Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, QC, Canada.
Neoplasia. 2012 Dec;14(12):1122-31. doi: 10.1593/neo.121252.
High circulating cholesterol is associated with hypercholesterolemia, atherosclerosis, and stroke. However, the relation between cholesterol and tumorigenesis/metastasis is controversial. The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol homeostasis by targeting the low-density lipoprotein receptor (LDLR) for degradation. PCSK9 is mostly expressed in liver, which is one of the most common sites for metastatic disease. To reveal the function of PCSK9 and also evaluate the impact of cholesterol in liver metastasis development, B16F1 melanoma cells were injected into wild-type (WT) and Pcsk9(-/-) mice to induce liver metastasis. On chow diet, Pcsk9(-/-) mice harbored two-fold less liver metastases than WT mice. This decrease is related to low cholesterol levels in Pcsk9(-/-) mice, as the protection was lost after normalizing Pcsk9(-/-) cholesterol levels by a 2-week high cholesterol diet. Furthermore, a prolongation of this diet strongly increased metastasis in both genotypes, suggesting that high cholesterol levels promote metastatic progression. The protective effect of the PCSK9 deficiency is also associated with increased apoptosis in liver stroma and metastases. Tumor necrosis factor.α (TNFα) mRNA and protein were, respectively, higher in liver stroma and plasma of injected mice, likely increasing the apoptotic TNFα signaling. Furthermore, the anti-apoptotic factor B-cell lymphoma 2 was downregulated. TNFα regulation is LDLR-independent, as its mRNA level was similarly upregulated in mice lacking both PCSK9 and LDLR. Our findings show that PCSK9 deficiency reduces liver metastasis by its ability to lower cholesterol levels and by possibly enhancing TNFα-mediated apoptosis.
高循环胆固醇与高胆固醇血症、动脉粥样硬化和中风有关。然而，胆固醇与肿瘤发生/转移的关系存在争议。前蛋白转化酶枯草溶菌素/克那霉 9（PCSK9）通过靶向低密度脂蛋白受体（LDLR）降解来调节低密度脂蛋白胆固醇稳态。PCSK9 主要在肝脏中表达，肝脏是转移性疾病最常见的部位之一。为了揭示 PCSK9 的功能，并评估胆固醇对肝脏转移发展的影响，将 B16F1 黑色素瘤细胞注射到野生型（WT）和 Pcsk9（-/-）小鼠中以诱导肝脏转移。在普通饮食中，Pcsk9（-/-）小鼠的肝脏转移瘤数量比 WT 小鼠少两倍。这种减少与 Pcsk9（-/-）小鼠的低胆固醇水平有关，因为在通过两周高胆固醇饮食使 Pcsk9（-/-）胆固醇水平正常化后，这种保护作用就会丧失。此外，延长这种饮食强烈增加了两种基因型的转移，表明高胆固醇水平促进了转移进展。PCSK9 缺乏的保护作用也与肝脏基质和转移中的细胞凋亡增加有关。肿瘤坏死因子。α（TNFα）mRNA 和蛋白分别在注射小鼠的肝脏基质和血浆中升高，可能增加了凋亡 TNFα 信号。此外，抗凋亡因子 B 细胞淋巴瘤 2 下调。TNFα 的调节与 LDLR 无关，因为在缺乏 PCSK9 和 LDLR 的小鼠中，其 mRNA 水平也类似地上调。我们的研究结果表明，PCSK9 缺乏通过降低胆固醇水平和可能增强 TNFα 介导的凋亡来减少肝脏转移。
