAT3 靶基因（Mcl-1、存活素和 VEGF）的表达。组成性激活的 STAT3 的过表达可以挽救 PF4 诱导的凋亡作用。此外，我们发现 PF4 诱导 SOCS3 的表达，SOCS3 是 STAT3 的抑制剂，SOCS3 的基因沉默消除了其抑制 STAT3 激活的能力，表明 SOCS3 在 PF4 诱导的 STAT3 抑制中起关键作用。LRP1 的敲低，LRP1 是 PF4 的假定受体，也可以消除 PF4 诱导的凋亡和 STAT3 抑制。最后，通过体内小鼠模型证实了 PF4 的肿瘤生长抑制作用。PF4 处理的兔子异种移植物骨免疫染色显示骨髓瘤细胞凋亡和血管生成抑制，这与 STAT3 活性的抑制有关。总之，我们的临床前数据表明 PF4 可能是治疗骨髓瘤的一种有潜力的新靶向药物。
